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Slide 1 - 1 Nama : Prof. Dr. H. Djanggan Sargowo, dr., SpPD., SpJP(K), FIHA, FACC, FESC, FCAPC, FASCC Tempat/Tgl lahir : Sragen, 21 September 1947 Alamat : Wilis Indah E-10 Malang, Telp. 0341-552395 Pendidikan : Lulus Dokter dari UGM, tahun 1974 Lulus Cardiologist dari Univ. Indonesia, tahun 1983 Lulus Internist dari Univ. Airlangga, tahun 1986 Lulus Doktor, Univ. Airlangga, tahun 1996 Advanced Cardiology Course, Univ. Hongkong, tahun 1984 Senior Visiting Program, Institut Jantung Negara, Kualalumpur, 1996 Fellow American College of Cardiology (FACC), September 2006. Fellow Collage Asia Pacific Society of Cardiology (FCAPC), Desember 2007 Fellow European Sociaty of Cardiology (FESC), 2008 Fellow Asean Collage of Cardiology (FASCC), 2008 Jabatan : Dosen Pengajar Program Pascasarjana Universitas Brawijaya Ketua MKEK Ikatan Dokter Indonesia Cabang Malang Raya Ketua PERKI Cabang Malang Raya Anggota Kolegium Kardiovaskuler Indonesia Dekan Fak. Kedokteran Univ. Wijaya Kusuma Surabaya Ketua Dewan Pengawas Rumah Sakit Pendidikan Ketua Program Studi Kardiovascular Fak. Kedokteran Univ. Brawijaya Curriculum Vitae
Slide 2 - 1 Nama : Prof. Dr. H. Djanggan Sargowo, dr., SpPD., SpJP(K), FIHA, FACC, FESC, FCAPC, FASCC Tempat/Tgl lahir : Sragen, 21 September 1947 Alamat : Wilis Indah E-10 Malang, Telp. 0341-552395 Pendidikan : Lulus Dokter dari UGM, tahun 1974 Lulus Cardiologist dari Univ. Indonesia, tahun 1983 Lulus Internist dari Univ. Airlangga, tahun 1986 Lulus Doktor, Univ. Airlangga, tahun 1996 Advanced Cardiology Course, Univ. Hongkong, tahun 1984 Senior Visiting Program, Institut Jantung Negara, Kualalumpur, 1996 Fellow American College of Cardiology (FACC), September 2006. Fellow Collage Asia Pacific Society of Cardiology (FCAPC), Desember 2007 Fellow European Sociaty of Cardiology (FESC), 2008 Fellow Asean Collage of Cardiology (FASCC), 2008 Jabatan : Dosen Pengajar Program Pascasarjana Universitas Brawijaya Ketua MKEK Ikatan Dokter Indonesia Cabang Malang Raya Ketua PERKI Cabang Malang Raya Anggota Kolegium Kardiovaskuler Indonesia Dekan Fak. Kedokteran Univ. Wijaya Kusuma Surabaya Ketua Dewan Pengawas Rumah Sakit Pendidikan Ketua Program Studi Kardiovascular Fak. Kedokteran Univ. Brawijaya Curriculum Vitae 2 Djanggan Sargowo Surabaya, 15 April 2012 INFLAMMATION IN ATHEROSCLEROSIS : FROM BENCH TO BEDSIDE
Slide 3 - 1 Nama : Prof. Dr. H. Djanggan Sargowo, dr., SpPD., SpJP(K), FIHA, FACC, FESC, FCAPC, FASCC Tempat/Tgl lahir : Sragen, 21 September 1947 Alamat : Wilis Indah E-10 Malang, Telp. 0341-552395 Pendidikan : Lulus Dokter dari UGM, tahun 1974 Lulus Cardiologist dari Univ. Indonesia, tahun 1983 Lulus Internist dari Univ. Airlangga, tahun 1986 Lulus Doktor, Univ. Airlangga, tahun 1996 Advanced Cardiology Course, Univ. Hongkong, tahun 1984 Senior Visiting Program, Institut Jantung Negara, Kualalumpur, 1996 Fellow American College of Cardiology (FACC), September 2006. Fellow Collage Asia Pacific Society of Cardiology (FCAPC), Desember 2007 Fellow European Sociaty of Cardiology (FESC), 2008 Fellow Asean Collage of Cardiology (FASCC), 2008 Jabatan : Dosen Pengajar Program Pascasarjana Universitas Brawijaya Ketua MKEK Ikatan Dokter Indonesia Cabang Malang Raya Ketua PERKI Cabang Malang Raya Anggota Kolegium Kardiovaskuler Indonesia Dekan Fak. Kedokteran Univ. Wijaya Kusuma Surabaya Ketua Dewan Pengawas Rumah Sakit Pendidikan Ketua Program Studi Kardiovascular Fak. Kedokteran Univ. Brawijaya Curriculum Vitae 2 Djanggan Sargowo Surabaya, 15 April 2012 INFLAMMATION IN ATHEROSCLEROSIS : FROM BENCH TO BEDSIDE 3
Slide 4 - 1 Nama : Prof. Dr. H. Djanggan Sargowo, dr., SpPD., SpJP(K), FIHA, FACC, FESC, FCAPC, FASCC Tempat/Tgl lahir : Sragen, 21 September 1947 Alamat : Wilis Indah E-10 Malang, Telp. 0341-552395 Pendidikan : Lulus Dokter dari UGM, tahun 1974 Lulus Cardiologist dari Univ. Indonesia, tahun 1983 Lulus Internist dari Univ. Airlangga, tahun 1986 Lulus Doktor, Univ. Airlangga, tahun 1996 Advanced Cardiology Course, Univ. Hongkong, tahun 1984 Senior Visiting Program, Institut Jantung Negara, Kualalumpur, 1996 Fellow American College of Cardiology (FACC), September 2006. Fellow Collage Asia Pacific Society of Cardiology (FCAPC), Desember 2007 Fellow European Sociaty of Cardiology (FESC), 2008 Fellow Asean Collage of Cardiology (FASCC), 2008 Jabatan : Dosen Pengajar Program Pascasarjana Universitas Brawijaya Ketua MKEK Ikatan Dokter Indonesia Cabang Malang Raya Ketua PERKI Cabang Malang Raya Anggota Kolegium Kardiovaskuler Indonesia Dekan Fak. Kedokteran Univ. Wijaya Kusuma Surabaya Ketua Dewan Pengawas Rumah Sakit Pendidikan Ketua Program Studi Kardiovascular Fak. Kedokteran Univ. Brawijaya Curriculum Vitae 2 Djanggan Sargowo Surabaya, 15 April 2012 INFLAMMATION IN ATHEROSCLEROSIS : FROM BENCH TO BEDSIDE 3 4 RUDOLF VIRCHOW Inflammation-based arterial changes as a mechanism of primary importance in atherogenesis mid 19th century Lamond, B. The American Journal of Pathology. 2008
Slide 5 - 1 Nama : Prof. Dr. H. Djanggan Sargowo, dr., SpPD., SpJP(K), FIHA, FACC, FESC, FCAPC, FASCC Tempat/Tgl lahir : Sragen, 21 September 1947 Alamat : Wilis Indah E-10 Malang, Telp. 0341-552395 Pendidikan : Lulus Dokter dari UGM, tahun 1974 Lulus Cardiologist dari Univ. Indonesia, tahun 1983 Lulus Internist dari Univ. Airlangga, tahun 1986 Lulus Doktor, Univ. Airlangga, tahun 1996 Advanced Cardiology Course, Univ. Hongkong, tahun 1984 Senior Visiting Program, Institut Jantung Negara, Kualalumpur, 1996 Fellow American College of Cardiology (FACC), September 2006. Fellow Collage Asia Pacific Society of Cardiology (FCAPC), Desember 2007 Fellow European Sociaty of Cardiology (FESC), 2008 Fellow Asean Collage of Cardiology (FASCC), 2008 Jabatan : Dosen Pengajar Program Pascasarjana Universitas Brawijaya Ketua MKEK Ikatan Dokter Indonesia Cabang Malang Raya Ketua PERKI Cabang Malang Raya Anggota Kolegium Kardiovaskuler Indonesia Dekan Fak. Kedokteran Univ. Wijaya Kusuma Surabaya Ketua Dewan Pengawas Rumah Sakit Pendidikan Ketua Program Studi Kardiovascular Fak. Kedokteran Univ. Brawijaya Curriculum Vitae 2 Djanggan Sargowo Surabaya, 15 April 2012 INFLAMMATION IN ATHEROSCLEROSIS : FROM BENCH TO BEDSIDE 3 4 RUDOLF VIRCHOW Inflammation-based arterial changes as a mechanism of primary importance in atherogenesis mid 19th century Lamond, B. The American Journal of Pathology. 2008 5 Atherosclerosis Start from very young To Old age ?
Slide 6 - 1 Nama : Prof. Dr. H. Djanggan Sargowo, dr., SpPD., SpJP(K), FIHA, FACC, FESC, FCAPC, FASCC Tempat/Tgl lahir : Sragen, 21 September 1947 Alamat : Wilis Indah E-10 Malang, Telp. 0341-552395 Pendidikan : Lulus Dokter dari UGM, tahun 1974 Lulus Cardiologist dari Univ. Indonesia, tahun 1983 Lulus Internist dari Univ. Airlangga, tahun 1986 Lulus Doktor, Univ. Airlangga, tahun 1996 Advanced Cardiology Course, Univ. Hongkong, tahun 1984 Senior Visiting Program, Institut Jantung Negara, Kualalumpur, 1996 Fellow American College of Cardiology (FACC), September 2006. Fellow Collage Asia Pacific Society of Cardiology (FCAPC), Desember 2007 Fellow European Sociaty of Cardiology (FESC), 2008 Fellow Asean Collage of Cardiology (FASCC), 2008 Jabatan : Dosen Pengajar Program Pascasarjana Universitas Brawijaya Ketua MKEK Ikatan Dokter Indonesia Cabang Malang Raya Ketua PERKI Cabang Malang Raya Anggota Kolegium Kardiovaskuler Indonesia Dekan Fak. Kedokteran Univ. Wijaya Kusuma Surabaya Ketua Dewan Pengawas Rumah Sakit Pendidikan Ketua Program Studi Kardiovascular Fak. Kedokteran Univ. Brawijaya Curriculum Vitae 2 Djanggan Sargowo Surabaya, 15 April 2012 INFLAMMATION IN ATHEROSCLEROSIS : FROM BENCH TO BEDSIDE 3 4 RUDOLF VIRCHOW Inflammation-based arterial changes as a mechanism of primary importance in atherogenesis mid 19th century Lamond, B. The American Journal of Pathology. 2008 5 Atherosclerosis Start from very young To Old age ? 6 Atherothrombosis* is aLeading Cause of Death Worldwide1† The World Health Report, 2002, WHO Geneva, 2002 28.7 17.8 12.6 9.1 6 5.1 0 5 10 15 20 25 30 Atherothrombosis* Infectious disease Cancer Injuries Pulmonary disease AIDS Mortality (%) * Ischemic heart disease, cerebrovascular disease, inflammatory heart disease and hypertensive heart disease † Worldwide defined as Member States by WHO Region (Africa, Americas, Eastern Mediterranean, European, South-East Asia and Western Pacific)
Slide 7 - 1 Nama : Prof. Dr. H. Djanggan Sargowo, dr., SpPD., SpJP(K), FIHA, FACC, FESC, FCAPC, FASCC Tempat/Tgl lahir : Sragen, 21 September 1947 Alamat : Wilis Indah E-10 Malang, Telp. 0341-552395 Pendidikan : Lulus Dokter dari UGM, tahun 1974 Lulus Cardiologist dari Univ. Indonesia, tahun 1983 Lulus Internist dari Univ. Airlangga, tahun 1986 Lulus Doktor, Univ. Airlangga, tahun 1996 Advanced Cardiology Course, Univ. Hongkong, tahun 1984 Senior Visiting Program, Institut Jantung Negara, Kualalumpur, 1996 Fellow American College of Cardiology (FACC), September 2006. Fellow Collage Asia Pacific Society of Cardiology (FCAPC), Desember 2007 Fellow European Sociaty of Cardiology (FESC), 2008 Fellow Asean Collage of Cardiology (FASCC), 2008 Jabatan : Dosen Pengajar Program Pascasarjana Universitas Brawijaya Ketua MKEK Ikatan Dokter Indonesia Cabang Malang Raya Ketua PERKI Cabang Malang Raya Anggota Kolegium Kardiovaskuler Indonesia Dekan Fak. Kedokteran Univ. Wijaya Kusuma Surabaya Ketua Dewan Pengawas Rumah Sakit Pendidikan Ketua Program Studi Kardiovascular Fak. Kedokteran Univ. Brawijaya Curriculum Vitae 2 Djanggan Sargowo Surabaya, 15 April 2012 INFLAMMATION IN ATHEROSCLEROSIS : FROM BENCH TO BEDSIDE 3 4 RUDOLF VIRCHOW Inflammation-based arterial changes as a mechanism of primary importance in atherogenesis mid 19th century Lamond, B. The American Journal of Pathology. 2008 5 Atherosclerosis Start from very young To Old age ? 6 Atherothrombosis* is aLeading Cause of Death Worldwide1† The World Health Report, 2002, WHO Geneva, 2002 28.7 17.8 12.6 9.1 6 5.1 0 5 10 15 20 25 30 Atherothrombosis* Infectious disease Cancer Injuries Pulmonary disease AIDS Mortality (%) * Ischemic heart disease, cerebrovascular disease, inflammatory heart disease and hypertensive heart disease † Worldwide defined as Member States by WHO Region (Africa, Americas, Eastern Mediterranean, European, South-East Asia and Western Pacific) 7 MAJOR CLINICAL MANIFESTATIONS OF ATHEROTHROMBOSIS Adapted from: Drouet L. Cerebrovasc Dis 2002; 13(suppl 1): 1–6. Transient ischemic attack Angina: Stable Unstable Ischemic stroke Myocardial infarction Peripheral arterial disease: Intermittent claudication Rest Pain Gangrene Necrosis
Slide 8 - 1 Nama : Prof. Dr. H. Djanggan Sargowo, dr., SpPD., SpJP(K), FIHA, FACC, FESC, FCAPC, FASCC Tempat/Tgl lahir : Sragen, 21 September 1947 Alamat : Wilis Indah E-10 Malang, Telp. 0341-552395 Pendidikan : Lulus Dokter dari UGM, tahun 1974 Lulus Cardiologist dari Univ. Indonesia, tahun 1983 Lulus Internist dari Univ. Airlangga, tahun 1986 Lulus Doktor, Univ. Airlangga, tahun 1996 Advanced Cardiology Course, Univ. Hongkong, tahun 1984 Senior Visiting Program, Institut Jantung Negara, Kualalumpur, 1996 Fellow American College of Cardiology (FACC), September 2006. Fellow Collage Asia Pacific Society of Cardiology (FCAPC), Desember 2007 Fellow European Sociaty of Cardiology (FESC), 2008 Fellow Asean Collage of Cardiology (FASCC), 2008 Jabatan : Dosen Pengajar Program Pascasarjana Universitas Brawijaya Ketua MKEK Ikatan Dokter Indonesia Cabang Malang Raya Ketua PERKI Cabang Malang Raya Anggota Kolegium Kardiovaskuler Indonesia Dekan Fak. Kedokteran Univ. Wijaya Kusuma Surabaya Ketua Dewan Pengawas Rumah Sakit Pendidikan Ketua Program Studi Kardiovascular Fak. Kedokteran Univ. Brawijaya Curriculum Vitae 2 Djanggan Sargowo Surabaya, 15 April 2012 INFLAMMATION IN ATHEROSCLEROSIS : FROM BENCH TO BEDSIDE 3 4 RUDOLF VIRCHOW Inflammation-based arterial changes as a mechanism of primary importance in atherogenesis mid 19th century Lamond, B. The American Journal of Pathology. 2008 5 Atherosclerosis Start from very young To Old age ? 6 Atherothrombosis* is aLeading Cause of Death Worldwide1† The World Health Report, 2002, WHO Geneva, 2002 28.7 17.8 12.6 9.1 6 5.1 0 5 10 15 20 25 30 Atherothrombosis* Infectious disease Cancer Injuries Pulmonary disease AIDS Mortality (%) * Ischemic heart disease, cerebrovascular disease, inflammatory heart disease and hypertensive heart disease † Worldwide defined as Member States by WHO Region (Africa, Americas, Eastern Mediterranean, European, South-East Asia and Western Pacific) 7 MAJOR CLINICAL MANIFESTATIONS OF ATHEROTHROMBOSIS Adapted from: Drouet L. Cerebrovasc Dis 2002; 13(suppl 1): 1–6. Transient ischemic attack Angina: Stable Unstable Ischemic stroke Myocardial infarction Peripheral arterial disease: Intermittent claudication Rest Pain Gangrene Necrosis 8  Dyslipidemia  Endothelial dysfunction  Free radicals  Immunologic Atherosclerosis/CAD THEORY AND CONCEPT OF ATHEROSCLEROSIS Inflamation (Sargowo, 1996)
Slide 9 - 1 Nama : Prof. Dr. H. Djanggan Sargowo, dr., SpPD., SpJP(K), FIHA, FACC, FESC, FCAPC, FASCC Tempat/Tgl lahir : Sragen, 21 September 1947 Alamat : Wilis Indah E-10 Malang, Telp. 0341-552395 Pendidikan : Lulus Dokter dari UGM, tahun 1974 Lulus Cardiologist dari Univ. Indonesia, tahun 1983 Lulus Internist dari Univ. Airlangga, tahun 1986 Lulus Doktor, Univ. Airlangga, tahun 1996 Advanced Cardiology Course, Univ. Hongkong, tahun 1984 Senior Visiting Program, Institut Jantung Negara, Kualalumpur, 1996 Fellow American College of Cardiology (FACC), September 2006. Fellow Collage Asia Pacific Society of Cardiology (FCAPC), Desember 2007 Fellow European Sociaty of Cardiology (FESC), 2008 Fellow Asean Collage of Cardiology (FASCC), 2008 Jabatan : Dosen Pengajar Program Pascasarjana Universitas Brawijaya Ketua MKEK Ikatan Dokter Indonesia Cabang Malang Raya Ketua PERKI Cabang Malang Raya Anggota Kolegium Kardiovaskuler Indonesia Dekan Fak. Kedokteran Univ. Wijaya Kusuma Surabaya Ketua Dewan Pengawas Rumah Sakit Pendidikan Ketua Program Studi Kardiovascular Fak. Kedokteran Univ. Brawijaya Curriculum Vitae 2 Djanggan Sargowo Surabaya, 15 April 2012 INFLAMMATION IN ATHEROSCLEROSIS : FROM BENCH TO BEDSIDE 3 4 RUDOLF VIRCHOW Inflammation-based arterial changes as a mechanism of primary importance in atherogenesis mid 19th century Lamond, B. The American Journal of Pathology. 2008 5 Atherosclerosis Start from very young To Old age ? 6 Atherothrombosis* is aLeading Cause of Death Worldwide1† The World Health Report, 2002, WHO Geneva, 2002 28.7 17.8 12.6 9.1 6 5.1 0 5 10 15 20 25 30 Atherothrombosis* Infectious disease Cancer Injuries Pulmonary disease AIDS Mortality (%) * Ischemic heart disease, cerebrovascular disease, inflammatory heart disease and hypertensive heart disease † Worldwide defined as Member States by WHO Region (Africa, Americas, Eastern Mediterranean, European, South-East Asia and Western Pacific) 7 MAJOR CLINICAL MANIFESTATIONS OF ATHEROTHROMBOSIS Adapted from: Drouet L. Cerebrovasc Dis 2002; 13(suppl 1): 1–6. Transient ischemic attack Angina: Stable Unstable Ischemic stroke Myocardial infarction Peripheral arterial disease: Intermittent claudication Rest Pain Gangrene Necrosis 8  Dyslipidemia  Endothelial dysfunction  Free radicals  Immunologic Atherosclerosis/CAD THEORY AND CONCEPT OF ATHEROSCLEROSIS Inflamation (Sargowo, 1996) 9 Free Radical ATHEROGENESIS (Sargowo, 1996)
Slide 10 - 1 Nama : Prof. Dr. H. Djanggan Sargowo, dr., SpPD., SpJP(K), FIHA, FACC, FESC, FCAPC, FASCC Tempat/Tgl lahir : Sragen, 21 September 1947 Alamat : Wilis Indah E-10 Malang, Telp. 0341-552395 Pendidikan : Lulus Dokter dari UGM, tahun 1974 Lulus Cardiologist dari Univ. Indonesia, tahun 1983 Lulus Internist dari Univ. Airlangga, tahun 1986 Lulus Doktor, Univ. Airlangga, tahun 1996 Advanced Cardiology Course, Univ. Hongkong, tahun 1984 Senior Visiting Program, Institut Jantung Negara, Kualalumpur, 1996 Fellow American College of Cardiology (FACC), September 2006. Fellow Collage Asia Pacific Society of Cardiology (FCAPC), Desember 2007 Fellow European Sociaty of Cardiology (FESC), 2008 Fellow Asean Collage of Cardiology (FASCC), 2008 Jabatan : Dosen Pengajar Program Pascasarjana Universitas Brawijaya Ketua MKEK Ikatan Dokter Indonesia Cabang Malang Raya Ketua PERKI Cabang Malang Raya Anggota Kolegium Kardiovaskuler Indonesia Dekan Fak. Kedokteran Univ. Wijaya Kusuma Surabaya Ketua Dewan Pengawas Rumah Sakit Pendidikan Ketua Program Studi Kardiovascular Fak. Kedokteran Univ. Brawijaya Curriculum Vitae 2 Djanggan Sargowo Surabaya, 15 April 2012 INFLAMMATION IN ATHEROSCLEROSIS : FROM BENCH TO BEDSIDE 3 4 RUDOLF VIRCHOW Inflammation-based arterial changes as a mechanism of primary importance in atherogenesis mid 19th century Lamond, B. The American Journal of Pathology. 2008 5 Atherosclerosis Start from very young To Old age ? 6 Atherothrombosis* is aLeading Cause of Death Worldwide1† The World Health Report, 2002, WHO Geneva, 2002 28.7 17.8 12.6 9.1 6 5.1 0 5 10 15 20 25 30 Atherothrombosis* Infectious disease Cancer Injuries Pulmonary disease AIDS Mortality (%) * Ischemic heart disease, cerebrovascular disease, inflammatory heart disease and hypertensive heart disease † Worldwide defined as Member States by WHO Region (Africa, Americas, Eastern Mediterranean, European, South-East Asia and Western Pacific) 7 MAJOR CLINICAL MANIFESTATIONS OF ATHEROTHROMBOSIS Adapted from: Drouet L. Cerebrovasc Dis 2002; 13(suppl 1): 1–6. Transient ischemic attack Angina: Stable Unstable Ischemic stroke Myocardial infarction Peripheral arterial disease: Intermittent claudication Rest Pain Gangrene Necrosis 8  Dyslipidemia  Endothelial dysfunction  Free radicals  Immunologic Atherosclerosis/CAD THEORY AND CONCEPT OF ATHEROSCLEROSIS Inflamation (Sargowo, 1996) 9 Free Radical ATHEROGENESIS (Sargowo, 1996) 10 IDENTIFYING THOSE AT RISK OF ATHEROTHROMBOSIS Yusuf S et al. Circulation 2001; 104: 2746–53. 2. Drouet L. Cerebrovasc Dis 2002;13(suppl 1):1–6. Lifestyle Smoking Diet Lack of exercise Genetic Genetic traits Gender Age Generalized disorders Obesity Diabetes Systemic conditions History of vascular events Hypertension Hyperlipidemia Hypercoagulable states Homocystinemia Local factors Elevated prothrombotic factors: fibrinogen, CRP, PAI-1 Blood flow patterns, vessel diameter, arterial wall structure Atherothrombosis manifestations (myocardial infarction, stroke, vascular death)
Slide 11 - 1 Nama : Prof. Dr. H. Djanggan Sargowo, dr., SpPD., SpJP(K), FIHA, FACC, FESC, FCAPC, FASCC Tempat/Tgl lahir : Sragen, 21 September 1947 Alamat : Wilis Indah E-10 Malang, Telp. 0341-552395 Pendidikan : Lulus Dokter dari UGM, tahun 1974 Lulus Cardiologist dari Univ. Indonesia, tahun 1983 Lulus Internist dari Univ. Airlangga, tahun 1986 Lulus Doktor, Univ. Airlangga, tahun 1996 Advanced Cardiology Course, Univ. Hongkong, tahun 1984 Senior Visiting Program, Institut Jantung Negara, Kualalumpur, 1996 Fellow American College of Cardiology (FACC), September 2006. Fellow Collage Asia Pacific Society of Cardiology (FCAPC), Desember 2007 Fellow European Sociaty of Cardiology (FESC), 2008 Fellow Asean Collage of Cardiology (FASCC), 2008 Jabatan : Dosen Pengajar Program Pascasarjana Universitas Brawijaya Ketua MKEK Ikatan Dokter Indonesia Cabang Malang Raya Ketua PERKI Cabang Malang Raya Anggota Kolegium Kardiovaskuler Indonesia Dekan Fak. Kedokteran Univ. Wijaya Kusuma Surabaya Ketua Dewan Pengawas Rumah Sakit Pendidikan Ketua Program Studi Kardiovascular Fak. Kedokteran Univ. Brawijaya Curriculum Vitae 2 Djanggan Sargowo Surabaya, 15 April 2012 INFLAMMATION IN ATHEROSCLEROSIS : FROM BENCH TO BEDSIDE 3 4 RUDOLF VIRCHOW Inflammation-based arterial changes as a mechanism of primary importance in atherogenesis mid 19th century Lamond, B. The American Journal of Pathology. 2008 5 Atherosclerosis Start from very young To Old age ? 6 Atherothrombosis* is aLeading Cause of Death Worldwide1† The World Health Report, 2002, WHO Geneva, 2002 28.7 17.8 12.6 9.1 6 5.1 0 5 10 15 20 25 30 Atherothrombosis* Infectious disease Cancer Injuries Pulmonary disease AIDS Mortality (%) * Ischemic heart disease, cerebrovascular disease, inflammatory heart disease and hypertensive heart disease † Worldwide defined as Member States by WHO Region (Africa, Americas, Eastern Mediterranean, European, South-East Asia and Western Pacific) 7 MAJOR CLINICAL MANIFESTATIONS OF ATHEROTHROMBOSIS Adapted from: Drouet L. Cerebrovasc Dis 2002; 13(suppl 1): 1–6. Transient ischemic attack Angina: Stable Unstable Ischemic stroke Myocardial infarction Peripheral arterial disease: Intermittent claudication Rest Pain Gangrene Necrosis 8  Dyslipidemia  Endothelial dysfunction  Free radicals  Immunologic Atherosclerosis/CAD THEORY AND CONCEPT OF ATHEROSCLEROSIS Inflamation (Sargowo, 1996) 9 Free Radical ATHEROGENESIS (Sargowo, 1996) 10 IDENTIFYING THOSE AT RISK OF ATHEROTHROMBOSIS Yusuf S et al. Circulation 2001; 104: 2746–53. 2. Drouet L. Cerebrovasc Dis 2002;13(suppl 1):1–6. Lifestyle Smoking Diet Lack of exercise Genetic Genetic traits Gender Age Generalized disorders Obesity Diabetes Systemic conditions History of vascular events Hypertension Hyperlipidemia Hypercoagulable states Homocystinemia Local factors Elevated prothrombotic factors: fibrinogen, CRP, PAI-1 Blood flow patterns, vessel diameter, arterial wall structure Atherothrombosis manifestations (myocardial infarction, stroke, vascular death) 11 Arici. 2010 Risk Factors for Atherosclerosis Classic Hypertension, Hyper-lipidemia, DM, Smoking Uremia Related Increase ox-LDL, Free radicals, Uremic toxin Infection Bacterial and viral infection Proinflammatory cytokine release Endothelial dysfunction Systemic inflammatory respones Acute phase response Elevated CRP Binding LDL, cemplement activation, tissue factor secretion Accelerated ATHEROSCLEROSIS
Slide 12 - 1 Nama : Prof. Dr. H. Djanggan Sargowo, dr., SpPD., SpJP(K), FIHA, FACC, FESC, FCAPC, FASCC Tempat/Tgl lahir : Sragen, 21 September 1947 Alamat : Wilis Indah E-10 Malang, Telp. 0341-552395 Pendidikan : Lulus Dokter dari UGM, tahun 1974 Lulus Cardiologist dari Univ. Indonesia, tahun 1983 Lulus Internist dari Univ. Airlangga, tahun 1986 Lulus Doktor, Univ. Airlangga, tahun 1996 Advanced Cardiology Course, Univ. Hongkong, tahun 1984 Senior Visiting Program, Institut Jantung Negara, Kualalumpur, 1996 Fellow American College of Cardiology (FACC), September 2006. Fellow Collage Asia Pacific Society of Cardiology (FCAPC), Desember 2007 Fellow European Sociaty of Cardiology (FESC), 2008 Fellow Asean Collage of Cardiology (FASCC), 2008 Jabatan : Dosen Pengajar Program Pascasarjana Universitas Brawijaya Ketua MKEK Ikatan Dokter Indonesia Cabang Malang Raya Ketua PERKI Cabang Malang Raya Anggota Kolegium Kardiovaskuler Indonesia Dekan Fak. Kedokteran Univ. Wijaya Kusuma Surabaya Ketua Dewan Pengawas Rumah Sakit Pendidikan Ketua Program Studi Kardiovascular Fak. Kedokteran Univ. Brawijaya Curriculum Vitae 2 Djanggan Sargowo Surabaya, 15 April 2012 INFLAMMATION IN ATHEROSCLEROSIS : FROM BENCH TO BEDSIDE 3 4 RUDOLF VIRCHOW Inflammation-based arterial changes as a mechanism of primary importance in atherogenesis mid 19th century Lamond, B. The American Journal of Pathology. 2008 5 Atherosclerosis Start from very young To Old age ? 6 Atherothrombosis* is aLeading Cause of Death Worldwide1† The World Health Report, 2002, WHO Geneva, 2002 28.7 17.8 12.6 9.1 6 5.1 0 5 10 15 20 25 30 Atherothrombosis* Infectious disease Cancer Injuries Pulmonary disease AIDS Mortality (%) * Ischemic heart disease, cerebrovascular disease, inflammatory heart disease and hypertensive heart disease † Worldwide defined as Member States by WHO Region (Africa, Americas, Eastern Mediterranean, European, South-East Asia and Western Pacific) 7 MAJOR CLINICAL MANIFESTATIONS OF ATHEROTHROMBOSIS Adapted from: Drouet L. Cerebrovasc Dis 2002; 13(suppl 1): 1–6. Transient ischemic attack Angina: Stable Unstable Ischemic stroke Myocardial infarction Peripheral arterial disease: Intermittent claudication Rest Pain Gangrene Necrosis 8  Dyslipidemia  Endothelial dysfunction  Free radicals  Immunologic Atherosclerosis/CAD THEORY AND CONCEPT OF ATHEROSCLEROSIS Inflamation (Sargowo, 1996) 9 Free Radical ATHEROGENESIS (Sargowo, 1996) 10 IDENTIFYING THOSE AT RISK OF ATHEROTHROMBOSIS Yusuf S et al. Circulation 2001; 104: 2746–53. 2. Drouet L. Cerebrovasc Dis 2002;13(suppl 1):1–6. Lifestyle Smoking Diet Lack of exercise Genetic Genetic traits Gender Age Generalized disorders Obesity Diabetes Systemic conditions History of vascular events Hypertension Hyperlipidemia Hypercoagulable states Homocystinemia Local factors Elevated prothrombotic factors: fibrinogen, CRP, PAI-1 Blood flow patterns, vessel diameter, arterial wall structure Atherothrombosis manifestations (myocardial infarction, stroke, vascular death) 11 Arici. 2010 Risk Factors for Atherosclerosis Classic Hypertension, Hyper-lipidemia, DM, Smoking Uremia Related Increase ox-LDL, Free radicals, Uremic toxin Infection Bacterial and viral infection Proinflammatory cytokine release Endothelial dysfunction Systemic inflammatory respones Acute phase response Elevated CRP Binding LDL, cemplement activation, tissue factor secretion Accelerated ATHEROSCLEROSIS 12 LDL CD40L=CD40 ligand; TNF-α=tumor necrosis factor-alpha; IL=interleukin; VCAM=vascular cell adhesion molecule; ICAM=intercellular adhesion molecule. Cockerill GW et al. Arterioscler Thromb Vasc Biol. 1995;15:1987-1994; Andre P et al. Circulation. 2002;106:896-899; Libby P. Circulation. 2001;104:365-372; Libby P et al. Circulation. 2002;105:1135-1143; Ross R. N Engl J Med. 1999;340:115-126. Vessel lumen Monocyte Macrophage Adhesionmolecules (VCAM-1, ICAM-1) Inflammatory mediators (CRP, CD40/CD40L, TNF-α, IL-1, IL-6) Intima Foam cell INFLAMMATION PROMOTES PROGRESSION OF ATHEROSCLEROSIS Endothelium LDL Ox-LDL
Slide 13 - 1 Nama : Prof. Dr. H. Djanggan Sargowo, dr., SpPD., SpJP(K), FIHA, FACC, FESC, FCAPC, FASCC Tempat/Tgl lahir : Sragen, 21 September 1947 Alamat : Wilis Indah E-10 Malang, Telp. 0341-552395 Pendidikan : Lulus Dokter dari UGM, tahun 1974 Lulus Cardiologist dari Univ. Indonesia, tahun 1983 Lulus Internist dari Univ. Airlangga, tahun 1986 Lulus Doktor, Univ. Airlangga, tahun 1996 Advanced Cardiology Course, Univ. Hongkong, tahun 1984 Senior Visiting Program, Institut Jantung Negara, Kualalumpur, 1996 Fellow American College of Cardiology (FACC), September 2006. Fellow Collage Asia Pacific Society of Cardiology (FCAPC), Desember 2007 Fellow European Sociaty of Cardiology (FESC), 2008 Fellow Asean Collage of Cardiology (FASCC), 2008 Jabatan : Dosen Pengajar Program Pascasarjana Universitas Brawijaya Ketua MKEK Ikatan Dokter Indonesia Cabang Malang Raya Ketua PERKI Cabang Malang Raya Anggota Kolegium Kardiovaskuler Indonesia Dekan Fak. Kedokteran Univ. Wijaya Kusuma Surabaya Ketua Dewan Pengawas Rumah Sakit Pendidikan Ketua Program Studi Kardiovascular Fak. Kedokteran Univ. Brawijaya Curriculum Vitae 2 Djanggan Sargowo Surabaya, 15 April 2012 INFLAMMATION IN ATHEROSCLEROSIS : FROM BENCH TO BEDSIDE 3 4 RUDOLF VIRCHOW Inflammation-based arterial changes as a mechanism of primary importance in atherogenesis mid 19th century Lamond, B. The American Journal of Pathology. 2008 5 Atherosclerosis Start from very young To Old age ? 6 Atherothrombosis* is aLeading Cause of Death Worldwide1† The World Health Report, 2002, WHO Geneva, 2002 28.7 17.8 12.6 9.1 6 5.1 0 5 10 15 20 25 30 Atherothrombosis* Infectious disease Cancer Injuries Pulmonary disease AIDS Mortality (%) * Ischemic heart disease, cerebrovascular disease, inflammatory heart disease and hypertensive heart disease † Worldwide defined as Member States by WHO Region (Africa, Americas, Eastern Mediterranean, European, South-East Asia and Western Pacific) 7 MAJOR CLINICAL MANIFESTATIONS OF ATHEROTHROMBOSIS Adapted from: Drouet L. Cerebrovasc Dis 2002; 13(suppl 1): 1–6. Transient ischemic attack Angina: Stable Unstable Ischemic stroke Myocardial infarction Peripheral arterial disease: Intermittent claudication Rest Pain Gangrene Necrosis 8  Dyslipidemia  Endothelial dysfunction  Free radicals  Immunologic Atherosclerosis/CAD THEORY AND CONCEPT OF ATHEROSCLEROSIS Inflamation (Sargowo, 1996) 9 Free Radical ATHEROGENESIS (Sargowo, 1996) 10 IDENTIFYING THOSE AT RISK OF ATHEROTHROMBOSIS Yusuf S et al. Circulation 2001; 104: 2746–53. 2. Drouet L. Cerebrovasc Dis 2002;13(suppl 1):1–6. Lifestyle Smoking Diet Lack of exercise Genetic Genetic traits Gender Age Generalized disorders Obesity Diabetes Systemic conditions History of vascular events Hypertension Hyperlipidemia Hypercoagulable states Homocystinemia Local factors Elevated prothrombotic factors: fibrinogen, CRP, PAI-1 Blood flow patterns, vessel diameter, arterial wall structure Atherothrombosis manifestations (myocardial infarction, stroke, vascular death) 11 Arici. 2010 Risk Factors for Atherosclerosis Classic Hypertension, Hyper-lipidemia, DM, Smoking Uremia Related Increase ox-LDL, Free radicals, Uremic toxin Infection Bacterial and viral infection Proinflammatory cytokine release Endothelial dysfunction Systemic inflammatory respones Acute phase response Elevated CRP Binding LDL, cemplement activation, tissue factor secretion Accelerated ATHEROSCLEROSIS 12 LDL CD40L=CD40 ligand; TNF-α=tumor necrosis factor-alpha; IL=interleukin; VCAM=vascular cell adhesion molecule; ICAM=intercellular adhesion molecule. Cockerill GW et al. Arterioscler Thromb Vasc Biol. 1995;15:1987-1994; Andre P et al. Circulation. 2002;106:896-899; Libby P. Circulation. 2001;104:365-372; Libby P et al. Circulation. 2002;105:1135-1143; Ross R. N Engl J Med. 1999;340:115-126. Vessel lumen Monocyte Macrophage Adhesionmolecules (VCAM-1, ICAM-1) Inflammatory mediators (CRP, CD40/CD40L, TNF-α, IL-1, IL-6) Intima Foam cell INFLAMMATION PROMOTES PROGRESSION OF ATHEROSCLEROSIS Endothelium LDL Ox-LDL 13
Slide 14 - 1 Nama : Prof. Dr. H. Djanggan Sargowo, dr., SpPD., SpJP(K), FIHA, FACC, FESC, FCAPC, FASCC Tempat/Tgl lahir : Sragen, 21 September 1947 Alamat : Wilis Indah E-10 Malang, Telp. 0341-552395 Pendidikan : Lulus Dokter dari UGM, tahun 1974 Lulus Cardiologist dari Univ. Indonesia, tahun 1983 Lulus Internist dari Univ. Airlangga, tahun 1986 Lulus Doktor, Univ. Airlangga, tahun 1996 Advanced Cardiology Course, Univ. Hongkong, tahun 1984 Senior Visiting Program, Institut Jantung Negara, Kualalumpur, 1996 Fellow American College of Cardiology (FACC), September 2006. Fellow Collage Asia Pacific Society of Cardiology (FCAPC), Desember 2007 Fellow European Sociaty of Cardiology (FESC), 2008 Fellow Asean Collage of Cardiology (FASCC), 2008 Jabatan : Dosen Pengajar Program Pascasarjana Universitas Brawijaya Ketua MKEK Ikatan Dokter Indonesia Cabang Malang Raya Ketua PERKI Cabang Malang Raya Anggota Kolegium Kardiovaskuler Indonesia Dekan Fak. Kedokteran Univ. Wijaya Kusuma Surabaya Ketua Dewan Pengawas Rumah Sakit Pendidikan Ketua Program Studi Kardiovascular Fak. Kedokteran Univ. Brawijaya Curriculum Vitae 2 Djanggan Sargowo Surabaya, 15 April 2012 INFLAMMATION IN ATHEROSCLEROSIS : FROM BENCH TO BEDSIDE 3 4 RUDOLF VIRCHOW Inflammation-based arterial changes as a mechanism of primary importance in atherogenesis mid 19th century Lamond, B. The American Journal of Pathology. 2008 5 Atherosclerosis Start from very young To Old age ? 6 Atherothrombosis* is aLeading Cause of Death Worldwide1† The World Health Report, 2002, WHO Geneva, 2002 28.7 17.8 12.6 9.1 6 5.1 0 5 10 15 20 25 30 Atherothrombosis* Infectious disease Cancer Injuries Pulmonary disease AIDS Mortality (%) * Ischemic heart disease, cerebrovascular disease, inflammatory heart disease and hypertensive heart disease † Worldwide defined as Member States by WHO Region (Africa, Americas, Eastern Mediterranean, European, South-East Asia and Western Pacific) 7 MAJOR CLINICAL MANIFESTATIONS OF ATHEROTHROMBOSIS Adapted from: Drouet L. Cerebrovasc Dis 2002; 13(suppl 1): 1–6. Transient ischemic attack Angina: Stable Unstable Ischemic stroke Myocardial infarction Peripheral arterial disease: Intermittent claudication Rest Pain Gangrene Necrosis 8  Dyslipidemia  Endothelial dysfunction  Free radicals  Immunologic Atherosclerosis/CAD THEORY AND CONCEPT OF ATHEROSCLEROSIS Inflamation (Sargowo, 1996) 9 Free Radical ATHEROGENESIS (Sargowo, 1996) 10 IDENTIFYING THOSE AT RISK OF ATHEROTHROMBOSIS Yusuf S et al. Circulation 2001; 104: 2746–53. 2. Drouet L. Cerebrovasc Dis 2002;13(suppl 1):1–6. Lifestyle Smoking Diet Lack of exercise Genetic Genetic traits Gender Age Generalized disorders Obesity Diabetes Systemic conditions History of vascular events Hypertension Hyperlipidemia Hypercoagulable states Homocystinemia Local factors Elevated prothrombotic factors: fibrinogen, CRP, PAI-1 Blood flow patterns, vessel diameter, arterial wall structure Atherothrombosis manifestations (myocardial infarction, stroke, vascular death) 11 Arici. 2010 Risk Factors for Atherosclerosis Classic Hypertension, Hyper-lipidemia, DM, Smoking Uremia Related Increase ox-LDL, Free radicals, Uremic toxin Infection Bacterial and viral infection Proinflammatory cytokine release Endothelial dysfunction Systemic inflammatory respones Acute phase response Elevated CRP Binding LDL, cemplement activation, tissue factor secretion Accelerated ATHEROSCLEROSIS 12 LDL CD40L=CD40 ligand; TNF-α=tumor necrosis factor-alpha; IL=interleukin; VCAM=vascular cell adhesion molecule; ICAM=intercellular adhesion molecule. Cockerill GW et al. Arterioscler Thromb Vasc Biol. 1995;15:1987-1994; Andre P et al. Circulation. 2002;106:896-899; Libby P. Circulation. 2001;104:365-372; Libby P et al. Circulation. 2002;105:1135-1143; Ross R. N Engl J Med. 1999;340:115-126. Vessel lumen Monocyte Macrophage Adhesionmolecules (VCAM-1, ICAM-1) Inflammatory mediators (CRP, CD40/CD40L, TNF-α, IL-1, IL-6) Intima Foam cell INFLAMMATION PROMOTES PROGRESSION OF ATHEROSCLEROSIS Endothelium LDL Ox-LDL 13 14 Atherosclerosis is a fibroproliferative and inflammatory process occurring ins response to a variety of vascular insults The insults come from classical risk factors ( HT, dyslipidemia, endothelial dysfunction, smoking, menopause, diabetes etc) and novel risk factors (Hcy, LVH, Lp(a), TG, oxidative stress, fibrinogen etc) Endothelial dysfunction is regarded as the first abnormality leading to atherosclerosis This implies that modulation of endothelial function may be used as strategy to intervene the process.
Slide 15 - 1 Nama : Prof. Dr. H. Djanggan Sargowo, dr., SpPD., SpJP(K), FIHA, FACC, FESC, FCAPC, FASCC Tempat/Tgl lahir : Sragen, 21 September 1947 Alamat : Wilis Indah E-10 Malang, Telp. 0341-552395 Pendidikan : Lulus Dokter dari UGM, tahun 1974 Lulus Cardiologist dari Univ. Indonesia, tahun 1983 Lulus Internist dari Univ. Airlangga, tahun 1986 Lulus Doktor, Univ. Airlangga, tahun 1996 Advanced Cardiology Course, Univ. Hongkong, tahun 1984 Senior Visiting Program, Institut Jantung Negara, Kualalumpur, 1996 Fellow American College of Cardiology (FACC), September 2006. Fellow Collage Asia Pacific Society of Cardiology (FCAPC), Desember 2007 Fellow European Sociaty of Cardiology (FESC), 2008 Fellow Asean Collage of Cardiology (FASCC), 2008 Jabatan : Dosen Pengajar Program Pascasarjana Universitas Brawijaya Ketua MKEK Ikatan Dokter Indonesia Cabang Malang Raya Ketua PERKI Cabang Malang Raya Anggota Kolegium Kardiovaskuler Indonesia Dekan Fak. Kedokteran Univ. Wijaya Kusuma Surabaya Ketua Dewan Pengawas Rumah Sakit Pendidikan Ketua Program Studi Kardiovascular Fak. Kedokteran Univ. Brawijaya Curriculum Vitae 2 Djanggan Sargowo Surabaya, 15 April 2012 INFLAMMATION IN ATHEROSCLEROSIS : FROM BENCH TO BEDSIDE 3 4 RUDOLF VIRCHOW Inflammation-based arterial changes as a mechanism of primary importance in atherogenesis mid 19th century Lamond, B. The American Journal of Pathology. 2008 5 Atherosclerosis Start from very young To Old age ? 6 Atherothrombosis* is aLeading Cause of Death Worldwide1† The World Health Report, 2002, WHO Geneva, 2002 28.7 17.8 12.6 9.1 6 5.1 0 5 10 15 20 25 30 Atherothrombosis* Infectious disease Cancer Injuries Pulmonary disease AIDS Mortality (%) * Ischemic heart disease, cerebrovascular disease, inflammatory heart disease and hypertensive heart disease † Worldwide defined as Member States by WHO Region (Africa, Americas, Eastern Mediterranean, European, South-East Asia and Western Pacific) 7 MAJOR CLINICAL MANIFESTATIONS OF ATHEROTHROMBOSIS Adapted from: Drouet L. Cerebrovasc Dis 2002; 13(suppl 1): 1–6. Transient ischemic attack Angina: Stable Unstable Ischemic stroke Myocardial infarction Peripheral arterial disease: Intermittent claudication Rest Pain Gangrene Necrosis 8  Dyslipidemia  Endothelial dysfunction  Free radicals  Immunologic Atherosclerosis/CAD THEORY AND CONCEPT OF ATHEROSCLEROSIS Inflamation (Sargowo, 1996) 9 Free Radical ATHEROGENESIS (Sargowo, 1996) 10 IDENTIFYING THOSE AT RISK OF ATHEROTHROMBOSIS Yusuf S et al. Circulation 2001; 104: 2746–53. 2. Drouet L. Cerebrovasc Dis 2002;13(suppl 1):1–6. Lifestyle Smoking Diet Lack of exercise Genetic Genetic traits Gender Age Generalized disorders Obesity Diabetes Systemic conditions History of vascular events Hypertension Hyperlipidemia Hypercoagulable states Homocystinemia Local factors Elevated prothrombotic factors: fibrinogen, CRP, PAI-1 Blood flow patterns, vessel diameter, arterial wall structure Atherothrombosis manifestations (myocardial infarction, stroke, vascular death) 11 Arici. 2010 Risk Factors for Atherosclerosis Classic Hypertension, Hyper-lipidemia, DM, Smoking Uremia Related Increase ox-LDL, Free radicals, Uremic toxin Infection Bacterial and viral infection Proinflammatory cytokine release Endothelial dysfunction Systemic inflammatory respones Acute phase response Elevated CRP Binding LDL, cemplement activation, tissue factor secretion Accelerated ATHEROSCLEROSIS 12 LDL CD40L=CD40 ligand; TNF-α=tumor necrosis factor-alpha; IL=interleukin; VCAM=vascular cell adhesion molecule; ICAM=intercellular adhesion molecule. Cockerill GW et al. Arterioscler Thromb Vasc Biol. 1995;15:1987-1994; Andre P et al. Circulation. 2002;106:896-899; Libby P. Circulation. 2001;104:365-372; Libby P et al. Circulation. 2002;105:1135-1143; Ross R. N Engl J Med. 1999;340:115-126. Vessel lumen Monocyte Macrophage Adhesionmolecules (VCAM-1, ICAM-1) Inflammatory mediators (CRP, CD40/CD40L, TNF-α, IL-1, IL-6) Intima Foam cell INFLAMMATION PROMOTES PROGRESSION OF ATHEROSCLEROSIS Endothelium LDL Ox-LDL 13 14 Atherosclerosis is a fibroproliferative and inflammatory process occurring ins response to a variety of vascular insults The insults come from classical risk factors ( HT, dyslipidemia, endothelial dysfunction, smoking, menopause, diabetes etc) and novel risk factors (Hcy, LVH, Lp(a), TG, oxidative stress, fibrinogen etc) Endothelial dysfunction is regarded as the first abnormality leading to atherosclerosis This implies that modulation of endothelial function may be used as strategy to intervene the process. 15 Two theories gain more acceptance: (a) the lipid theory (b) inflammation theory Endothelial dysfunction is now regarded as the first abnormality leading to AS. More novel cardiovascular risk factors are known, e.g.: Fibrinogen b. PAI-1 Homocysteins d. AT-1 e. CRP f. Lp(a) g. small-dense LDL h. infectious agents i. and more are emerging
Slide 16 - 1 Nama : Prof. Dr. H. Djanggan Sargowo, dr., SpPD., SpJP(K), FIHA, FACC, FESC, FCAPC, FASCC Tempat/Tgl lahir : Sragen, 21 September 1947 Alamat : Wilis Indah E-10 Malang, Telp. 0341-552395 Pendidikan : Lulus Dokter dari UGM, tahun 1974 Lulus Cardiologist dari Univ. Indonesia, tahun 1983 Lulus Internist dari Univ. Airlangga, tahun 1986 Lulus Doktor, Univ. Airlangga, tahun 1996 Advanced Cardiology Course, Univ. Hongkong, tahun 1984 Senior Visiting Program, Institut Jantung Negara, Kualalumpur, 1996 Fellow American College of Cardiology (FACC), September 2006. Fellow Collage Asia Pacific Society of Cardiology (FCAPC), Desember 2007 Fellow European Sociaty of Cardiology (FESC), 2008 Fellow Asean Collage of Cardiology (FASCC), 2008 Jabatan : Dosen Pengajar Program Pascasarjana Universitas Brawijaya Ketua MKEK Ikatan Dokter Indonesia Cabang Malang Raya Ketua PERKI Cabang Malang Raya Anggota Kolegium Kardiovaskuler Indonesia Dekan Fak. Kedokteran Univ. Wijaya Kusuma Surabaya Ketua Dewan Pengawas Rumah Sakit Pendidikan Ketua Program Studi Kardiovascular Fak. Kedokteran Univ. Brawijaya Curriculum Vitae 2 Djanggan Sargowo Surabaya, 15 April 2012 INFLAMMATION IN ATHEROSCLEROSIS : FROM BENCH TO BEDSIDE 3 4 RUDOLF VIRCHOW Inflammation-based arterial changes as a mechanism of primary importance in atherogenesis mid 19th century Lamond, B. The American Journal of Pathology. 2008 5 Atherosclerosis Start from very young To Old age ? 6 Atherothrombosis* is aLeading Cause of Death Worldwide1† The World Health Report, 2002, WHO Geneva, 2002 28.7 17.8 12.6 9.1 6 5.1 0 5 10 15 20 25 30 Atherothrombosis* Infectious disease Cancer Injuries Pulmonary disease AIDS Mortality (%) * Ischemic heart disease, cerebrovascular disease, inflammatory heart disease and hypertensive heart disease † Worldwide defined as Member States by WHO Region (Africa, Americas, Eastern Mediterranean, European, South-East Asia and Western Pacific) 7 MAJOR CLINICAL MANIFESTATIONS OF ATHEROTHROMBOSIS Adapted from: Drouet L. Cerebrovasc Dis 2002; 13(suppl 1): 1–6. Transient ischemic attack Angina: Stable Unstable Ischemic stroke Myocardial infarction Peripheral arterial disease: Intermittent claudication Rest Pain Gangrene Necrosis 8  Dyslipidemia  Endothelial dysfunction  Free radicals  Immunologic Atherosclerosis/CAD THEORY AND CONCEPT OF ATHEROSCLEROSIS Inflamation (Sargowo, 1996) 9 Free Radical ATHEROGENESIS (Sargowo, 1996) 10 IDENTIFYING THOSE AT RISK OF ATHEROTHROMBOSIS Yusuf S et al. Circulation 2001; 104: 2746–53. 2. Drouet L. Cerebrovasc Dis 2002;13(suppl 1):1–6. Lifestyle Smoking Diet Lack of exercise Genetic Genetic traits Gender Age Generalized disorders Obesity Diabetes Systemic conditions History of vascular events Hypertension Hyperlipidemia Hypercoagulable states Homocystinemia Local factors Elevated prothrombotic factors: fibrinogen, CRP, PAI-1 Blood flow patterns, vessel diameter, arterial wall structure Atherothrombosis manifestations (myocardial infarction, stroke, vascular death) 11 Arici. 2010 Risk Factors for Atherosclerosis Classic Hypertension, Hyper-lipidemia, DM, Smoking Uremia Related Increase ox-LDL, Free radicals, Uremic toxin Infection Bacterial and viral infection Proinflammatory cytokine release Endothelial dysfunction Systemic inflammatory respones Acute phase response Elevated CRP Binding LDL, cemplement activation, tissue factor secretion Accelerated ATHEROSCLEROSIS 12 LDL CD40L=CD40 ligand; TNF-α=tumor necrosis factor-alpha; IL=interleukin; VCAM=vascular cell adhesion molecule; ICAM=intercellular adhesion molecule. Cockerill GW et al. Arterioscler Thromb Vasc Biol. 1995;15:1987-1994; Andre P et al. Circulation. 2002;106:896-899; Libby P. Circulation. 2001;104:365-372; Libby P et al. Circulation. 2002;105:1135-1143; Ross R. N Engl J Med. 1999;340:115-126. Vessel lumen Monocyte Macrophage Adhesionmolecules (VCAM-1, ICAM-1) Inflammatory mediators (CRP, CD40/CD40L, TNF-α, IL-1, IL-6) Intima Foam cell INFLAMMATION PROMOTES PROGRESSION OF ATHEROSCLEROSIS Endothelium LDL Ox-LDL 13 14 Atherosclerosis is a fibroproliferative and inflammatory process occurring ins response to a variety of vascular insults The insults come from classical risk factors ( HT, dyslipidemia, endothelial dysfunction, smoking, menopause, diabetes etc) and novel risk factors (Hcy, LVH, Lp(a), TG, oxidative stress, fibrinogen etc) Endothelial dysfunction is regarded as the first abnormality leading to atherosclerosis This implies that modulation of endothelial function may be used as strategy to intervene the process. 15 Two theories gain more acceptance: (a) the lipid theory (b) inflammation theory Endothelial dysfunction is now regarded as the first abnormality leading to AS. More novel cardiovascular risk factors are known, e.g.: Fibrinogen b. PAI-1 Homocysteins d. AT-1 e. CRP f. Lp(a) g. small-dense LDL h. infectious agents i. and more are emerging 16 Acute Coronary Syndrome (endocrine viewpoints) atherosclerotic lesions vascular funtions b.1. inflammatory reaction b.2. thrombogeneity b.3. vasoreactivity b.4. plaque stability b.5. shoulder of plaque endothelium balance between c.1. vasodilating, antithrombotic, antiproliferative factors (NO, prostacyclin, C-natriuretic peptide, EDHF) c.2. vasoconstricting, prothrombotic, proliferative factors (ET, superoxide, thromoboxan A2)
Slide 17 - 1 Nama : Prof. Dr. H. Djanggan Sargowo, dr., SpPD., SpJP(K), FIHA, FACC, FESC, FCAPC, FASCC Tempat/Tgl lahir : Sragen, 21 September 1947 Alamat : Wilis Indah E-10 Malang, Telp. 0341-552395 Pendidikan : Lulus Dokter dari UGM, tahun 1974 Lulus Cardiologist dari Univ. Indonesia, tahun 1983 Lulus Internist dari Univ. Airlangga, tahun 1986 Lulus Doktor, Univ. Airlangga, tahun 1996 Advanced Cardiology Course, Univ. Hongkong, tahun 1984 Senior Visiting Program, Institut Jantung Negara, Kualalumpur, 1996 Fellow American College of Cardiology (FACC), September 2006. Fellow Collage Asia Pacific Society of Cardiology (FCAPC), Desember 2007 Fellow European Sociaty of Cardiology (FESC), 2008 Fellow Asean Collage of Cardiology (FASCC), 2008 Jabatan : Dosen Pengajar Program Pascasarjana Universitas Brawijaya Ketua MKEK Ikatan Dokter Indonesia Cabang Malang Raya Ketua PERKI Cabang Malang Raya Anggota Kolegium Kardiovaskuler Indonesia Dekan Fak. Kedokteran Univ. Wijaya Kusuma Surabaya Ketua Dewan Pengawas Rumah Sakit Pendidikan Ketua Program Studi Kardiovascular Fak. Kedokteran Univ. Brawijaya Curriculum Vitae 2 Djanggan Sargowo Surabaya, 15 April 2012 INFLAMMATION IN ATHEROSCLEROSIS : FROM BENCH TO BEDSIDE 3 4 RUDOLF VIRCHOW Inflammation-based arterial changes as a mechanism of primary importance in atherogenesis mid 19th century Lamond, B. The American Journal of Pathology. 2008 5 Atherosclerosis Start from very young To Old age ? 6 Atherothrombosis* is aLeading Cause of Death Worldwide1† The World Health Report, 2002, WHO Geneva, 2002 28.7 17.8 12.6 9.1 6 5.1 0 5 10 15 20 25 30 Atherothrombosis* Infectious disease Cancer Injuries Pulmonary disease AIDS Mortality (%) * Ischemic heart disease, cerebrovascular disease, inflammatory heart disease and hypertensive heart disease † Worldwide defined as Member States by WHO Region (Africa, Americas, Eastern Mediterranean, European, South-East Asia and Western Pacific) 7 MAJOR CLINICAL MANIFESTATIONS OF ATHEROTHROMBOSIS Adapted from: Drouet L. Cerebrovasc Dis 2002; 13(suppl 1): 1–6. Transient ischemic attack Angina: Stable Unstable Ischemic stroke Myocardial infarction Peripheral arterial disease: Intermittent claudication Rest Pain Gangrene Necrosis 8  Dyslipidemia  Endothelial dysfunction  Free radicals  Immunologic Atherosclerosis/CAD THEORY AND CONCEPT OF ATHEROSCLEROSIS Inflamation (Sargowo, 1996) 9 Free Radical ATHEROGENESIS (Sargowo, 1996) 10 IDENTIFYING THOSE AT RISK OF ATHEROTHROMBOSIS Yusuf S et al. Circulation 2001; 104: 2746–53. 2. Drouet L. Cerebrovasc Dis 2002;13(suppl 1):1–6. Lifestyle Smoking Diet Lack of exercise Genetic Genetic traits Gender Age Generalized disorders Obesity Diabetes Systemic conditions History of vascular events Hypertension Hyperlipidemia Hypercoagulable states Homocystinemia Local factors Elevated prothrombotic factors: fibrinogen, CRP, PAI-1 Blood flow patterns, vessel diameter, arterial wall structure Atherothrombosis manifestations (myocardial infarction, stroke, vascular death) 11 Arici. 2010 Risk Factors for Atherosclerosis Classic Hypertension, Hyper-lipidemia, DM, Smoking Uremia Related Increase ox-LDL, Free radicals, Uremic toxin Infection Bacterial and viral infection Proinflammatory cytokine release Endothelial dysfunction Systemic inflammatory respones Acute phase response Elevated CRP Binding LDL, cemplement activation, tissue factor secretion Accelerated ATHEROSCLEROSIS 12 LDL CD40L=CD40 ligand; TNF-α=tumor necrosis factor-alpha; IL=interleukin; VCAM=vascular cell adhesion molecule; ICAM=intercellular adhesion molecule. Cockerill GW et al. Arterioscler Thromb Vasc Biol. 1995;15:1987-1994; Andre P et al. Circulation. 2002;106:896-899; Libby P. Circulation. 2001;104:365-372; Libby P et al. Circulation. 2002;105:1135-1143; Ross R. N Engl J Med. 1999;340:115-126. Vessel lumen Monocyte Macrophage Adhesionmolecules (VCAM-1, ICAM-1) Inflammatory mediators (CRP, CD40/CD40L, TNF-α, IL-1, IL-6) Intima Foam cell INFLAMMATION PROMOTES PROGRESSION OF ATHEROSCLEROSIS Endothelium LDL Ox-LDL 13 14 Atherosclerosis is a fibroproliferative and inflammatory process occurring ins response to a variety of vascular insults The insults come from classical risk factors ( HT, dyslipidemia, endothelial dysfunction, smoking, menopause, diabetes etc) and novel risk factors (Hcy, LVH, Lp(a), TG, oxidative stress, fibrinogen etc) Endothelial dysfunction is regarded as the first abnormality leading to atherosclerosis This implies that modulation of endothelial function may be used as strategy to intervene the process. 15 Two theories gain more acceptance: (a) the lipid theory (b) inflammation theory Endothelial dysfunction is now regarded as the first abnormality leading to AS. More novel cardiovascular risk factors are known, e.g.: Fibrinogen b. PAI-1 Homocysteins d. AT-1 e. CRP f. Lp(a) g. small-dense LDL h. infectious agents i. and more are emerging 16 Acute Coronary Syndrome (endocrine viewpoints) atherosclerotic lesions vascular funtions b.1. inflammatory reaction b.2. thrombogeneity b.3. vasoreactivity b.4. plaque stability b.5. shoulder of plaque endothelium balance between c.1. vasodilating, antithrombotic, antiproliferative factors (NO, prostacyclin, C-natriuretic peptide, EDHF) c.2. vasoconstricting, prothrombotic, proliferative factors (ET, superoxide, thromoboxan A2) 17 NATURAL HISTORY OF CORONARY ATHEROSCLEROSIS Chatzizisis et all. JACC. 2007. Asymtomatic Stable Angina Acute Coronary Syndrome Early fibroatheroma Compensatory expansive remodeling Quiescent plaque Contrictive remodeling Stenotic plaque Exessive expansive remodeling Thin cap fibroatheroma Erosion Physiologic coronary artery Local factors, e.g. low ESS Systemic factors, e.g. hyperlipidemia Genetic factors Physiologic ESS Limited inflammation Fibroproliferation Microruptures
Slide 18 - 1 Nama : Prof. Dr. H. Djanggan Sargowo, dr., SpPD., SpJP(K), FIHA, FACC, FESC, FCAPC, FASCC Tempat/Tgl lahir : Sragen, 21 September 1947 Alamat : Wilis Indah E-10 Malang, Telp. 0341-552395 Pendidikan : Lulus Dokter dari UGM, tahun 1974 Lulus Cardiologist dari Univ. Indonesia, tahun 1983 Lulus Internist dari Univ. Airlangga, tahun 1986 Lulus Doktor, Univ. Airlangga, tahun 1996 Advanced Cardiology Course, Univ. Hongkong, tahun 1984 Senior Visiting Program, Institut Jantung Negara, Kualalumpur, 1996 Fellow American College of Cardiology (FACC), September 2006. Fellow Collage Asia Pacific Society of Cardiology (FCAPC), Desember 2007 Fellow European Sociaty of Cardiology (FESC), 2008 Fellow Asean Collage of Cardiology (FASCC), 2008 Jabatan : Dosen Pengajar Program Pascasarjana Universitas Brawijaya Ketua MKEK Ikatan Dokter Indonesia Cabang Malang Raya Ketua PERKI Cabang Malang Raya Anggota Kolegium Kardiovaskuler Indonesia Dekan Fak. Kedokteran Univ. Wijaya Kusuma Surabaya Ketua Dewan Pengawas Rumah Sakit Pendidikan Ketua Program Studi Kardiovascular Fak. Kedokteran Univ. Brawijaya Curriculum Vitae 2 Djanggan Sargowo Surabaya, 15 April 2012 INFLAMMATION IN ATHEROSCLEROSIS : FROM BENCH TO BEDSIDE 3 4 RUDOLF VIRCHOW Inflammation-based arterial changes as a mechanism of primary importance in atherogenesis mid 19th century Lamond, B. The American Journal of Pathology. 2008 5 Atherosclerosis Start from very young To Old age ? 6 Atherothrombosis* is aLeading Cause of Death Worldwide1† The World Health Report, 2002, WHO Geneva, 2002 28.7 17.8 12.6 9.1 6 5.1 0 5 10 15 20 25 30 Atherothrombosis* Infectious disease Cancer Injuries Pulmonary disease AIDS Mortality (%) * Ischemic heart disease, cerebrovascular disease, inflammatory heart disease and hypertensive heart disease † Worldwide defined as Member States by WHO Region (Africa, Americas, Eastern Mediterranean, European, South-East Asia and Western Pacific) 7 MAJOR CLINICAL MANIFESTATIONS OF ATHEROTHROMBOSIS Adapted from: Drouet L. Cerebrovasc Dis 2002; 13(suppl 1): 1–6. Transient ischemic attack Angina: Stable Unstable Ischemic stroke Myocardial infarction Peripheral arterial disease: Intermittent claudication Rest Pain Gangrene Necrosis 8  Dyslipidemia  Endothelial dysfunction  Free radicals  Immunologic Atherosclerosis/CAD THEORY AND CONCEPT OF ATHEROSCLEROSIS Inflamation (Sargowo, 1996) 9 Free Radical ATHEROGENESIS (Sargowo, 1996) 10 IDENTIFYING THOSE AT RISK OF ATHEROTHROMBOSIS Yusuf S et al. Circulation 2001; 104: 2746–53. 2. Drouet L. Cerebrovasc Dis 2002;13(suppl 1):1–6. Lifestyle Smoking Diet Lack of exercise Genetic Genetic traits Gender Age Generalized disorders Obesity Diabetes Systemic conditions History of vascular events Hypertension Hyperlipidemia Hypercoagulable states Homocystinemia Local factors Elevated prothrombotic factors: fibrinogen, CRP, PAI-1 Blood flow patterns, vessel diameter, arterial wall structure Atherothrombosis manifestations (myocardial infarction, stroke, vascular death) 11 Arici. 2010 Risk Factors for Atherosclerosis Classic Hypertension, Hyper-lipidemia, DM, Smoking Uremia Related Increase ox-LDL, Free radicals, Uremic toxin Infection Bacterial and viral infection Proinflammatory cytokine release Endothelial dysfunction Systemic inflammatory respones Acute phase response Elevated CRP Binding LDL, cemplement activation, tissue factor secretion Accelerated ATHEROSCLEROSIS 12 LDL CD40L=CD40 ligand; TNF-α=tumor necrosis factor-alpha; IL=interleukin; VCAM=vascular cell adhesion molecule; ICAM=intercellular adhesion molecule. Cockerill GW et al. Arterioscler Thromb Vasc Biol. 1995;15:1987-1994; Andre P et al. Circulation. 2002;106:896-899; Libby P. Circulation. 2001;104:365-372; Libby P et al. Circulation. 2002;105:1135-1143; Ross R. N Engl J Med. 1999;340:115-126. Vessel lumen Monocyte Macrophage Adhesionmolecules (VCAM-1, ICAM-1) Inflammatory mediators (CRP, CD40/CD40L, TNF-α, IL-1, IL-6) Intima Foam cell INFLAMMATION PROMOTES PROGRESSION OF ATHEROSCLEROSIS Endothelium LDL Ox-LDL 13 14 Atherosclerosis is a fibroproliferative and inflammatory process occurring ins response to a variety of vascular insults The insults come from classical risk factors ( HT, dyslipidemia, endothelial dysfunction, smoking, menopause, diabetes etc) and novel risk factors (Hcy, LVH, Lp(a), TG, oxidative stress, fibrinogen etc) Endothelial dysfunction is regarded as the first abnormality leading to atherosclerosis This implies that modulation of endothelial function may be used as strategy to intervene the process. 15 Two theories gain more acceptance: (a) the lipid theory (b) inflammation theory Endothelial dysfunction is now regarded as the first abnormality leading to AS. More novel cardiovascular risk factors are known, e.g.: Fibrinogen b. PAI-1 Homocysteins d. AT-1 e. CRP f. Lp(a) g. small-dense LDL h. infectious agents i. and more are emerging 16 Acute Coronary Syndrome (endocrine viewpoints) atherosclerotic lesions vascular funtions b.1. inflammatory reaction b.2. thrombogeneity b.3. vasoreactivity b.4. plaque stability b.5. shoulder of plaque endothelium balance between c.1. vasodilating, antithrombotic, antiproliferative factors (NO, prostacyclin, C-natriuretic peptide, EDHF) c.2. vasoconstricting, prothrombotic, proliferative factors (ET, superoxide, thromoboxan A2) 17 NATURAL HISTORY OF CORONARY ATHEROSCLEROSIS Chatzizisis et all. JACC. 2007. Asymtomatic Stable Angina Acute Coronary Syndrome Early fibroatheroma Compensatory expansive remodeling Quiescent plaque Contrictive remodeling Stenotic plaque Exessive expansive remodeling Thin cap fibroatheroma Erosion Physiologic coronary artery Local factors, e.g. low ESS Systemic factors, e.g. hyperlipidemia Genetic factors Physiologic ESS Limited inflammation Fibroproliferation Microruptures 18 ATHEROSCLEROSIS IS AN INFLAMMATORY DISEASE Libby P. Circulation. 2001;104:365-372; Ross R. N Engl J Med. 1999;340:115-126. Monocyte LDL-C Adhesion molecule Macrophage Foam cell OxidizedLDL-C Plaque rupture Smooth muscle cells CRP Plaque instability and thrombus Oxidation Inflammation Endothelial dysfunction
Slide 19 - 1 Nama : Prof. Dr. H. Djanggan Sargowo, dr., SpPD., SpJP(K), FIHA, FACC, FESC, FCAPC, FASCC Tempat/Tgl lahir : Sragen, 21 September 1947 Alamat : Wilis Indah E-10 Malang, Telp. 0341-552395 Pendidikan : Lulus Dokter dari UGM, tahun 1974 Lulus Cardiologist dari Univ. Indonesia, tahun 1983 Lulus Internist dari Univ. Airlangga, tahun 1986 Lulus Doktor, Univ. Airlangga, tahun 1996 Advanced Cardiology Course, Univ. Hongkong, tahun 1984 Senior Visiting Program, Institut Jantung Negara, Kualalumpur, 1996 Fellow American College of Cardiology (FACC), September 2006. Fellow Collage Asia Pacific Society of Cardiology (FCAPC), Desember 2007 Fellow European Sociaty of Cardiology (FESC), 2008 Fellow Asean Collage of Cardiology (FASCC), 2008 Jabatan : Dosen Pengajar Program Pascasarjana Universitas Brawijaya Ketua MKEK Ikatan Dokter Indonesia Cabang Malang Raya Ketua PERKI Cabang Malang Raya Anggota Kolegium Kardiovaskuler Indonesia Dekan Fak. Kedokteran Univ. Wijaya Kusuma Surabaya Ketua Dewan Pengawas Rumah Sakit Pendidikan Ketua Program Studi Kardiovascular Fak. Kedokteran Univ. Brawijaya Curriculum Vitae 2 Djanggan Sargowo Surabaya, 15 April 2012 INFLAMMATION IN ATHEROSCLEROSIS : FROM BENCH TO BEDSIDE 3 4 RUDOLF VIRCHOW Inflammation-based arterial changes as a mechanism of primary importance in atherogenesis mid 19th century Lamond, B. The American Journal of Pathology. 2008 5 Atherosclerosis Start from very young To Old age ? 6 Atherothrombosis* is aLeading Cause of Death Worldwide1† The World Health Report, 2002, WHO Geneva, 2002 28.7 17.8 12.6 9.1 6 5.1 0 5 10 15 20 25 30 Atherothrombosis* Infectious disease Cancer Injuries Pulmonary disease AIDS Mortality (%) * Ischemic heart disease, cerebrovascular disease, inflammatory heart disease and hypertensive heart disease † Worldwide defined as Member States by WHO Region (Africa, Americas, Eastern Mediterranean, European, South-East Asia and Western Pacific) 7 MAJOR CLINICAL MANIFESTATIONS OF ATHEROTHROMBOSIS Adapted from: Drouet L. Cerebrovasc Dis 2002; 13(suppl 1): 1–6. Transient ischemic attack Angina: Stable Unstable Ischemic stroke Myocardial infarction Peripheral arterial disease: Intermittent claudication Rest Pain Gangrene Necrosis 8  Dyslipidemia  Endothelial dysfunction  Free radicals  Immunologic Atherosclerosis/CAD THEORY AND CONCEPT OF ATHEROSCLEROSIS Inflamation (Sargowo, 1996) 9 Free Radical ATHEROGENESIS (Sargowo, 1996) 10 IDENTIFYING THOSE AT RISK OF ATHEROTHROMBOSIS Yusuf S et al. Circulation 2001; 104: 2746–53. 2. Drouet L. Cerebrovasc Dis 2002;13(suppl 1):1–6. Lifestyle Smoking Diet Lack of exercise Genetic Genetic traits Gender Age Generalized disorders Obesity Diabetes Systemic conditions History of vascular events Hypertension Hyperlipidemia Hypercoagulable states Homocystinemia Local factors Elevated prothrombotic factors: fibrinogen, CRP, PAI-1 Blood flow patterns, vessel diameter, arterial wall structure Atherothrombosis manifestations (myocardial infarction, stroke, vascular death) 11 Arici. 2010 Risk Factors for Atherosclerosis Classic Hypertension, Hyper-lipidemia, DM, Smoking Uremia Related Increase ox-LDL, Free radicals, Uremic toxin Infection Bacterial and viral infection Proinflammatory cytokine release Endothelial dysfunction Systemic inflammatory respones Acute phase response Elevated CRP Binding LDL, cemplement activation, tissue factor secretion Accelerated ATHEROSCLEROSIS 12 LDL CD40L=CD40 ligand; TNF-α=tumor necrosis factor-alpha; IL=interleukin; VCAM=vascular cell adhesion molecule; ICAM=intercellular adhesion molecule. Cockerill GW et al. Arterioscler Thromb Vasc Biol. 1995;15:1987-1994; Andre P et al. Circulation. 2002;106:896-899; Libby P. Circulation. 2001;104:365-372; Libby P et al. Circulation. 2002;105:1135-1143; Ross R. N Engl J Med. 1999;340:115-126. Vessel lumen Monocyte Macrophage Adhesionmolecules (VCAM-1, ICAM-1) Inflammatory mediators (CRP, CD40/CD40L, TNF-α, IL-1, IL-6) Intima Foam cell INFLAMMATION PROMOTES PROGRESSION OF ATHEROSCLEROSIS Endothelium LDL Ox-LDL 13 14 Atherosclerosis is a fibroproliferative and inflammatory process occurring ins response to a variety of vascular insults The insults come from classical risk factors ( HT, dyslipidemia, endothelial dysfunction, smoking, menopause, diabetes etc) and novel risk factors (Hcy, LVH, Lp(a), TG, oxidative stress, fibrinogen etc) Endothelial dysfunction is regarded as the first abnormality leading to atherosclerosis This implies that modulation of endothelial function may be used as strategy to intervene the process. 15 Two theories gain more acceptance: (a) the lipid theory (b) inflammation theory Endothelial dysfunction is now regarded as the first abnormality leading to AS. More novel cardiovascular risk factors are known, e.g.: Fibrinogen b. PAI-1 Homocysteins d. AT-1 e. CRP f. Lp(a) g. small-dense LDL h. infectious agents i. and more are emerging 16 Acute Coronary Syndrome (endocrine viewpoints) atherosclerotic lesions vascular funtions b.1. inflammatory reaction b.2. thrombogeneity b.3. vasoreactivity b.4. plaque stability b.5. shoulder of plaque endothelium balance between c.1. vasodilating, antithrombotic, antiproliferative factors (NO, prostacyclin, C-natriuretic peptide, EDHF) c.2. vasoconstricting, prothrombotic, proliferative factors (ET, superoxide, thromoboxan A2) 17 NATURAL HISTORY OF CORONARY ATHEROSCLEROSIS Chatzizisis et all. JACC. 2007. Asymtomatic Stable Angina Acute Coronary Syndrome Early fibroatheroma Compensatory expansive remodeling Quiescent plaque Contrictive remodeling Stenotic plaque Exessive expansive remodeling Thin cap fibroatheroma Erosion Physiologic coronary artery Local factors, e.g. low ESS Systemic factors, e.g. hyperlipidemia Genetic factors Physiologic ESS Limited inflammation Fibroproliferation Microruptures 18 ATHEROSCLEROSIS IS AN INFLAMMATORY DISEASE Libby P. Circulation. 2001;104:365-372; Ross R. N Engl J Med. 1999;340:115-126. Monocyte LDL-C Adhesion molecule Macrophage Foam cell OxidizedLDL-C Plaque rupture Smooth muscle cells CRP Plaque instability and thrombus Oxidation Inflammation Endothelial dysfunction 19
Slide 20 - 1 Nama : Prof. Dr. H. Djanggan Sargowo, dr., SpPD., SpJP(K), FIHA, FACC, FESC, FCAPC, FASCC Tempat/Tgl lahir : Sragen, 21 September 1947 Alamat : Wilis Indah E-10 Malang, Telp. 0341-552395 Pendidikan : Lulus Dokter dari UGM, tahun 1974 Lulus Cardiologist dari Univ. Indonesia, tahun 1983 Lulus Internist dari Univ. Airlangga, tahun 1986 Lulus Doktor, Univ. Airlangga, tahun 1996 Advanced Cardiology Course, Univ. Hongkong, tahun 1984 Senior Visiting Program, Institut Jantung Negara, Kualalumpur, 1996 Fellow American College of Cardiology (FACC), September 2006. Fellow Collage Asia Pacific Society of Cardiology (FCAPC), Desember 2007 Fellow European Sociaty of Cardiology (FESC), 2008 Fellow Asean Collage of Cardiology (FASCC), 2008 Jabatan : Dosen Pengajar Program Pascasarjana Universitas Brawijaya Ketua MKEK Ikatan Dokter Indonesia Cabang Malang Raya Ketua PERKI Cabang Malang Raya Anggota Kolegium Kardiovaskuler Indonesia Dekan Fak. Kedokteran Univ. Wijaya Kusuma Surabaya Ketua Dewan Pengawas Rumah Sakit Pendidikan Ketua Program Studi Kardiovascular Fak. Kedokteran Univ. Brawijaya Curriculum Vitae 2 Djanggan Sargowo Surabaya, 15 April 2012 INFLAMMATION IN ATHEROSCLEROSIS : FROM BENCH TO BEDSIDE 3 4 RUDOLF VIRCHOW Inflammation-based arterial changes as a mechanism of primary importance in atherogenesis mid 19th century Lamond, B. The American Journal of Pathology. 2008 5 Atherosclerosis Start from very young To Old age ? 6 Atherothrombosis* is aLeading Cause of Death Worldwide1† The World Health Report, 2002, WHO Geneva, 2002 28.7 17.8 12.6 9.1 6 5.1 0 5 10 15 20 25 30 Atherothrombosis* Infectious disease Cancer Injuries Pulmonary disease AIDS Mortality (%) * Ischemic heart disease, cerebrovascular disease, inflammatory heart disease and hypertensive heart disease † Worldwide defined as Member States by WHO Region (Africa, Americas, Eastern Mediterranean, European, South-East Asia and Western Pacific) 7 MAJOR CLINICAL MANIFESTATIONS OF ATHEROTHROMBOSIS Adapted from: Drouet L. Cerebrovasc Dis 2002; 13(suppl 1): 1–6. Transient ischemic attack Angina: Stable Unstable Ischemic stroke Myocardial infarction Peripheral arterial disease: Intermittent claudication Rest Pain Gangrene Necrosis 8  Dyslipidemia  Endothelial dysfunction  Free radicals  Immunologic Atherosclerosis/CAD THEORY AND CONCEPT OF ATHEROSCLEROSIS Inflamation (Sargowo, 1996) 9 Free Radical ATHEROGENESIS (Sargowo, 1996) 10 IDENTIFYING THOSE AT RISK OF ATHEROTHROMBOSIS Yusuf S et al. Circulation 2001; 104: 2746–53. 2. Drouet L. Cerebrovasc Dis 2002;13(suppl 1):1–6. Lifestyle Smoking Diet Lack of exercise Genetic Genetic traits Gender Age Generalized disorders Obesity Diabetes Systemic conditions History of vascular events Hypertension Hyperlipidemia Hypercoagulable states Homocystinemia Local factors Elevated prothrombotic factors: fibrinogen, CRP, PAI-1 Blood flow patterns, vessel diameter, arterial wall structure Atherothrombosis manifestations (myocardial infarction, stroke, vascular death) 11 Arici. 2010 Risk Factors for Atherosclerosis Classic Hypertension, Hyper-lipidemia, DM, Smoking Uremia Related Increase ox-LDL, Free radicals, Uremic toxin Infection Bacterial and viral infection Proinflammatory cytokine release Endothelial dysfunction Systemic inflammatory respones Acute phase response Elevated CRP Binding LDL, cemplement activation, tissue factor secretion Accelerated ATHEROSCLEROSIS 12 LDL CD40L=CD40 ligand; TNF-α=tumor necrosis factor-alpha; IL=interleukin; VCAM=vascular cell adhesion molecule; ICAM=intercellular adhesion molecule. Cockerill GW et al. Arterioscler Thromb Vasc Biol. 1995;15:1987-1994; Andre P et al. Circulation. 2002;106:896-899; Libby P. Circulation. 2001;104:365-372; Libby P et al. Circulation. 2002;105:1135-1143; Ross R. N Engl J Med. 1999;340:115-126. Vessel lumen Monocyte Macrophage Adhesionmolecules (VCAM-1, ICAM-1) Inflammatory mediators (CRP, CD40/CD40L, TNF-α, IL-1, IL-6) Intima Foam cell INFLAMMATION PROMOTES PROGRESSION OF ATHEROSCLEROSIS Endothelium LDL Ox-LDL 13 14 Atherosclerosis is a fibroproliferative and inflammatory process occurring ins response to a variety of vascular insults The insults come from classical risk factors ( HT, dyslipidemia, endothelial dysfunction, smoking, menopause, diabetes etc) and novel risk factors (Hcy, LVH, Lp(a), TG, oxidative stress, fibrinogen etc) Endothelial dysfunction is regarded as the first abnormality leading to atherosclerosis This implies that modulation of endothelial function may be used as strategy to intervene the process. 15 Two theories gain more acceptance: (a) the lipid theory (b) inflammation theory Endothelial dysfunction is now regarded as the first abnormality leading to AS. More novel cardiovascular risk factors are known, e.g.: Fibrinogen b. PAI-1 Homocysteins d. AT-1 e. CRP f. Lp(a) g. small-dense LDL h. infectious agents i. and more are emerging 16 Acute Coronary Syndrome (endocrine viewpoints) atherosclerotic lesions vascular funtions b.1. inflammatory reaction b.2. thrombogeneity b.3. vasoreactivity b.4. plaque stability b.5. shoulder of plaque endothelium balance between c.1. vasodilating, antithrombotic, antiproliferative factors (NO, prostacyclin, C-natriuretic peptide, EDHF) c.2. vasoconstricting, prothrombotic, proliferative factors (ET, superoxide, thromoboxan A2) 17 NATURAL HISTORY OF CORONARY ATHEROSCLEROSIS Chatzizisis et all. JACC. 2007. Asymtomatic Stable Angina Acute Coronary Syndrome Early fibroatheroma Compensatory expansive remodeling Quiescent plaque Contrictive remodeling Stenotic plaque Exessive expansive remodeling Thin cap fibroatheroma Erosion Physiologic coronary artery Local factors, e.g. low ESS Systemic factors, e.g. hyperlipidemia Genetic factors Physiologic ESS Limited inflammation Fibroproliferation Microruptures 18 ATHEROSCLEROSIS IS AN INFLAMMATORY DISEASE Libby P. Circulation. 2001;104:365-372; Ross R. N Engl J Med. 1999;340:115-126. Monocyte LDL-C Adhesion molecule Macrophage Foam cell OxidizedLDL-C Plaque rupture Smooth muscle cells CRP Plaque instability and thrombus Oxidation Inflammation Endothelial dysfunction 19 20 Reverse Cholesterol Transport Monocyte CRP TXA2 PGI2 Thrombin LDL Platelets HDL HDL Ox-LDL MCP-1 Macrophage P-selectin CD 40L PDGF Foam cell MMP T cell E-selectins CD 40L VCAM-1 ICAM-1 IL-1 Reilly, et.all. 2005
Slide 21 - 1 Nama : Prof. Dr. H. Djanggan Sargowo, dr., SpPD., SpJP(K), FIHA, FACC, FESC, FCAPC, FASCC Tempat/Tgl lahir : Sragen, 21 September 1947 Alamat : Wilis Indah E-10 Malang, Telp. 0341-552395 Pendidikan : Lulus Dokter dari UGM, tahun 1974 Lulus Cardiologist dari Univ. Indonesia, tahun 1983 Lulus Internist dari Univ. Airlangga, tahun 1986 Lulus Doktor, Univ. Airlangga, tahun 1996 Advanced Cardiology Course, Univ. Hongkong, tahun 1984 Senior Visiting Program, Institut Jantung Negara, Kualalumpur, 1996 Fellow American College of Cardiology (FACC), September 2006. Fellow Collage Asia Pacific Society of Cardiology (FCAPC), Desember 2007 Fellow European Sociaty of Cardiology (FESC), 2008 Fellow Asean Collage of Cardiology (FASCC), 2008 Jabatan : Dosen Pengajar Program Pascasarjana Universitas Brawijaya Ketua MKEK Ikatan Dokter Indonesia Cabang Malang Raya Ketua PERKI Cabang Malang Raya Anggota Kolegium Kardiovaskuler Indonesia Dekan Fak. Kedokteran Univ. Wijaya Kusuma Surabaya Ketua Dewan Pengawas Rumah Sakit Pendidikan Ketua Program Studi Kardiovascular Fak. Kedokteran Univ. Brawijaya Curriculum Vitae 2 Djanggan Sargowo Surabaya, 15 April 2012 INFLAMMATION IN ATHEROSCLEROSIS : FROM BENCH TO BEDSIDE 3 4 RUDOLF VIRCHOW Inflammation-based arterial changes as a mechanism of primary importance in atherogenesis mid 19th century Lamond, B. The American Journal of Pathology. 2008 5 Atherosclerosis Start from very young To Old age ? 6 Atherothrombosis* is aLeading Cause of Death Worldwide1† The World Health Report, 2002, WHO Geneva, 2002 28.7 17.8 12.6 9.1 6 5.1 0 5 10 15 20 25 30 Atherothrombosis* Infectious disease Cancer Injuries Pulmonary disease AIDS Mortality (%) * Ischemic heart disease, cerebrovascular disease, inflammatory heart disease and hypertensive heart disease † Worldwide defined as Member States by WHO Region (Africa, Americas, Eastern Mediterranean, European, South-East Asia and Western Pacific) 7 MAJOR CLINICAL MANIFESTATIONS OF ATHEROTHROMBOSIS Adapted from: Drouet L. Cerebrovasc Dis 2002; 13(suppl 1): 1–6. Transient ischemic attack Angina: Stable Unstable Ischemic stroke Myocardial infarction Peripheral arterial disease: Intermittent claudication Rest Pain Gangrene Necrosis 8  Dyslipidemia  Endothelial dysfunction  Free radicals  Immunologic Atherosclerosis/CAD THEORY AND CONCEPT OF ATHEROSCLEROSIS Inflamation (Sargowo, 1996) 9 Free Radical ATHEROGENESIS (Sargowo, 1996) 10 IDENTIFYING THOSE AT RISK OF ATHEROTHROMBOSIS Yusuf S et al. Circulation 2001; 104: 2746–53. 2. Drouet L. Cerebrovasc Dis 2002;13(suppl 1):1–6. Lifestyle Smoking Diet Lack of exercise Genetic Genetic traits Gender Age Generalized disorders Obesity Diabetes Systemic conditions History of vascular events Hypertension Hyperlipidemia Hypercoagulable states Homocystinemia Local factors Elevated prothrombotic factors: fibrinogen, CRP, PAI-1 Blood flow patterns, vessel diameter, arterial wall structure Atherothrombosis manifestations (myocardial infarction, stroke, vascular death) 11 Arici. 2010 Risk Factors for Atherosclerosis Classic Hypertension, Hyper-lipidemia, DM, Smoking Uremia Related Increase ox-LDL, Free radicals, Uremic toxin Infection Bacterial and viral infection Proinflammatory cytokine release Endothelial dysfunction Systemic inflammatory respones Acute phase response Elevated CRP Binding LDL, cemplement activation, tissue factor secretion Accelerated ATHEROSCLEROSIS 12 LDL CD40L=CD40 ligand; TNF-α=tumor necrosis factor-alpha; IL=interleukin; VCAM=vascular cell adhesion molecule; ICAM=intercellular adhesion molecule. Cockerill GW et al. Arterioscler Thromb Vasc Biol. 1995;15:1987-1994; Andre P et al. Circulation. 2002;106:896-899; Libby P. Circulation. 2001;104:365-372; Libby P et al. Circulation. 2002;105:1135-1143; Ross R. N Engl J Med. 1999;340:115-126. Vessel lumen Monocyte Macrophage Adhesionmolecules (VCAM-1, ICAM-1) Inflammatory mediators (CRP, CD40/CD40L, TNF-α, IL-1, IL-6) Intima Foam cell INFLAMMATION PROMOTES PROGRESSION OF ATHEROSCLEROSIS Endothelium LDL Ox-LDL 13 14 Atherosclerosis is a fibroproliferative and inflammatory process occurring ins response to a variety of vascular insults The insults come from classical risk factors ( HT, dyslipidemia, endothelial dysfunction, smoking, menopause, diabetes etc) and novel risk factors (Hcy, LVH, Lp(a), TG, oxidative stress, fibrinogen etc) Endothelial dysfunction is regarded as the first abnormality leading to atherosclerosis This implies that modulation of endothelial function may be used as strategy to intervene the process. 15 Two theories gain more acceptance: (a) the lipid theory (b) inflammation theory Endothelial dysfunction is now regarded as the first abnormality leading to AS. More novel cardiovascular risk factors are known, e.g.: Fibrinogen b. PAI-1 Homocysteins d. AT-1 e. CRP f. Lp(a) g. small-dense LDL h. infectious agents i. and more are emerging 16 Acute Coronary Syndrome (endocrine viewpoints) atherosclerotic lesions vascular funtions b.1. inflammatory reaction b.2. thrombogeneity b.3. vasoreactivity b.4. plaque stability b.5. shoulder of plaque endothelium balance between c.1. vasodilating, antithrombotic, antiproliferative factors (NO, prostacyclin, C-natriuretic peptide, EDHF) c.2. vasoconstricting, prothrombotic, proliferative factors (ET, superoxide, thromoboxan A2) 17 NATURAL HISTORY OF CORONARY ATHEROSCLEROSIS Chatzizisis et all. JACC. 2007. Asymtomatic Stable Angina Acute Coronary Syndrome Early fibroatheroma Compensatory expansive remodeling Quiescent plaque Contrictive remodeling Stenotic plaque Exessive expansive remodeling Thin cap fibroatheroma Erosion Physiologic coronary artery Local factors, e.g. low ESS Systemic factors, e.g. hyperlipidemia Genetic factors Physiologic ESS Limited inflammation Fibroproliferation Microruptures 18 ATHEROSCLEROSIS IS AN INFLAMMATORY DISEASE Libby P. Circulation. 2001;104:365-372; Ross R. N Engl J Med. 1999;340:115-126. Monocyte LDL-C Adhesion molecule Macrophage Foam cell OxidizedLDL-C Plaque rupture Smooth muscle cells CRP Plaque instability and thrombus Oxidation Inflammation Endothelial dysfunction 19 20 Reverse Cholesterol Transport Monocyte CRP TXA2 PGI2 Thrombin LDL Platelets HDL HDL Ox-LDL MCP-1 Macrophage P-selectin CD 40L PDGF Foam cell MMP T cell E-selectins CD 40L VCAM-1 ICAM-1 IL-1 Reilly, et.all. 2005 21 THE ROLE OF Lp-PLA2 IN CHD LUMEN Monocytes Adhesion Molecules Oxidated LDL INTIMA MEDIA Lp-PLA2 Lyso-PC OxFA Cytokines Plaque Formation Foam Cell Macrophage
Slide 22 - 1 Nama : Prof. Dr. H. Djanggan Sargowo, dr., SpPD., SpJP(K), FIHA, FACC, FESC, FCAPC, FASCC Tempat/Tgl lahir : Sragen, 21 September 1947 Alamat : Wilis Indah E-10 Malang, Telp. 0341-552395 Pendidikan : Lulus Dokter dari UGM, tahun 1974 Lulus Cardiologist dari Univ. Indonesia, tahun 1983 Lulus Internist dari Univ. Airlangga, tahun 1986 Lulus Doktor, Univ. Airlangga, tahun 1996 Advanced Cardiology Course, Univ. Hongkong, tahun 1984 Senior Visiting Program, Institut Jantung Negara, Kualalumpur, 1996 Fellow American College of Cardiology (FACC), September 2006. Fellow Collage Asia Pacific Society of Cardiology (FCAPC), Desember 2007 Fellow European Sociaty of Cardiology (FESC), 2008 Fellow Asean Collage of Cardiology (FASCC), 2008 Jabatan : Dosen Pengajar Program Pascasarjana Universitas Brawijaya Ketua MKEK Ikatan Dokter Indonesia Cabang Malang Raya Ketua PERKI Cabang Malang Raya Anggota Kolegium Kardiovaskuler Indonesia Dekan Fak. Kedokteran Univ. Wijaya Kusuma Surabaya Ketua Dewan Pengawas Rumah Sakit Pendidikan Ketua Program Studi Kardiovascular Fak. Kedokteran Univ. Brawijaya Curriculum Vitae 2 Djanggan Sargowo Surabaya, 15 April 2012 INFLAMMATION IN ATHEROSCLEROSIS : FROM BENCH TO BEDSIDE 3 4 RUDOLF VIRCHOW Inflammation-based arterial changes as a mechanism of primary importance in atherogenesis mid 19th century Lamond, B. The American Journal of Pathology. 2008 5 Atherosclerosis Start from very young To Old age ? 6 Atherothrombosis* is aLeading Cause of Death Worldwide1† The World Health Report, 2002, WHO Geneva, 2002 28.7 17.8 12.6 9.1 6 5.1 0 5 10 15 20 25 30 Atherothrombosis* Infectious disease Cancer Injuries Pulmonary disease AIDS Mortality (%) * Ischemic heart disease, cerebrovascular disease, inflammatory heart disease and hypertensive heart disease † Worldwide defined as Member States by WHO Region (Africa, Americas, Eastern Mediterranean, European, South-East Asia and Western Pacific) 7 MAJOR CLINICAL MANIFESTATIONS OF ATHEROTHROMBOSIS Adapted from: Drouet L. Cerebrovasc Dis 2002; 13(suppl 1): 1–6. Transient ischemic attack Angina: Stable Unstable Ischemic stroke Myocardial infarction Peripheral arterial disease: Intermittent claudication Rest Pain Gangrene Necrosis 8  Dyslipidemia  Endothelial dysfunction  Free radicals  Immunologic Atherosclerosis/CAD THEORY AND CONCEPT OF ATHEROSCLEROSIS Inflamation (Sargowo, 1996) 9 Free Radical ATHEROGENESIS (Sargowo, 1996) 10 IDENTIFYING THOSE AT RISK OF ATHEROTHROMBOSIS Yusuf S et al. Circulation 2001; 104: 2746–53. 2. Drouet L. Cerebrovasc Dis 2002;13(suppl 1):1–6. Lifestyle Smoking Diet Lack of exercise Genetic Genetic traits Gender Age Generalized disorders Obesity Diabetes Systemic conditions History of vascular events Hypertension Hyperlipidemia Hypercoagulable states Homocystinemia Local factors Elevated prothrombotic factors: fibrinogen, CRP, PAI-1 Blood flow patterns, vessel diameter, arterial wall structure Atherothrombosis manifestations (myocardial infarction, stroke, vascular death) 11 Arici. 2010 Risk Factors for Atherosclerosis Classic Hypertension, Hyper-lipidemia, DM, Smoking Uremia Related Increase ox-LDL, Free radicals, Uremic toxin Infection Bacterial and viral infection Proinflammatory cytokine release Endothelial dysfunction Systemic inflammatory respones Acute phase response Elevated CRP Binding LDL, cemplement activation, tissue factor secretion Accelerated ATHEROSCLEROSIS 12 LDL CD40L=CD40 ligand; TNF-α=tumor necrosis factor-alpha; IL=interleukin; VCAM=vascular cell adhesion molecule; ICAM=intercellular adhesion molecule. Cockerill GW et al. Arterioscler Thromb Vasc Biol. 1995;15:1987-1994; Andre P et al. Circulation. 2002;106:896-899; Libby P. Circulation. 2001;104:365-372; Libby P et al. Circulation. 2002;105:1135-1143; Ross R. N Engl J Med. 1999;340:115-126. Vessel lumen Monocyte Macrophage Adhesionmolecules (VCAM-1, ICAM-1) Inflammatory mediators (CRP, CD40/CD40L, TNF-α, IL-1, IL-6) Intima Foam cell INFLAMMATION PROMOTES PROGRESSION OF ATHEROSCLEROSIS Endothelium LDL Ox-LDL 13 14 Atherosclerosis is a fibroproliferative and inflammatory process occurring ins response to a variety of vascular insults The insults come from classical risk factors ( HT, dyslipidemia, endothelial dysfunction, smoking, menopause, diabetes etc) and novel risk factors (Hcy, LVH, Lp(a), TG, oxidative stress, fibrinogen etc) Endothelial dysfunction is regarded as the first abnormality leading to atherosclerosis This implies that modulation of endothelial function may be used as strategy to intervene the process. 15 Two theories gain more acceptance: (a) the lipid theory (b) inflammation theory Endothelial dysfunction is now regarded as the first abnormality leading to AS. More novel cardiovascular risk factors are known, e.g.: Fibrinogen b. PAI-1 Homocysteins d. AT-1 e. CRP f. Lp(a) g. small-dense LDL h. infectious agents i. and more are emerging 16 Acute Coronary Syndrome (endocrine viewpoints) atherosclerotic lesions vascular funtions b.1. inflammatory reaction b.2. thrombogeneity b.3. vasoreactivity b.4. plaque stability b.5. shoulder of plaque endothelium balance between c.1. vasodilating, antithrombotic, antiproliferative factors (NO, prostacyclin, C-natriuretic peptide, EDHF) c.2. vasoconstricting, prothrombotic, proliferative factors (ET, superoxide, thromoboxan A2) 17 NATURAL HISTORY OF CORONARY ATHEROSCLEROSIS Chatzizisis et all. JACC. 2007. Asymtomatic Stable Angina Acute Coronary Syndrome Early fibroatheroma Compensatory expansive remodeling Quiescent plaque Contrictive remodeling Stenotic plaque Exessive expansive remodeling Thin cap fibroatheroma Erosion Physiologic coronary artery Local factors, e.g. low ESS Systemic factors, e.g. hyperlipidemia Genetic factors Physiologic ESS Limited inflammation Fibroproliferation Microruptures 18 ATHEROSCLEROSIS IS AN INFLAMMATORY DISEASE Libby P. Circulation. 2001;104:365-372; Ross R. N Engl J Med. 1999;340:115-126. Monocyte LDL-C Adhesion molecule Macrophage Foam cell OxidizedLDL-C Plaque rupture Smooth muscle cells CRP Plaque instability and thrombus Oxidation Inflammation Endothelial dysfunction 19 20 Reverse Cholesterol Transport Monocyte CRP TXA2 PGI2 Thrombin LDL Platelets HDL HDL Ox-LDL MCP-1 Macrophage P-selectin CD 40L PDGF Foam cell MMP T cell E-selectins CD 40L VCAM-1 ICAM-1 IL-1 Reilly, et.all. 2005 21 THE ROLE OF Lp-PLA2 IN CHD LUMEN Monocytes Adhesion Molecules Oxidated LDL INTIMA MEDIA Lp-PLA2 Lyso-PC OxFA Cytokines Plaque Formation Foam Cell Macrophage 22 MC T T FC FC LDL Oxidation Lyso-PC Ox-chol Cytokines Cytokines ? C5a C’ MCP-1 F SMC
Slide 23 - 1 Nama : Prof. Dr. H. Djanggan Sargowo, dr., SpPD., SpJP(K), FIHA, FACC, FESC, FCAPC, FASCC Tempat/Tgl lahir : Sragen, 21 September 1947 Alamat : Wilis Indah E-10 Malang, Telp. 0341-552395 Pendidikan : Lulus Dokter dari UGM, tahun 1974 Lulus Cardiologist dari Univ. Indonesia, tahun 1983 Lulus Internist dari Univ. Airlangga, tahun 1986 Lulus Doktor, Univ. Airlangga, tahun 1996 Advanced Cardiology Course, Univ. Hongkong, tahun 1984 Senior Visiting Program, Institut Jantung Negara, Kualalumpur, 1996 Fellow American College of Cardiology (FACC), September 2006. Fellow Collage Asia Pacific Society of Cardiology (FCAPC), Desember 2007 Fellow European Sociaty of Cardiology (FESC), 2008 Fellow Asean Collage of Cardiology (FASCC), 2008 Jabatan : Dosen Pengajar Program Pascasarjana Universitas Brawijaya Ketua MKEK Ikatan Dokter Indonesia Cabang Malang Raya Ketua PERKI Cabang Malang Raya Anggota Kolegium Kardiovaskuler Indonesia Dekan Fak. Kedokteran Univ. Wijaya Kusuma Surabaya Ketua Dewan Pengawas Rumah Sakit Pendidikan Ketua Program Studi Kardiovascular Fak. Kedokteran Univ. Brawijaya Curriculum Vitae 2 Djanggan Sargowo Surabaya, 15 April 2012 INFLAMMATION IN ATHEROSCLEROSIS : FROM BENCH TO BEDSIDE 3 4 RUDOLF VIRCHOW Inflammation-based arterial changes as a mechanism of primary importance in atherogenesis mid 19th century Lamond, B. The American Journal of Pathology. 2008 5 Atherosclerosis Start from very young To Old age ? 6 Atherothrombosis* is aLeading Cause of Death Worldwide1† The World Health Report, 2002, WHO Geneva, 2002 28.7 17.8 12.6 9.1 6 5.1 0 5 10 15 20 25 30 Atherothrombosis* Infectious disease Cancer Injuries Pulmonary disease AIDS Mortality (%) * Ischemic heart disease, cerebrovascular disease, inflammatory heart disease and hypertensive heart disease † Worldwide defined as Member States by WHO Region (Africa, Americas, Eastern Mediterranean, European, South-East Asia and Western Pacific) 7 MAJOR CLINICAL MANIFESTATIONS OF ATHEROTHROMBOSIS Adapted from: Drouet L. Cerebrovasc Dis 2002; 13(suppl 1): 1–6. Transient ischemic attack Angina: Stable Unstable Ischemic stroke Myocardial infarction Peripheral arterial disease: Intermittent claudication Rest Pain Gangrene Necrosis 8  Dyslipidemia  Endothelial dysfunction  Free radicals  Immunologic Atherosclerosis/CAD THEORY AND CONCEPT OF ATHEROSCLEROSIS Inflamation (Sargowo, 1996) 9 Free Radical ATHEROGENESIS (Sargowo, 1996) 10 IDENTIFYING THOSE AT RISK OF ATHEROTHROMBOSIS Yusuf S et al. Circulation 2001; 104: 2746–53. 2. Drouet L. Cerebrovasc Dis 2002;13(suppl 1):1–6. Lifestyle Smoking Diet Lack of exercise Genetic Genetic traits Gender Age Generalized disorders Obesity Diabetes Systemic conditions History of vascular events Hypertension Hyperlipidemia Hypercoagulable states Homocystinemia Local factors Elevated prothrombotic factors: fibrinogen, CRP, PAI-1 Blood flow patterns, vessel diameter, arterial wall structure Atherothrombosis manifestations (myocardial infarction, stroke, vascular death) 11 Arici. 2010 Risk Factors for Atherosclerosis Classic Hypertension, Hyper-lipidemia, DM, Smoking Uremia Related Increase ox-LDL, Free radicals, Uremic toxin Infection Bacterial and viral infection Proinflammatory cytokine release Endothelial dysfunction Systemic inflammatory respones Acute phase response Elevated CRP Binding LDL, cemplement activation, tissue factor secretion Accelerated ATHEROSCLEROSIS 12 LDL CD40L=CD40 ligand; TNF-α=tumor necrosis factor-alpha; IL=interleukin; VCAM=vascular cell adhesion molecule; ICAM=intercellular adhesion molecule. Cockerill GW et al. Arterioscler Thromb Vasc Biol. 1995;15:1987-1994; Andre P et al. Circulation. 2002;106:896-899; Libby P. Circulation. 2001;104:365-372; Libby P et al. Circulation. 2002;105:1135-1143; Ross R. N Engl J Med. 1999;340:115-126. Vessel lumen Monocyte Macrophage Adhesionmolecules (VCAM-1, ICAM-1) Inflammatory mediators (CRP, CD40/CD40L, TNF-α, IL-1, IL-6) Intima Foam cell INFLAMMATION PROMOTES PROGRESSION OF ATHEROSCLEROSIS Endothelium LDL Ox-LDL 13 14 Atherosclerosis is a fibroproliferative and inflammatory process occurring ins response to a variety of vascular insults The insults come from classical risk factors ( HT, dyslipidemia, endothelial dysfunction, smoking, menopause, diabetes etc) and novel risk factors (Hcy, LVH, Lp(a), TG, oxidative stress, fibrinogen etc) Endothelial dysfunction is regarded as the first abnormality leading to atherosclerosis This implies that modulation of endothelial function may be used as strategy to intervene the process. 15 Two theories gain more acceptance: (a) the lipid theory (b) inflammation theory Endothelial dysfunction is now regarded as the first abnormality leading to AS. More novel cardiovascular risk factors are known, e.g.: Fibrinogen b. PAI-1 Homocysteins d. AT-1 e. CRP f. Lp(a) g. small-dense LDL h. infectious agents i. and more are emerging 16 Acute Coronary Syndrome (endocrine viewpoints) atherosclerotic lesions vascular funtions b.1. inflammatory reaction b.2. thrombogeneity b.3. vasoreactivity b.4. plaque stability b.5. shoulder of plaque endothelium balance between c.1. vasodilating, antithrombotic, antiproliferative factors (NO, prostacyclin, C-natriuretic peptide, EDHF) c.2. vasoconstricting, prothrombotic, proliferative factors (ET, superoxide, thromoboxan A2) 17 NATURAL HISTORY OF CORONARY ATHEROSCLEROSIS Chatzizisis et all. JACC. 2007. Asymtomatic Stable Angina Acute Coronary Syndrome Early fibroatheroma Compensatory expansive remodeling Quiescent plaque Contrictive remodeling Stenotic plaque Exessive expansive remodeling Thin cap fibroatheroma Erosion Physiologic coronary artery Local factors, e.g. low ESS Systemic factors, e.g. hyperlipidemia Genetic factors Physiologic ESS Limited inflammation Fibroproliferation Microruptures 18 ATHEROSCLEROSIS IS AN INFLAMMATORY DISEASE Libby P. Circulation. 2001;104:365-372; Ross R. N Engl J Med. 1999;340:115-126. Monocyte LDL-C Adhesion molecule Macrophage Foam cell OxidizedLDL-C Plaque rupture Smooth muscle cells CRP Plaque instability and thrombus Oxidation Inflammation Endothelial dysfunction 19 20 Reverse Cholesterol Transport Monocyte CRP TXA2 PGI2 Thrombin LDL Platelets HDL HDL Ox-LDL MCP-1 Macrophage P-selectin CD 40L PDGF Foam cell MMP T cell E-selectins CD 40L VCAM-1 ICAM-1 IL-1 Reilly, et.all. 2005 21 THE ROLE OF Lp-PLA2 IN CHD LUMEN Monocytes Adhesion Molecules Oxidated LDL INTIMA MEDIA Lp-PLA2 Lyso-PC OxFA Cytokines Plaque Formation Foam Cell Macrophage 22 MC T T FC FC LDL Oxidation Lyso-PC Ox-chol Cytokines Cytokines ? C5a C’ MCP-1 F SMC 23 Intracelluler proteolysis and fusion of LDL Figure : Proposed Dual Action of Exocytosed Mast Cell Granules (The Granule Remnants) of Lipoprotein Metabolism in The Arterial Intima
Slide 24 - 1 Nama : Prof. Dr. H. Djanggan Sargowo, dr., SpPD., SpJP(K), FIHA, FACC, FESC, FCAPC, FASCC Tempat/Tgl lahir : Sragen, 21 September 1947 Alamat : Wilis Indah E-10 Malang, Telp. 0341-552395 Pendidikan : Lulus Dokter dari UGM, tahun 1974 Lulus Cardiologist dari Univ. Indonesia, tahun 1983 Lulus Internist dari Univ. Airlangga, tahun 1986 Lulus Doktor, Univ. Airlangga, tahun 1996 Advanced Cardiology Course, Univ. Hongkong, tahun 1984 Senior Visiting Program, Institut Jantung Negara, Kualalumpur, 1996 Fellow American College of Cardiology (FACC), September 2006. Fellow Collage Asia Pacific Society of Cardiology (FCAPC), Desember 2007 Fellow European Sociaty of Cardiology (FESC), 2008 Fellow Asean Collage of Cardiology (FASCC), 2008 Jabatan : Dosen Pengajar Program Pascasarjana Universitas Brawijaya Ketua MKEK Ikatan Dokter Indonesia Cabang Malang Raya Ketua PERKI Cabang Malang Raya Anggota Kolegium Kardiovaskuler Indonesia Dekan Fak. Kedokteran Univ. Wijaya Kusuma Surabaya Ketua Dewan Pengawas Rumah Sakit Pendidikan Ketua Program Studi Kardiovascular Fak. Kedokteran Univ. Brawijaya Curriculum Vitae 2 Djanggan Sargowo Surabaya, 15 April 2012 INFLAMMATION IN ATHEROSCLEROSIS : FROM BENCH TO BEDSIDE 3 4 RUDOLF VIRCHOW Inflammation-based arterial changes as a mechanism of primary importance in atherogenesis mid 19th century Lamond, B. The American Journal of Pathology. 2008 5 Atherosclerosis Start from very young To Old age ? 6 Atherothrombosis* is aLeading Cause of Death Worldwide1† The World Health Report, 2002, WHO Geneva, 2002 28.7 17.8 12.6 9.1 6 5.1 0 5 10 15 20 25 30 Atherothrombosis* Infectious disease Cancer Injuries Pulmonary disease AIDS Mortality (%) * Ischemic heart disease, cerebrovascular disease, inflammatory heart disease and hypertensive heart disease † Worldwide defined as Member States by WHO Region (Africa, Americas, Eastern Mediterranean, European, South-East Asia and Western Pacific) 7 MAJOR CLINICAL MANIFESTATIONS OF ATHEROTHROMBOSIS Adapted from: Drouet L. Cerebrovasc Dis 2002; 13(suppl 1): 1–6. Transient ischemic attack Angina: Stable Unstable Ischemic stroke Myocardial infarction Peripheral arterial disease: Intermittent claudication Rest Pain Gangrene Necrosis 8  Dyslipidemia  Endothelial dysfunction  Free radicals  Immunologic Atherosclerosis/CAD THEORY AND CONCEPT OF ATHEROSCLEROSIS Inflamation (Sargowo, 1996) 9 Free Radical ATHEROGENESIS (Sargowo, 1996) 10 IDENTIFYING THOSE AT RISK OF ATHEROTHROMBOSIS Yusuf S et al. Circulation 2001; 104: 2746–53. 2. Drouet L. Cerebrovasc Dis 2002;13(suppl 1):1–6. Lifestyle Smoking Diet Lack of exercise Genetic Genetic traits Gender Age Generalized disorders Obesity Diabetes Systemic conditions History of vascular events Hypertension Hyperlipidemia Hypercoagulable states Homocystinemia Local factors Elevated prothrombotic factors: fibrinogen, CRP, PAI-1 Blood flow patterns, vessel diameter, arterial wall structure Atherothrombosis manifestations (myocardial infarction, stroke, vascular death) 11 Arici. 2010 Risk Factors for Atherosclerosis Classic Hypertension, Hyper-lipidemia, DM, Smoking Uremia Related Increase ox-LDL, Free radicals, Uremic toxin Infection Bacterial and viral infection Proinflammatory cytokine release Endothelial dysfunction Systemic inflammatory respones Acute phase response Elevated CRP Binding LDL, cemplement activation, tissue factor secretion Accelerated ATHEROSCLEROSIS 12 LDL CD40L=CD40 ligand; TNF-α=tumor necrosis factor-alpha; IL=interleukin; VCAM=vascular cell adhesion molecule; ICAM=intercellular adhesion molecule. Cockerill GW et al. Arterioscler Thromb Vasc Biol. 1995;15:1987-1994; Andre P et al. Circulation. 2002;106:896-899; Libby P. Circulation. 2001;104:365-372; Libby P et al. Circulation. 2002;105:1135-1143; Ross R. N Engl J Med. 1999;340:115-126. Vessel lumen Monocyte Macrophage Adhesionmolecules (VCAM-1, ICAM-1) Inflammatory mediators (CRP, CD40/CD40L, TNF-α, IL-1, IL-6) Intima Foam cell INFLAMMATION PROMOTES PROGRESSION OF ATHEROSCLEROSIS Endothelium LDL Ox-LDL 13 14 Atherosclerosis is a fibroproliferative and inflammatory process occurring ins response to a variety of vascular insults The insults come from classical risk factors ( HT, dyslipidemia, endothelial dysfunction, smoking, menopause, diabetes etc) and novel risk factors (Hcy, LVH, Lp(a), TG, oxidative stress, fibrinogen etc) Endothelial dysfunction is regarded as the first abnormality leading to atherosclerosis This implies that modulation of endothelial function may be used as strategy to intervene the process. 15 Two theories gain more acceptance: (a) the lipid theory (b) inflammation theory Endothelial dysfunction is now regarded as the first abnormality leading to AS. More novel cardiovascular risk factors are known, e.g.: Fibrinogen b. PAI-1 Homocysteins d. AT-1 e. CRP f. Lp(a) g. small-dense LDL h. infectious agents i. and more are emerging 16 Acute Coronary Syndrome (endocrine viewpoints) atherosclerotic lesions vascular funtions b.1. inflammatory reaction b.2. thrombogeneity b.3. vasoreactivity b.4. plaque stability b.5. shoulder of plaque endothelium balance between c.1. vasodilating, antithrombotic, antiproliferative factors (NO, prostacyclin, C-natriuretic peptide, EDHF) c.2. vasoconstricting, prothrombotic, proliferative factors (ET, superoxide, thromoboxan A2) 17 NATURAL HISTORY OF CORONARY ATHEROSCLEROSIS Chatzizisis et all. JACC. 2007. Asymtomatic Stable Angina Acute Coronary Syndrome Early fibroatheroma Compensatory expansive remodeling Quiescent plaque Contrictive remodeling Stenotic plaque Exessive expansive remodeling Thin cap fibroatheroma Erosion Physiologic coronary artery Local factors, e.g. low ESS Systemic factors, e.g. hyperlipidemia Genetic factors Physiologic ESS Limited inflammation Fibroproliferation Microruptures 18 ATHEROSCLEROSIS IS AN INFLAMMATORY DISEASE Libby P. Circulation. 2001;104:365-372; Ross R. N Engl J Med. 1999;340:115-126. Monocyte LDL-C Adhesion molecule Macrophage Foam cell OxidizedLDL-C Plaque rupture Smooth muscle cells CRP Plaque instability and thrombus Oxidation Inflammation Endothelial dysfunction 19 20 Reverse Cholesterol Transport Monocyte CRP TXA2 PGI2 Thrombin LDL Platelets HDL HDL Ox-LDL MCP-1 Macrophage P-selectin CD 40L PDGF Foam cell MMP T cell E-selectins CD 40L VCAM-1 ICAM-1 IL-1 Reilly, et.all. 2005 21 THE ROLE OF Lp-PLA2 IN CHD LUMEN Monocytes Adhesion Molecules Oxidated LDL INTIMA MEDIA Lp-PLA2 Lyso-PC OxFA Cytokines Plaque Formation Foam Cell Macrophage 22 MC T T FC FC LDL Oxidation Lyso-PC Ox-chol Cytokines Cytokines ? C5a C’ MCP-1 F SMC 23 Intracelluler proteolysis and fusion of LDL Figure : Proposed Dual Action of Exocytosed Mast Cell Granules (The Granule Remnants) of Lipoprotein Metabolism in The Arterial Intima 24 HSCRP
Slide 25 - 1 Nama : Prof. Dr. H. Djanggan Sargowo, dr., SpPD., SpJP(K), FIHA, FACC, FESC, FCAPC, FASCC Tempat/Tgl lahir : Sragen, 21 September 1947 Alamat : Wilis Indah E-10 Malang, Telp. 0341-552395 Pendidikan : Lulus Dokter dari UGM, tahun 1974 Lulus Cardiologist dari Univ. Indonesia, tahun 1983 Lulus Internist dari Univ. Airlangga, tahun 1986 Lulus Doktor, Univ. Airlangga, tahun 1996 Advanced Cardiology Course, Univ. Hongkong, tahun 1984 Senior Visiting Program, Institut Jantung Negara, Kualalumpur, 1996 Fellow American College of Cardiology (FACC), September 2006. Fellow Collage Asia Pacific Society of Cardiology (FCAPC), Desember 2007 Fellow European Sociaty of Cardiology (FESC), 2008 Fellow Asean Collage of Cardiology (FASCC), 2008 Jabatan : Dosen Pengajar Program Pascasarjana Universitas Brawijaya Ketua MKEK Ikatan Dokter Indonesia Cabang Malang Raya Ketua PERKI Cabang Malang Raya Anggota Kolegium Kardiovaskuler Indonesia Dekan Fak. Kedokteran Univ. Wijaya Kusuma Surabaya Ketua Dewan Pengawas Rumah Sakit Pendidikan Ketua Program Studi Kardiovascular Fak. Kedokteran Univ. Brawijaya Curriculum Vitae 2 Djanggan Sargowo Surabaya, 15 April 2012 INFLAMMATION IN ATHEROSCLEROSIS : FROM BENCH TO BEDSIDE 3 4 RUDOLF VIRCHOW Inflammation-based arterial changes as a mechanism of primary importance in atherogenesis mid 19th century Lamond, B. The American Journal of Pathology. 2008 5 Atherosclerosis Start from very young To Old age ? 6 Atherothrombosis* is aLeading Cause of Death Worldwide1† The World Health Report, 2002, WHO Geneva, 2002 28.7 17.8 12.6 9.1 6 5.1 0 5 10 15 20 25 30 Atherothrombosis* Infectious disease Cancer Injuries Pulmonary disease AIDS Mortality (%) * Ischemic heart disease, cerebrovascular disease, inflammatory heart disease and hypertensive heart disease † Worldwide defined as Member States by WHO Region (Africa, Americas, Eastern Mediterranean, European, South-East Asia and Western Pacific) 7 MAJOR CLINICAL MANIFESTATIONS OF ATHEROTHROMBOSIS Adapted from: Drouet L. Cerebrovasc Dis 2002; 13(suppl 1): 1–6. Transient ischemic attack Angina: Stable Unstable Ischemic stroke Myocardial infarction Peripheral arterial disease: Intermittent claudication Rest Pain Gangrene Necrosis 8  Dyslipidemia  Endothelial dysfunction  Free radicals  Immunologic Atherosclerosis/CAD THEORY AND CONCEPT OF ATHEROSCLEROSIS Inflamation (Sargowo, 1996) 9 Free Radical ATHEROGENESIS (Sargowo, 1996) 10 IDENTIFYING THOSE AT RISK OF ATHEROTHROMBOSIS Yusuf S et al. Circulation 2001; 104: 2746–53. 2. Drouet L. Cerebrovasc Dis 2002;13(suppl 1):1–6. Lifestyle Smoking Diet Lack of exercise Genetic Genetic traits Gender Age Generalized disorders Obesity Diabetes Systemic conditions History of vascular events Hypertension Hyperlipidemia Hypercoagulable states Homocystinemia Local factors Elevated prothrombotic factors: fibrinogen, CRP, PAI-1 Blood flow patterns, vessel diameter, arterial wall structure Atherothrombosis manifestations (myocardial infarction, stroke, vascular death) 11 Arici. 2010 Risk Factors for Atherosclerosis Classic Hypertension, Hyper-lipidemia, DM, Smoking Uremia Related Increase ox-LDL, Free radicals, Uremic toxin Infection Bacterial and viral infection Proinflammatory cytokine release Endothelial dysfunction Systemic inflammatory respones Acute phase response Elevated CRP Binding LDL, cemplement activation, tissue factor secretion Accelerated ATHEROSCLEROSIS 12 LDL CD40L=CD40 ligand; TNF-α=tumor necrosis factor-alpha; IL=interleukin; VCAM=vascular cell adhesion molecule; ICAM=intercellular adhesion molecule. Cockerill GW et al. Arterioscler Thromb Vasc Biol. 1995;15:1987-1994; Andre P et al. Circulation. 2002;106:896-899; Libby P. Circulation. 2001;104:365-372; Libby P et al. Circulation. 2002;105:1135-1143; Ross R. N Engl J Med. 1999;340:115-126. Vessel lumen Monocyte Macrophage Adhesionmolecules (VCAM-1, ICAM-1) Inflammatory mediators (CRP, CD40/CD40L, TNF-α, IL-1, IL-6) Intima Foam cell INFLAMMATION PROMOTES PROGRESSION OF ATHEROSCLEROSIS Endothelium LDL Ox-LDL 13 14 Atherosclerosis is a fibroproliferative and inflammatory process occurring ins response to a variety of vascular insults The insults come from classical risk factors ( HT, dyslipidemia, endothelial dysfunction, smoking, menopause, diabetes etc) and novel risk factors (Hcy, LVH, Lp(a), TG, oxidative stress, fibrinogen etc) Endothelial dysfunction is regarded as the first abnormality leading to atherosclerosis This implies that modulation of endothelial function may be used as strategy to intervene the process. 15 Two theories gain more acceptance: (a) the lipid theory (b) inflammation theory Endothelial dysfunction is now regarded as the first abnormality leading to AS. More novel cardiovascular risk factors are known, e.g.: Fibrinogen b. PAI-1 Homocysteins d. AT-1 e. CRP f. Lp(a) g. small-dense LDL h. infectious agents i. and more are emerging 16 Acute Coronary Syndrome (endocrine viewpoints) atherosclerotic lesions vascular funtions b.1. inflammatory reaction b.2. thrombogeneity b.3. vasoreactivity b.4. plaque stability b.5. shoulder of plaque endothelium balance between c.1. vasodilating, antithrombotic, antiproliferative factors (NO, prostacyclin, C-natriuretic peptide, EDHF) c.2. vasoconstricting, prothrombotic, proliferative factors (ET, superoxide, thromoboxan A2) 17 NATURAL HISTORY OF CORONARY ATHEROSCLEROSIS Chatzizisis et all. JACC. 2007. Asymtomatic Stable Angina Acute Coronary Syndrome Early fibroatheroma Compensatory expansive remodeling Quiescent plaque Contrictive remodeling Stenotic plaque Exessive expansive remodeling Thin cap fibroatheroma Erosion Physiologic coronary artery Local factors, e.g. low ESS Systemic factors, e.g. hyperlipidemia Genetic factors Physiologic ESS Limited inflammation Fibroproliferation Microruptures 18 ATHEROSCLEROSIS IS AN INFLAMMATORY DISEASE Libby P. Circulation. 2001;104:365-372; Ross R. N Engl J Med. 1999;340:115-126. Monocyte LDL-C Adhesion molecule Macrophage Foam cell OxidizedLDL-C Plaque rupture Smooth muscle cells CRP Plaque instability and thrombus Oxidation Inflammation Endothelial dysfunction 19 20 Reverse Cholesterol Transport Monocyte CRP TXA2 PGI2 Thrombin LDL Platelets HDL HDL Ox-LDL MCP-1 Macrophage P-selectin CD 40L PDGF Foam cell MMP T cell E-selectins CD 40L VCAM-1 ICAM-1 IL-1 Reilly, et.all. 2005 21 THE ROLE OF Lp-PLA2 IN CHD LUMEN Monocytes Adhesion Molecules Oxidated LDL INTIMA MEDIA Lp-PLA2 Lyso-PC OxFA Cytokines Plaque Formation Foam Cell Macrophage 22 MC T T FC FC LDL Oxidation Lyso-PC Ox-chol Cytokines Cytokines ? C5a C’ MCP-1 F SMC 23 Intracelluler proteolysis and fusion of LDL Figure : Proposed Dual Action of Exocytosed Mast Cell Granules (The Granule Remnants) of Lipoprotein Metabolism in The Arterial Intima 24 HSCRP 25
Slide 26 - 1 Nama : Prof. Dr. H. Djanggan Sargowo, dr., SpPD., SpJP(K), FIHA, FACC, FESC, FCAPC, FASCC Tempat/Tgl lahir : Sragen, 21 September 1947 Alamat : Wilis Indah E-10 Malang, Telp. 0341-552395 Pendidikan : Lulus Dokter dari UGM, tahun 1974 Lulus Cardiologist dari Univ. Indonesia, tahun 1983 Lulus Internist dari Univ. Airlangga, tahun 1986 Lulus Doktor, Univ. Airlangga, tahun 1996 Advanced Cardiology Course, Univ. Hongkong, tahun 1984 Senior Visiting Program, Institut Jantung Negara, Kualalumpur, 1996 Fellow American College of Cardiology (FACC), September 2006. Fellow Collage Asia Pacific Society of Cardiology (FCAPC), Desember 2007 Fellow European Sociaty of Cardiology (FESC), 2008 Fellow Asean Collage of Cardiology (FASCC), 2008 Jabatan : Dosen Pengajar Program Pascasarjana Universitas Brawijaya Ketua MKEK Ikatan Dokter Indonesia Cabang Malang Raya Ketua PERKI Cabang Malang Raya Anggota Kolegium Kardiovaskuler Indonesia Dekan Fak. Kedokteran Univ. Wijaya Kusuma Surabaya Ketua Dewan Pengawas Rumah Sakit Pendidikan Ketua Program Studi Kardiovascular Fak. Kedokteran Univ. Brawijaya Curriculum Vitae 2 Djanggan Sargowo Surabaya, 15 April 2012 INFLAMMATION IN ATHEROSCLEROSIS : FROM BENCH TO BEDSIDE 3 4 RUDOLF VIRCHOW Inflammation-based arterial changes as a mechanism of primary importance in atherogenesis mid 19th century Lamond, B. The American Journal of Pathology. 2008 5 Atherosclerosis Start from very young To Old age ? 6 Atherothrombosis* is aLeading Cause of Death Worldwide1† The World Health Report, 2002, WHO Geneva, 2002 28.7 17.8 12.6 9.1 6 5.1 0 5 10 15 20 25 30 Atherothrombosis* Infectious disease Cancer Injuries Pulmonary disease AIDS Mortality (%) * Ischemic heart disease, cerebrovascular disease, inflammatory heart disease and hypertensive heart disease † Worldwide defined as Member States by WHO Region (Africa, Americas, Eastern Mediterranean, European, South-East Asia and Western Pacific) 7 MAJOR CLINICAL MANIFESTATIONS OF ATHEROTHROMBOSIS Adapted from: Drouet L. Cerebrovasc Dis 2002; 13(suppl 1): 1–6. Transient ischemic attack Angina: Stable Unstable Ischemic stroke Myocardial infarction Peripheral arterial disease: Intermittent claudication Rest Pain Gangrene Necrosis 8  Dyslipidemia  Endothelial dysfunction  Free radicals  Immunologic Atherosclerosis/CAD THEORY AND CONCEPT OF ATHEROSCLEROSIS Inflamation (Sargowo, 1996) 9 Free Radical ATHEROGENESIS (Sargowo, 1996) 10 IDENTIFYING THOSE AT RISK OF ATHEROTHROMBOSIS Yusuf S et al. Circulation 2001; 104: 2746–53. 2. Drouet L. Cerebrovasc Dis 2002;13(suppl 1):1–6. Lifestyle Smoking Diet Lack of exercise Genetic Genetic traits Gender Age Generalized disorders Obesity Diabetes Systemic conditions History of vascular events Hypertension Hyperlipidemia Hypercoagulable states Homocystinemia Local factors Elevated prothrombotic factors: fibrinogen, CRP, PAI-1 Blood flow patterns, vessel diameter, arterial wall structure Atherothrombosis manifestations (myocardial infarction, stroke, vascular death) 11 Arici. 2010 Risk Factors for Atherosclerosis Classic Hypertension, Hyper-lipidemia, DM, Smoking Uremia Related Increase ox-LDL, Free radicals, Uremic toxin Infection Bacterial and viral infection Proinflammatory cytokine release Endothelial dysfunction Systemic inflammatory respones Acute phase response Elevated CRP Binding LDL, cemplement activation, tissue factor secretion Accelerated ATHEROSCLEROSIS 12 LDL CD40L=CD40 ligand; TNF-α=tumor necrosis factor-alpha; IL=interleukin; VCAM=vascular cell adhesion molecule; ICAM=intercellular adhesion molecule. Cockerill GW et al. Arterioscler Thromb Vasc Biol. 1995;15:1987-1994; Andre P et al. Circulation. 2002;106:896-899; Libby P. Circulation. 2001;104:365-372; Libby P et al. Circulation. 2002;105:1135-1143; Ross R. N Engl J Med. 1999;340:115-126. Vessel lumen Monocyte Macrophage Adhesionmolecules (VCAM-1, ICAM-1) Inflammatory mediators (CRP, CD40/CD40L, TNF-α, IL-1, IL-6) Intima Foam cell INFLAMMATION PROMOTES PROGRESSION OF ATHEROSCLEROSIS Endothelium LDL Ox-LDL 13 14 Atherosclerosis is a fibroproliferative and inflammatory process occurring ins response to a variety of vascular insults The insults come from classical risk factors ( HT, dyslipidemia, endothelial dysfunction, smoking, menopause, diabetes etc) and novel risk factors (Hcy, LVH, Lp(a), TG, oxidative stress, fibrinogen etc) Endothelial dysfunction is regarded as the first abnormality leading to atherosclerosis This implies that modulation of endothelial function may be used as strategy to intervene the process. 15 Two theories gain more acceptance: (a) the lipid theory (b) inflammation theory Endothelial dysfunction is now regarded as the first abnormality leading to AS. More novel cardiovascular risk factors are known, e.g.: Fibrinogen b. PAI-1 Homocysteins d. AT-1 e. CRP f. Lp(a) g. small-dense LDL h. infectious agents i. and more are emerging 16 Acute Coronary Syndrome (endocrine viewpoints) atherosclerotic lesions vascular funtions b.1. inflammatory reaction b.2. thrombogeneity b.3. vasoreactivity b.4. plaque stability b.5. shoulder of plaque endothelium balance between c.1. vasodilating, antithrombotic, antiproliferative factors (NO, prostacyclin, C-natriuretic peptide, EDHF) c.2. vasoconstricting, prothrombotic, proliferative factors (ET, superoxide, thromoboxan A2) 17 NATURAL HISTORY OF CORONARY ATHEROSCLEROSIS Chatzizisis et all. JACC. 2007. Asymtomatic Stable Angina Acute Coronary Syndrome Early fibroatheroma Compensatory expansive remodeling Quiescent plaque Contrictive remodeling Stenotic plaque Exessive expansive remodeling Thin cap fibroatheroma Erosion Physiologic coronary artery Local factors, e.g. low ESS Systemic factors, e.g. hyperlipidemia Genetic factors Physiologic ESS Limited inflammation Fibroproliferation Microruptures 18 ATHEROSCLEROSIS IS AN INFLAMMATORY DISEASE Libby P. Circulation. 2001;104:365-372; Ross R. N Engl J Med. 1999;340:115-126. Monocyte LDL-C Adhesion molecule Macrophage Foam cell OxidizedLDL-C Plaque rupture Smooth muscle cells CRP Plaque instability and thrombus Oxidation Inflammation Endothelial dysfunction 19 20 Reverse Cholesterol Transport Monocyte CRP TXA2 PGI2 Thrombin LDL Platelets HDL HDL Ox-LDL MCP-1 Macrophage P-selectin CD 40L PDGF Foam cell MMP T cell E-selectins CD 40L VCAM-1 ICAM-1 IL-1 Reilly, et.all. 2005 21 THE ROLE OF Lp-PLA2 IN CHD LUMEN Monocytes Adhesion Molecules Oxidated LDL INTIMA MEDIA Lp-PLA2 Lyso-PC OxFA Cytokines Plaque Formation Foam Cell Macrophage 22 MC T T FC FC LDL Oxidation Lyso-PC Ox-chol Cytokines Cytokines ? C5a C’ MCP-1 F SMC 23 Intracelluler proteolysis and fusion of LDL Figure : Proposed Dual Action of Exocytosed Mast Cell Granules (The Granule Remnants) of Lipoprotein Metabolism in The Arterial Intima 24 HSCRP 25 26 GM-CSF VCAM-1 MPC-1 Transcription Factors : Endothelial Cell Pro-inflammatory Genes Oxidative Stress NF-xB AP-1 Leucocyte infiltration / activation Plaque Rupture Gibbons, 97 LEUCOCYTE ACTIVATION IN ATHEROGENESIS : IMPLICATIONS FOR ACUTE ISCHEMIC SYNDROMES
Slide 27 - 1 Nama : Prof. Dr. H. Djanggan Sargowo, dr., SpPD., SpJP(K), FIHA, FACC, FESC, FCAPC, FASCC Tempat/Tgl lahir : Sragen, 21 September 1947 Alamat : Wilis Indah E-10 Malang, Telp. 0341-552395 Pendidikan : Lulus Dokter dari UGM, tahun 1974 Lulus Cardiologist dari Univ. Indonesia, tahun 1983 Lulus Internist dari Univ. Airlangga, tahun 1986 Lulus Doktor, Univ. Airlangga, tahun 1996 Advanced Cardiology Course, Univ. Hongkong, tahun 1984 Senior Visiting Program, Institut Jantung Negara, Kualalumpur, 1996 Fellow American College of Cardiology (FACC), September 2006. Fellow Collage Asia Pacific Society of Cardiology (FCAPC), Desember 2007 Fellow European Sociaty of Cardiology (FESC), 2008 Fellow Asean Collage of Cardiology (FASCC), 2008 Jabatan : Dosen Pengajar Program Pascasarjana Universitas Brawijaya Ketua MKEK Ikatan Dokter Indonesia Cabang Malang Raya Ketua PERKI Cabang Malang Raya Anggota Kolegium Kardiovaskuler Indonesia Dekan Fak. Kedokteran Univ. Wijaya Kusuma Surabaya Ketua Dewan Pengawas Rumah Sakit Pendidikan Ketua Program Studi Kardiovascular Fak. Kedokteran Univ. Brawijaya Curriculum Vitae 2 Djanggan Sargowo Surabaya, 15 April 2012 INFLAMMATION IN ATHEROSCLEROSIS : FROM BENCH TO BEDSIDE 3 4 RUDOLF VIRCHOW Inflammation-based arterial changes as a mechanism of primary importance in atherogenesis mid 19th century Lamond, B. The American Journal of Pathology. 2008 5 Atherosclerosis Start from very young To Old age ? 6 Atherothrombosis* is aLeading Cause of Death Worldwide1† The World Health Report, 2002, WHO Geneva, 2002 28.7 17.8 12.6 9.1 6 5.1 0 5 10 15 20 25 30 Atherothrombosis* Infectious disease Cancer Injuries Pulmonary disease AIDS Mortality (%) * Ischemic heart disease, cerebrovascular disease, inflammatory heart disease and hypertensive heart disease † Worldwide defined as Member States by WHO Region (Africa, Americas, Eastern Mediterranean, European, South-East Asia and Western Pacific) 7 MAJOR CLINICAL MANIFESTATIONS OF ATHEROTHROMBOSIS Adapted from: Drouet L. Cerebrovasc Dis 2002; 13(suppl 1): 1–6. Transient ischemic attack Angina: Stable Unstable Ischemic stroke Myocardial infarction Peripheral arterial disease: Intermittent claudication Rest Pain Gangrene Necrosis 8  Dyslipidemia  Endothelial dysfunction  Free radicals  Immunologic Atherosclerosis/CAD THEORY AND CONCEPT OF ATHEROSCLEROSIS Inflamation (Sargowo, 1996) 9 Free Radical ATHEROGENESIS (Sargowo, 1996) 10 IDENTIFYING THOSE AT RISK OF ATHEROTHROMBOSIS Yusuf S et al. Circulation 2001; 104: 2746–53. 2. Drouet L. Cerebrovasc Dis 2002;13(suppl 1):1–6. Lifestyle Smoking Diet Lack of exercise Genetic Genetic traits Gender Age Generalized disorders Obesity Diabetes Systemic conditions History of vascular events Hypertension Hyperlipidemia Hypercoagulable states Homocystinemia Local factors Elevated prothrombotic factors: fibrinogen, CRP, PAI-1 Blood flow patterns, vessel diameter, arterial wall structure Atherothrombosis manifestations (myocardial infarction, stroke, vascular death) 11 Arici. 2010 Risk Factors for Atherosclerosis Classic Hypertension, Hyper-lipidemia, DM, Smoking Uremia Related Increase ox-LDL, Free radicals, Uremic toxin Infection Bacterial and viral infection Proinflammatory cytokine release Endothelial dysfunction Systemic inflammatory respones Acute phase response Elevated CRP Binding LDL, cemplement activation, tissue factor secretion Accelerated ATHEROSCLEROSIS 12 LDL CD40L=CD40 ligand; TNF-α=tumor necrosis factor-alpha; IL=interleukin; VCAM=vascular cell adhesion molecule; ICAM=intercellular adhesion molecule. Cockerill GW et al. Arterioscler Thromb Vasc Biol. 1995;15:1987-1994; Andre P et al. Circulation. 2002;106:896-899; Libby P. Circulation. 2001;104:365-372; Libby P et al. Circulation. 2002;105:1135-1143; Ross R. N Engl J Med. 1999;340:115-126. Vessel lumen Monocyte Macrophage Adhesionmolecules (VCAM-1, ICAM-1) Inflammatory mediators (CRP, CD40/CD40L, TNF-α, IL-1, IL-6) Intima Foam cell INFLAMMATION PROMOTES PROGRESSION OF ATHEROSCLEROSIS Endothelium LDL Ox-LDL 13 14 Atherosclerosis is a fibroproliferative and inflammatory process occurring ins response to a variety of vascular insults The insults come from classical risk factors ( HT, dyslipidemia, endothelial dysfunction, smoking, menopause, diabetes etc) and novel risk factors (Hcy, LVH, Lp(a), TG, oxidative stress, fibrinogen etc) Endothelial dysfunction is regarded as the first abnormality leading to atherosclerosis This implies that modulation of endothelial function may be used as strategy to intervene the process. 15 Two theories gain more acceptance: (a) the lipid theory (b) inflammation theory Endothelial dysfunction is now regarded as the first abnormality leading to AS. More novel cardiovascular risk factors are known, e.g.: Fibrinogen b. PAI-1 Homocysteins d. AT-1 e. CRP f. Lp(a) g. small-dense LDL h. infectious agents i. and more are emerging 16 Acute Coronary Syndrome (endocrine viewpoints) atherosclerotic lesions vascular funtions b.1. inflammatory reaction b.2. thrombogeneity b.3. vasoreactivity b.4. plaque stability b.5. shoulder of plaque endothelium balance between c.1. vasodilating, antithrombotic, antiproliferative factors (NO, prostacyclin, C-natriuretic peptide, EDHF) c.2. vasoconstricting, prothrombotic, proliferative factors (ET, superoxide, thromoboxan A2) 17 NATURAL HISTORY OF CORONARY ATHEROSCLEROSIS Chatzizisis et all. JACC. 2007. Asymtomatic Stable Angina Acute Coronary Syndrome Early fibroatheroma Compensatory expansive remodeling Quiescent plaque Contrictive remodeling Stenotic plaque Exessive expansive remodeling Thin cap fibroatheroma Erosion Physiologic coronary artery Local factors, e.g. low ESS Systemic factors, e.g. hyperlipidemia Genetic factors Physiologic ESS Limited inflammation Fibroproliferation Microruptures 18 ATHEROSCLEROSIS IS AN INFLAMMATORY DISEASE Libby P. Circulation. 2001;104:365-372; Ross R. N Engl J Med. 1999;340:115-126. Monocyte LDL-C Adhesion molecule Macrophage Foam cell OxidizedLDL-C Plaque rupture Smooth muscle cells CRP Plaque instability and thrombus Oxidation Inflammation Endothelial dysfunction 19 20 Reverse Cholesterol Transport Monocyte CRP TXA2 PGI2 Thrombin LDL Platelets HDL HDL Ox-LDL MCP-1 Macrophage P-selectin CD 40L PDGF Foam cell MMP T cell E-selectins CD 40L VCAM-1 ICAM-1 IL-1 Reilly, et.all. 2005 21 THE ROLE OF Lp-PLA2 IN CHD LUMEN Monocytes Adhesion Molecules Oxidated LDL INTIMA MEDIA Lp-PLA2 Lyso-PC OxFA Cytokines Plaque Formation Foam Cell Macrophage 22 MC T T FC FC LDL Oxidation Lyso-PC Ox-chol Cytokines Cytokines ? C5a C’ MCP-1 F SMC 23 Intracelluler proteolysis and fusion of LDL Figure : Proposed Dual Action of Exocytosed Mast Cell Granules (The Granule Remnants) of Lipoprotein Metabolism in The Arterial Intima 24 HSCRP 25 26 GM-CSF VCAM-1 MPC-1 Transcription Factors : Endothelial Cell Pro-inflammatory Genes Oxidative Stress NF-xB AP-1 Leucocyte infiltration / activation Plaque Rupture Gibbons, 97 LEUCOCYTE ACTIVATION IN ATHEROGENESIS : IMPLICATIONS FOR ACUTE ISCHEMIC SYNDROMES 27 p38 c-Jun activation Caspases Apoptosis NIK ? ? MEKK1?   CKII IKK complex TNFR-1 TNFR-1 IL-1R Shear stress p65 p50 CBP/p300 Gene activation p65 p50 IB pKAc IB Ub Target genes : - IL-1, IL-8, IL-6, IFN  - TNF, MCP-1 - CSFs, c-myc - VCAM-1, ICAM-1, E-selectin - Tissue factor - Survival factor Thurberg and Collins : Curr Opin Lipidol 9:387-396,1998 Ub Ox-LDL ROIs ??? Lipid peroxides ? H2O2 Ubiquitination and proteosome degradation T R A D D R I P F A D D R I P T R A D D T R A F 2 T R A F 6
Slide 28 - 1 Nama : Prof. Dr. H. Djanggan Sargowo, dr., SpPD., SpJP(K), FIHA, FACC, FESC, FCAPC, FASCC Tempat/Tgl lahir : Sragen, 21 September 1947 Alamat : Wilis Indah E-10 Malang, Telp. 0341-552395 Pendidikan : Lulus Dokter dari UGM, tahun 1974 Lulus Cardiologist dari Univ. Indonesia, tahun 1983 Lulus Internist dari Univ. Airlangga, tahun 1986 Lulus Doktor, Univ. Airlangga, tahun 1996 Advanced Cardiology Course, Univ. Hongkong, tahun 1984 Senior Visiting Program, Institut Jantung Negara, Kualalumpur, 1996 Fellow American College of Cardiology (FACC), September 2006. Fellow Collage Asia Pacific Society of Cardiology (FCAPC), Desember 2007 Fellow European Sociaty of Cardiology (FESC), 2008 Fellow Asean Collage of Cardiology (FASCC), 2008 Jabatan : Dosen Pengajar Program Pascasarjana Universitas Brawijaya Ketua MKEK Ikatan Dokter Indonesia Cabang Malang Raya Ketua PERKI Cabang Malang Raya Anggota Kolegium Kardiovaskuler Indonesia Dekan Fak. Kedokteran Univ. Wijaya Kusuma Surabaya Ketua Dewan Pengawas Rumah Sakit Pendidikan Ketua Program Studi Kardiovascular Fak. Kedokteran Univ. Brawijaya Curriculum Vitae 2 Djanggan Sargowo Surabaya, 15 April 2012 INFLAMMATION IN ATHEROSCLEROSIS : FROM BENCH TO BEDSIDE 3 4 RUDOLF VIRCHOW Inflammation-based arterial changes as a mechanism of primary importance in atherogenesis mid 19th century Lamond, B. The American Journal of Pathology. 2008 5 Atherosclerosis Start from very young To Old age ? 6 Atherothrombosis* is aLeading Cause of Death Worldwide1† The World Health Report, 2002, WHO Geneva, 2002 28.7 17.8 12.6 9.1 6 5.1 0 5 10 15 20 25 30 Atherothrombosis* Infectious disease Cancer Injuries Pulmonary disease AIDS Mortality (%) * Ischemic heart disease, cerebrovascular disease, inflammatory heart disease and hypertensive heart disease † Worldwide defined as Member States by WHO Region (Africa, Americas, Eastern Mediterranean, European, South-East Asia and Western Pacific) 7 MAJOR CLINICAL MANIFESTATIONS OF ATHEROTHROMBOSIS Adapted from: Drouet L. Cerebrovasc Dis 2002; 13(suppl 1): 1–6. Transient ischemic attack Angina: Stable Unstable Ischemic stroke Myocardial infarction Peripheral arterial disease: Intermittent claudication Rest Pain Gangrene Necrosis 8  Dyslipidemia  Endothelial dysfunction  Free radicals  Immunologic Atherosclerosis/CAD THEORY AND CONCEPT OF ATHEROSCLEROSIS Inflamation (Sargowo, 1996) 9 Free Radical ATHEROGENESIS (Sargowo, 1996) 10 IDENTIFYING THOSE AT RISK OF ATHEROTHROMBOSIS Yusuf S et al. Circulation 2001; 104: 2746–53. 2. Drouet L. Cerebrovasc Dis 2002;13(suppl 1):1–6. Lifestyle Smoking Diet Lack of exercise Genetic Genetic traits Gender Age Generalized disorders Obesity Diabetes Systemic conditions History of vascular events Hypertension Hyperlipidemia Hypercoagulable states Homocystinemia Local factors Elevated prothrombotic factors: fibrinogen, CRP, PAI-1 Blood flow patterns, vessel diameter, arterial wall structure Atherothrombosis manifestations (myocardial infarction, stroke, vascular death) 11 Arici. 2010 Risk Factors for Atherosclerosis Classic Hypertension, Hyper-lipidemia, DM, Smoking Uremia Related Increase ox-LDL, Free radicals, Uremic toxin Infection Bacterial and viral infection Proinflammatory cytokine release Endothelial dysfunction Systemic inflammatory respones Acute phase response Elevated CRP Binding LDL, cemplement activation, tissue factor secretion Accelerated ATHEROSCLEROSIS 12 LDL CD40L=CD40 ligand; TNF-α=tumor necrosis factor-alpha; IL=interleukin; VCAM=vascular cell adhesion molecule; ICAM=intercellular adhesion molecule. Cockerill GW et al. Arterioscler Thromb Vasc Biol. 1995;15:1987-1994; Andre P et al. Circulation. 2002;106:896-899; Libby P. Circulation. 2001;104:365-372; Libby P et al. Circulation. 2002;105:1135-1143; Ross R. N Engl J Med. 1999;340:115-126. Vessel lumen Monocyte Macrophage Adhesionmolecules (VCAM-1, ICAM-1) Inflammatory mediators (CRP, CD40/CD40L, TNF-α, IL-1, IL-6) Intima Foam cell INFLAMMATION PROMOTES PROGRESSION OF ATHEROSCLEROSIS Endothelium LDL Ox-LDL 13 14 Atherosclerosis is a fibroproliferative and inflammatory process occurring ins response to a variety of vascular insults The insults come from classical risk factors ( HT, dyslipidemia, endothelial dysfunction, smoking, menopause, diabetes etc) and novel risk factors (Hcy, LVH, Lp(a), TG, oxidative stress, fibrinogen etc) Endothelial dysfunction is regarded as the first abnormality leading to atherosclerosis This implies that modulation of endothelial function may be used as strategy to intervene the process. 15 Two theories gain more acceptance: (a) the lipid theory (b) inflammation theory Endothelial dysfunction is now regarded as the first abnormality leading to AS. More novel cardiovascular risk factors are known, e.g.: Fibrinogen b. PAI-1 Homocysteins d. AT-1 e. CRP f. Lp(a) g. small-dense LDL h. infectious agents i. and more are emerging 16 Acute Coronary Syndrome (endocrine viewpoints) atherosclerotic lesions vascular funtions b.1. inflammatory reaction b.2. thrombogeneity b.3. vasoreactivity b.4. plaque stability b.5. shoulder of plaque endothelium balance between c.1. vasodilating, antithrombotic, antiproliferative factors (NO, prostacyclin, C-natriuretic peptide, EDHF) c.2. vasoconstricting, prothrombotic, proliferative factors (ET, superoxide, thromoboxan A2) 17 NATURAL HISTORY OF CORONARY ATHEROSCLEROSIS Chatzizisis et all. JACC. 2007. Asymtomatic Stable Angina Acute Coronary Syndrome Early fibroatheroma Compensatory expansive remodeling Quiescent plaque Contrictive remodeling Stenotic plaque Exessive expansive remodeling Thin cap fibroatheroma Erosion Physiologic coronary artery Local factors, e.g. low ESS Systemic factors, e.g. hyperlipidemia Genetic factors Physiologic ESS Limited inflammation Fibroproliferation Microruptures 18 ATHEROSCLEROSIS IS AN INFLAMMATORY DISEASE Libby P. Circulation. 2001;104:365-372; Ross R. N Engl J Med. 1999;340:115-126. Monocyte LDL-C Adhesion molecule Macrophage Foam cell OxidizedLDL-C Plaque rupture Smooth muscle cells CRP Plaque instability and thrombus Oxidation Inflammation Endothelial dysfunction 19 20 Reverse Cholesterol Transport Monocyte CRP TXA2 PGI2 Thrombin LDL Platelets HDL HDL Ox-LDL MCP-1 Macrophage P-selectin CD 40L PDGF Foam cell MMP T cell E-selectins CD 40L VCAM-1 ICAM-1 IL-1 Reilly, et.all. 2005 21 THE ROLE OF Lp-PLA2 IN CHD LUMEN Monocytes Adhesion Molecules Oxidated LDL INTIMA MEDIA Lp-PLA2 Lyso-PC OxFA Cytokines Plaque Formation Foam Cell Macrophage 22 MC T T FC FC LDL Oxidation Lyso-PC Ox-chol Cytokines Cytokines ? C5a C’ MCP-1 F SMC 23 Intracelluler proteolysis and fusion of LDL Figure : Proposed Dual Action of Exocytosed Mast Cell Granules (The Granule Remnants) of Lipoprotein Metabolism in The Arterial Intima 24 HSCRP 25 26 GM-CSF VCAM-1 MPC-1 Transcription Factors : Endothelial Cell Pro-inflammatory Genes Oxidative Stress NF-xB AP-1 Leucocyte infiltration / activation Plaque Rupture Gibbons, 97 LEUCOCYTE ACTIVATION IN ATHEROGENESIS : IMPLICATIONS FOR ACUTE ISCHEMIC SYNDROMES 27 p38 c-Jun activation Caspases Apoptosis NIK ? ? MEKK1?   CKII IKK complex TNFR-1 TNFR-1 IL-1R Shear stress p65 p50 CBP/p300 Gene activation p65 p50 IB pKAc IB Ub Target genes : - IL-1, IL-8, IL-6, IFN  - TNF, MCP-1 - CSFs, c-myc - VCAM-1, ICAM-1, E-selectin - Tissue factor - Survival factor Thurberg and Collins : Curr Opin Lipidol 9:387-396,1998 Ub Ox-LDL ROIs ??? Lipid peroxides ? H2O2 Ubiquitination and proteosome degradation T R A D D R I P F A D D R I P T R A D D T R A F 2 T R A F 6 28 Visual Medica. 2009
Slide 29 - 1 Nama : Prof. Dr. H. Djanggan Sargowo, dr., SpPD., SpJP(K), FIHA, FACC, FESC, FCAPC, FASCC Tempat/Tgl lahir : Sragen, 21 September 1947 Alamat : Wilis Indah E-10 Malang, Telp. 0341-552395 Pendidikan : Lulus Dokter dari UGM, tahun 1974 Lulus Cardiologist dari Univ. Indonesia, tahun 1983 Lulus Internist dari Univ. Airlangga, tahun 1986 Lulus Doktor, Univ. Airlangga, tahun 1996 Advanced Cardiology Course, Univ. Hongkong, tahun 1984 Senior Visiting Program, Institut Jantung Negara, Kualalumpur, 1996 Fellow American College of Cardiology (FACC), September 2006. Fellow Collage Asia Pacific Society of Cardiology (FCAPC), Desember 2007 Fellow European Sociaty of Cardiology (FESC), 2008 Fellow Asean Collage of Cardiology (FASCC), 2008 Jabatan : Dosen Pengajar Program Pascasarjana Universitas Brawijaya Ketua MKEK Ikatan Dokter Indonesia Cabang Malang Raya Ketua PERKI Cabang Malang Raya Anggota Kolegium Kardiovaskuler Indonesia Dekan Fak. Kedokteran Univ. Wijaya Kusuma Surabaya Ketua Dewan Pengawas Rumah Sakit Pendidikan Ketua Program Studi Kardiovascular Fak. Kedokteran Univ. Brawijaya Curriculum Vitae 2 Djanggan Sargowo Surabaya, 15 April 2012 INFLAMMATION IN ATHEROSCLEROSIS : FROM BENCH TO BEDSIDE 3 4 RUDOLF VIRCHOW Inflammation-based arterial changes as a mechanism of primary importance in atherogenesis mid 19th century Lamond, B. The American Journal of Pathology. 2008 5 Atherosclerosis Start from very young To Old age ? 6 Atherothrombosis* is aLeading Cause of Death Worldwide1† The World Health Report, 2002, WHO Geneva, 2002 28.7 17.8 12.6 9.1 6 5.1 0 5 10 15 20 25 30 Atherothrombosis* Infectious disease Cancer Injuries Pulmonary disease AIDS Mortality (%) * Ischemic heart disease, cerebrovascular disease, inflammatory heart disease and hypertensive heart disease † Worldwide defined as Member States by WHO Region (Africa, Americas, Eastern Mediterranean, European, South-East Asia and Western Pacific) 7 MAJOR CLINICAL MANIFESTATIONS OF ATHEROTHROMBOSIS Adapted from: Drouet L. Cerebrovasc Dis 2002; 13(suppl 1): 1–6. Transient ischemic attack Angina: Stable Unstable Ischemic stroke Myocardial infarction Peripheral arterial disease: Intermittent claudication Rest Pain Gangrene Necrosis 8  Dyslipidemia  Endothelial dysfunction  Free radicals  Immunologic Atherosclerosis/CAD THEORY AND CONCEPT OF ATHEROSCLEROSIS Inflamation (Sargowo, 1996) 9 Free Radical ATHEROGENESIS (Sargowo, 1996) 10 IDENTIFYING THOSE AT RISK OF ATHEROTHROMBOSIS Yusuf S et al. Circulation 2001; 104: 2746–53. 2. Drouet L. Cerebrovasc Dis 2002;13(suppl 1):1–6. Lifestyle Smoking Diet Lack of exercise Genetic Genetic traits Gender Age Generalized disorders Obesity Diabetes Systemic conditions History of vascular events Hypertension Hyperlipidemia Hypercoagulable states Homocystinemia Local factors Elevated prothrombotic factors: fibrinogen, CRP, PAI-1 Blood flow patterns, vessel diameter, arterial wall structure Atherothrombosis manifestations (myocardial infarction, stroke, vascular death) 11 Arici. 2010 Risk Factors for Atherosclerosis Classic Hypertension, Hyper-lipidemia, DM, Smoking Uremia Related Increase ox-LDL, Free radicals, Uremic toxin Infection Bacterial and viral infection Proinflammatory cytokine release Endothelial dysfunction Systemic inflammatory respones Acute phase response Elevated CRP Binding LDL, cemplement activation, tissue factor secretion Accelerated ATHEROSCLEROSIS 12 LDL CD40L=CD40 ligand; TNF-α=tumor necrosis factor-alpha; IL=interleukin; VCAM=vascular cell adhesion molecule; ICAM=intercellular adhesion molecule. Cockerill GW et al. Arterioscler Thromb Vasc Biol. 1995;15:1987-1994; Andre P et al. Circulation. 2002;106:896-899; Libby P. Circulation. 2001;104:365-372; Libby P et al. Circulation. 2002;105:1135-1143; Ross R. N Engl J Med. 1999;340:115-126. Vessel lumen Monocyte Macrophage Adhesionmolecules (VCAM-1, ICAM-1) Inflammatory mediators (CRP, CD40/CD40L, TNF-α, IL-1, IL-6) Intima Foam cell INFLAMMATION PROMOTES PROGRESSION OF ATHEROSCLEROSIS Endothelium LDL Ox-LDL 13 14 Atherosclerosis is a fibroproliferative and inflammatory process occurring ins response to a variety of vascular insults The insults come from classical risk factors ( HT, dyslipidemia, endothelial dysfunction, smoking, menopause, diabetes etc) and novel risk factors (Hcy, LVH, Lp(a), TG, oxidative stress, fibrinogen etc) Endothelial dysfunction is regarded as the first abnormality leading to atherosclerosis This implies that modulation of endothelial function may be used as strategy to intervene the process. 15 Two theories gain more acceptance: (a) the lipid theory (b) inflammation theory Endothelial dysfunction is now regarded as the first abnormality leading to AS. More novel cardiovascular risk factors are known, e.g.: Fibrinogen b. PAI-1 Homocysteins d. AT-1 e. CRP f. Lp(a) g. small-dense LDL h. infectious agents i. and more are emerging 16 Acute Coronary Syndrome (endocrine viewpoints) atherosclerotic lesions vascular funtions b.1. inflammatory reaction b.2. thrombogeneity b.3. vasoreactivity b.4. plaque stability b.5. shoulder of plaque endothelium balance between c.1. vasodilating, antithrombotic, antiproliferative factors (NO, prostacyclin, C-natriuretic peptide, EDHF) c.2. vasoconstricting, prothrombotic, proliferative factors (ET, superoxide, thromoboxan A2) 17 NATURAL HISTORY OF CORONARY ATHEROSCLEROSIS Chatzizisis et all. JACC. 2007. Asymtomatic Stable Angina Acute Coronary Syndrome Early fibroatheroma Compensatory expansive remodeling Quiescent plaque Contrictive remodeling Stenotic plaque Exessive expansive remodeling Thin cap fibroatheroma Erosion Physiologic coronary artery Local factors, e.g. low ESS Systemic factors, e.g. hyperlipidemia Genetic factors Physiologic ESS Limited inflammation Fibroproliferation Microruptures 18 ATHEROSCLEROSIS IS AN INFLAMMATORY DISEASE Libby P. Circulation. 2001;104:365-372; Ross R. N Engl J Med. 1999;340:115-126. Monocyte LDL-C Adhesion molecule Macrophage Foam cell OxidizedLDL-C Plaque rupture Smooth muscle cells CRP Plaque instability and thrombus Oxidation Inflammation Endothelial dysfunction 19 20 Reverse Cholesterol Transport Monocyte CRP TXA2 PGI2 Thrombin LDL Platelets HDL HDL Ox-LDL MCP-1 Macrophage P-selectin CD 40L PDGF Foam cell MMP T cell E-selectins CD 40L VCAM-1 ICAM-1 IL-1 Reilly, et.all. 2005 21 THE ROLE OF Lp-PLA2 IN CHD LUMEN Monocytes Adhesion Molecules Oxidated LDL INTIMA MEDIA Lp-PLA2 Lyso-PC OxFA Cytokines Plaque Formation Foam Cell Macrophage 22 MC T T FC FC LDL Oxidation Lyso-PC Ox-chol Cytokines Cytokines ? C5a C’ MCP-1 F SMC 23 Intracelluler proteolysis and fusion of LDL Figure : Proposed Dual Action of Exocytosed Mast Cell Granules (The Granule Remnants) of Lipoprotein Metabolism in The Arterial Intima 24 HSCRP 25 26 GM-CSF VCAM-1 MPC-1 Transcription Factors : Endothelial Cell Pro-inflammatory Genes Oxidative Stress NF-xB AP-1 Leucocyte infiltration / activation Plaque Rupture Gibbons, 97 LEUCOCYTE ACTIVATION IN ATHEROGENESIS : IMPLICATIONS FOR ACUTE ISCHEMIC SYNDROMES 27 p38 c-Jun activation Caspases Apoptosis NIK ? ? MEKK1?   CKII IKK complex TNFR-1 TNFR-1 IL-1R Shear stress p65 p50 CBP/p300 Gene activation p65 p50 IB pKAc IB Ub Target genes : - IL-1, IL-8, IL-6, IFN  - TNF, MCP-1 - CSFs, c-myc - VCAM-1, ICAM-1, E-selectin - Tissue factor - Survival factor Thurberg and Collins : Curr Opin Lipidol 9:387-396,1998 Ub Ox-LDL ROIs ??? Lipid peroxides ? H2O2 Ubiquitination and proteosome degradation T R A D D R I P F A D D R I P T R A D D T R A F 2 T R A F 6 28 Visual Medica. 2009 29 Stockley. 2006 Cytokines : IL-6, TNF-α MACROPHAGE FOAM CELL Oxidized LDL CRP CRP Chemokines: MCO-1 Atherosclerotic plaque MONOCYTE Inflammatory Mediators: CRP Prothrombotic factors FCR Receptor
Slide 30 - 1 Nama : Prof. Dr. H. Djanggan Sargowo, dr., SpPD., SpJP(K), FIHA, FACC, FESC, FCAPC, FASCC Tempat/Tgl lahir : Sragen, 21 September 1947 Alamat : Wilis Indah E-10 Malang, Telp. 0341-552395 Pendidikan : Lulus Dokter dari UGM, tahun 1974 Lulus Cardiologist dari Univ. Indonesia, tahun 1983 Lulus Internist dari Univ. Airlangga, tahun 1986 Lulus Doktor, Univ. Airlangga, tahun 1996 Advanced Cardiology Course, Univ. Hongkong, tahun 1984 Senior Visiting Program, Institut Jantung Negara, Kualalumpur, 1996 Fellow American College of Cardiology (FACC), September 2006. Fellow Collage Asia Pacific Society of Cardiology (FCAPC), Desember 2007 Fellow European Sociaty of Cardiology (FESC), 2008 Fellow Asean Collage of Cardiology (FASCC), 2008 Jabatan : Dosen Pengajar Program Pascasarjana Universitas Brawijaya Ketua MKEK Ikatan Dokter Indonesia Cabang Malang Raya Ketua PERKI Cabang Malang Raya Anggota Kolegium Kardiovaskuler Indonesia Dekan Fak. Kedokteran Univ. Wijaya Kusuma Surabaya Ketua Dewan Pengawas Rumah Sakit Pendidikan Ketua Program Studi Kardiovascular Fak. Kedokteran Univ. Brawijaya Curriculum Vitae 2 Djanggan Sargowo Surabaya, 15 April 2012 INFLAMMATION IN ATHEROSCLEROSIS : FROM BENCH TO BEDSIDE 3 4 RUDOLF VIRCHOW Inflammation-based arterial changes as a mechanism of primary importance in atherogenesis mid 19th century Lamond, B. The American Journal of Pathology. 2008 5 Atherosclerosis Start from very young To Old age ? 6 Atherothrombosis* is aLeading Cause of Death Worldwide1† The World Health Report, 2002, WHO Geneva, 2002 28.7 17.8 12.6 9.1 6 5.1 0 5 10 15 20 25 30 Atherothrombosis* Infectious disease Cancer Injuries Pulmonary disease AIDS Mortality (%) * Ischemic heart disease, cerebrovascular disease, inflammatory heart disease and hypertensive heart disease † Worldwide defined as Member States by WHO Region (Africa, Americas, Eastern Mediterranean, European, South-East Asia and Western Pacific) 7 MAJOR CLINICAL MANIFESTATIONS OF ATHEROTHROMBOSIS Adapted from: Drouet L. Cerebrovasc Dis 2002; 13(suppl 1): 1–6. Transient ischemic attack Angina: Stable Unstable Ischemic stroke Myocardial infarction Peripheral arterial disease: Intermittent claudication Rest Pain Gangrene Necrosis 8  Dyslipidemia  Endothelial dysfunction  Free radicals  Immunologic Atherosclerosis/CAD THEORY AND CONCEPT OF ATHEROSCLEROSIS Inflamation (Sargowo, 1996) 9 Free Radical ATHEROGENESIS (Sargowo, 1996) 10 IDENTIFYING THOSE AT RISK OF ATHEROTHROMBOSIS Yusuf S et al. Circulation 2001; 104: 2746–53. 2. Drouet L. Cerebrovasc Dis 2002;13(suppl 1):1–6. Lifestyle Smoking Diet Lack of exercise Genetic Genetic traits Gender Age Generalized disorders Obesity Diabetes Systemic conditions History of vascular events Hypertension Hyperlipidemia Hypercoagulable states Homocystinemia Local factors Elevated prothrombotic factors: fibrinogen, CRP, PAI-1 Blood flow patterns, vessel diameter, arterial wall structure Atherothrombosis manifestations (myocardial infarction, stroke, vascular death) 11 Arici. 2010 Risk Factors for Atherosclerosis Classic Hypertension, Hyper-lipidemia, DM, Smoking Uremia Related Increase ox-LDL, Free radicals, Uremic toxin Infection Bacterial and viral infection Proinflammatory cytokine release Endothelial dysfunction Systemic inflammatory respones Acute phase response Elevated CRP Binding LDL, cemplement activation, tissue factor secretion Accelerated ATHEROSCLEROSIS 12 LDL CD40L=CD40 ligand; TNF-α=tumor necrosis factor-alpha; IL=interleukin; VCAM=vascular cell adhesion molecule; ICAM=intercellular adhesion molecule. Cockerill GW et al. Arterioscler Thromb Vasc Biol. 1995;15:1987-1994; Andre P et al. Circulation. 2002;106:896-899; Libby P. Circulation. 2001;104:365-372; Libby P et al. Circulation. 2002;105:1135-1143; Ross R. N Engl J Med. 1999;340:115-126. Vessel lumen Monocyte Macrophage Adhesionmolecules (VCAM-1, ICAM-1) Inflammatory mediators (CRP, CD40/CD40L, TNF-α, IL-1, IL-6) Intima Foam cell INFLAMMATION PROMOTES PROGRESSION OF ATHEROSCLEROSIS Endothelium LDL Ox-LDL 13 14 Atherosclerosis is a fibroproliferative and inflammatory process occurring ins response to a variety of vascular insults The insults come from classical risk factors ( HT, dyslipidemia, endothelial dysfunction, smoking, menopause, diabetes etc) and novel risk factors (Hcy, LVH, Lp(a), TG, oxidative stress, fibrinogen etc) Endothelial dysfunction is regarded as the first abnormality leading to atherosclerosis This implies that modulation of endothelial function may be used as strategy to intervene the process. 15 Two theories gain more acceptance: (a) the lipid theory (b) inflammation theory Endothelial dysfunction is now regarded as the first abnormality leading to AS. More novel cardiovascular risk factors are known, e.g.: Fibrinogen b. PAI-1 Homocysteins d. AT-1 e. CRP f. Lp(a) g. small-dense LDL h. infectious agents i. and more are emerging 16 Acute Coronary Syndrome (endocrine viewpoints) atherosclerotic lesions vascular funtions b.1. inflammatory reaction b.2. thrombogeneity b.3. vasoreactivity b.4. plaque stability b.5. shoulder of plaque endothelium balance between c.1. vasodilating, antithrombotic, antiproliferative factors (NO, prostacyclin, C-natriuretic peptide, EDHF) c.2. vasoconstricting, prothrombotic, proliferative factors (ET, superoxide, thromoboxan A2) 17 NATURAL HISTORY OF CORONARY ATHEROSCLEROSIS Chatzizisis et all. JACC. 2007. Asymtomatic Stable Angina Acute Coronary Syndrome Early fibroatheroma Compensatory expansive remodeling Quiescent plaque Contrictive remodeling Stenotic plaque Exessive expansive remodeling Thin cap fibroatheroma Erosion Physiologic coronary artery Local factors, e.g. low ESS Systemic factors, e.g. hyperlipidemia Genetic factors Physiologic ESS Limited inflammation Fibroproliferation Microruptures 18 ATHEROSCLEROSIS IS AN INFLAMMATORY DISEASE Libby P. Circulation. 2001;104:365-372; Ross R. N Engl J Med. 1999;340:115-126. Monocyte LDL-C Adhesion molecule Macrophage Foam cell OxidizedLDL-C Plaque rupture Smooth muscle cells CRP Plaque instability and thrombus Oxidation Inflammation Endothelial dysfunction 19 20 Reverse Cholesterol Transport Monocyte CRP TXA2 PGI2 Thrombin LDL Platelets HDL HDL Ox-LDL MCP-1 Macrophage P-selectin CD 40L PDGF Foam cell MMP T cell E-selectins CD 40L VCAM-1 ICAM-1 IL-1 Reilly, et.all. 2005 21 THE ROLE OF Lp-PLA2 IN CHD LUMEN Monocytes Adhesion Molecules Oxidated LDL INTIMA MEDIA Lp-PLA2 Lyso-PC OxFA Cytokines Plaque Formation Foam Cell Macrophage 22 MC T T FC FC LDL Oxidation Lyso-PC Ox-chol Cytokines Cytokines ? C5a C’ MCP-1 F SMC 23 Intracelluler proteolysis and fusion of LDL Figure : Proposed Dual Action of Exocytosed Mast Cell Granules (The Granule Remnants) of Lipoprotein Metabolism in The Arterial Intima 24 HSCRP 25 26 GM-CSF VCAM-1 MPC-1 Transcription Factors : Endothelial Cell Pro-inflammatory Genes Oxidative Stress NF-xB AP-1 Leucocyte infiltration / activation Plaque Rupture Gibbons, 97 LEUCOCYTE ACTIVATION IN ATHEROGENESIS : IMPLICATIONS FOR ACUTE ISCHEMIC SYNDROMES 27 p38 c-Jun activation Caspases Apoptosis NIK ? ? MEKK1?   CKII IKK complex TNFR-1 TNFR-1 IL-1R Shear stress p65 p50 CBP/p300 Gene activation p65 p50 IB pKAc IB Ub Target genes : - IL-1, IL-8, IL-6, IFN  - TNF, MCP-1 - CSFs, c-myc - VCAM-1, ICAM-1, E-selectin - Tissue factor - Survival factor Thurberg and Collins : Curr Opin Lipidol 9:387-396,1998 Ub Ox-LDL ROIs ??? Lipid peroxides ? H2O2 Ubiquitination and proteosome degradation T R A D D R I P F A D D R I P T R A D D T R A F 2 T R A F 6 28 Visual Medica. 2009 29 Stockley. 2006 Cytokines : IL-6, TNF-α MACROPHAGE FOAM CELL Oxidized LDL CRP CRP Chemokines: MCO-1 Atherosclerotic plaque MONOCYTE Inflammatory Mediators: CRP Prothrombotic factors FCR Receptor 30 POTENTIAL MECHANISM OF CRP Stevens, R. 2005 CRP LDL opsonisation Monocyte infiltration Foam cell formation Increased MCP-1 and CAM EC activation Inflammatory cell recruitment Atherosclerosis plaque formation Complement activation EC sensitisation T-cell attack EC damage Atherosclerotic plaque rupture
Slide 31 - 1 Nama : Prof. Dr. H. Djanggan Sargowo, dr., SpPD., SpJP(K), FIHA, FACC, FESC, FCAPC, FASCC Tempat/Tgl lahir : Sragen, 21 September 1947 Alamat : Wilis Indah E-10 Malang, Telp. 0341-552395 Pendidikan : Lulus Dokter dari UGM, tahun 1974 Lulus Cardiologist dari Univ. Indonesia, tahun 1983 Lulus Internist dari Univ. Airlangga, tahun 1986 Lulus Doktor, Univ. Airlangga, tahun 1996 Advanced Cardiology Course, Univ. Hongkong, tahun 1984 Senior Visiting Program, Institut Jantung Negara, Kualalumpur, 1996 Fellow American College of Cardiology (FACC), September 2006. Fellow Collage Asia Pacific Society of Cardiology (FCAPC), Desember 2007 Fellow European Sociaty of Cardiology (FESC), 2008 Fellow Asean Collage of Cardiology (FASCC), 2008 Jabatan : Dosen Pengajar Program Pascasarjana Universitas Brawijaya Ketua MKEK Ikatan Dokter Indonesia Cabang Malang Raya Ketua PERKI Cabang Malang Raya Anggota Kolegium Kardiovaskuler Indonesia Dekan Fak. Kedokteran Univ. Wijaya Kusuma Surabaya Ketua Dewan Pengawas Rumah Sakit Pendidikan Ketua Program Studi Kardiovascular Fak. Kedokteran Univ. Brawijaya Curriculum Vitae 2 Djanggan Sargowo Surabaya, 15 April 2012 INFLAMMATION IN ATHEROSCLEROSIS : FROM BENCH TO BEDSIDE 3 4 RUDOLF VIRCHOW Inflammation-based arterial changes as a mechanism of primary importance in atherogenesis mid 19th century Lamond, B. The American Journal of Pathology. 2008 5 Atherosclerosis Start from very young To Old age ? 6 Atherothrombosis* is aLeading Cause of Death Worldwide1† The World Health Report, 2002, WHO Geneva, 2002 28.7 17.8 12.6 9.1 6 5.1 0 5 10 15 20 25 30 Atherothrombosis* Infectious disease Cancer Injuries Pulmonary disease AIDS Mortality (%) * Ischemic heart disease, cerebrovascular disease, inflammatory heart disease and hypertensive heart disease † Worldwide defined as Member States by WHO Region (Africa, Americas, Eastern Mediterranean, European, South-East Asia and Western Pacific) 7 MAJOR CLINICAL MANIFESTATIONS OF ATHEROTHROMBOSIS Adapted from: Drouet L. Cerebrovasc Dis 2002; 13(suppl 1): 1–6. Transient ischemic attack Angina: Stable Unstable Ischemic stroke Myocardial infarction Peripheral arterial disease: Intermittent claudication Rest Pain Gangrene Necrosis 8  Dyslipidemia  Endothelial dysfunction  Free radicals  Immunologic Atherosclerosis/CAD THEORY AND CONCEPT OF ATHEROSCLEROSIS Inflamation (Sargowo, 1996) 9 Free Radical ATHEROGENESIS (Sargowo, 1996) 10 IDENTIFYING THOSE AT RISK OF ATHEROTHROMBOSIS Yusuf S et al. Circulation 2001; 104: 2746–53. 2. Drouet L. Cerebrovasc Dis 2002;13(suppl 1):1–6. Lifestyle Smoking Diet Lack of exercise Genetic Genetic traits Gender Age Generalized disorders Obesity Diabetes Systemic conditions History of vascular events Hypertension Hyperlipidemia Hypercoagulable states Homocystinemia Local factors Elevated prothrombotic factors: fibrinogen, CRP, PAI-1 Blood flow patterns, vessel diameter, arterial wall structure Atherothrombosis manifestations (myocardial infarction, stroke, vascular death) 11 Arici. 2010 Risk Factors for Atherosclerosis Classic Hypertension, Hyper-lipidemia, DM, Smoking Uremia Related Increase ox-LDL, Free radicals, Uremic toxin Infection Bacterial and viral infection Proinflammatory cytokine release Endothelial dysfunction Systemic inflammatory respones Acute phase response Elevated CRP Binding LDL, cemplement activation, tissue factor secretion Accelerated ATHEROSCLEROSIS 12 LDL CD40L=CD40 ligand; TNF-α=tumor necrosis factor-alpha; IL=interleukin; VCAM=vascular cell adhesion molecule; ICAM=intercellular adhesion molecule. Cockerill GW et al. Arterioscler Thromb Vasc Biol. 1995;15:1987-1994; Andre P et al. Circulation. 2002;106:896-899; Libby P. Circulation. 2001;104:365-372; Libby P et al. Circulation. 2002;105:1135-1143; Ross R. N Engl J Med. 1999;340:115-126. Vessel lumen Monocyte Macrophage Adhesionmolecules (VCAM-1, ICAM-1) Inflammatory mediators (CRP, CD40/CD40L, TNF-α, IL-1, IL-6) Intima Foam cell INFLAMMATION PROMOTES PROGRESSION OF ATHEROSCLEROSIS Endothelium LDL Ox-LDL 13 14 Atherosclerosis is a fibroproliferative and inflammatory process occurring ins response to a variety of vascular insults The insults come from classical risk factors ( HT, dyslipidemia, endothelial dysfunction, smoking, menopause, diabetes etc) and novel risk factors (Hcy, LVH, Lp(a), TG, oxidative stress, fibrinogen etc) Endothelial dysfunction is regarded as the first abnormality leading to atherosclerosis This implies that modulation of endothelial function may be used as strategy to intervene the process. 15 Two theories gain more acceptance: (a) the lipid theory (b) inflammation theory Endothelial dysfunction is now regarded as the first abnormality leading to AS. More novel cardiovascular risk factors are known, e.g.: Fibrinogen b. PAI-1 Homocysteins d. AT-1 e. CRP f. Lp(a) g. small-dense LDL h. infectious agents i. and more are emerging 16 Acute Coronary Syndrome (endocrine viewpoints) atherosclerotic lesions vascular funtions b.1. inflammatory reaction b.2. thrombogeneity b.3. vasoreactivity b.4. plaque stability b.5. shoulder of plaque endothelium balance between c.1. vasodilating, antithrombotic, antiproliferative factors (NO, prostacyclin, C-natriuretic peptide, EDHF) c.2. vasoconstricting, prothrombotic, proliferative factors (ET, superoxide, thromoboxan A2) 17 NATURAL HISTORY OF CORONARY ATHEROSCLEROSIS Chatzizisis et all. JACC. 2007. Asymtomatic Stable Angina Acute Coronary Syndrome Early fibroatheroma Compensatory expansive remodeling Quiescent plaque Contrictive remodeling Stenotic plaque Exessive expansive remodeling Thin cap fibroatheroma Erosion Physiologic coronary artery Local factors, e.g. low ESS Systemic factors, e.g. hyperlipidemia Genetic factors Physiologic ESS Limited inflammation Fibroproliferation Microruptures 18 ATHEROSCLEROSIS IS AN INFLAMMATORY DISEASE Libby P. Circulation. 2001;104:365-372; Ross R. N Engl J Med. 1999;340:115-126. Monocyte LDL-C Adhesion molecule Macrophage Foam cell OxidizedLDL-C Plaque rupture Smooth muscle cells CRP Plaque instability and thrombus Oxidation Inflammation Endothelial dysfunction 19 20 Reverse Cholesterol Transport Monocyte CRP TXA2 PGI2 Thrombin LDL Platelets HDL HDL Ox-LDL MCP-1 Macrophage P-selectin CD 40L PDGF Foam cell MMP T cell E-selectins CD 40L VCAM-1 ICAM-1 IL-1 Reilly, et.all. 2005 21 THE ROLE OF Lp-PLA2 IN CHD LUMEN Monocytes Adhesion Molecules Oxidated LDL INTIMA MEDIA Lp-PLA2 Lyso-PC OxFA Cytokines Plaque Formation Foam Cell Macrophage 22 MC T T FC FC LDL Oxidation Lyso-PC Ox-chol Cytokines Cytokines ? C5a C’ MCP-1 F SMC 23 Intracelluler proteolysis and fusion of LDL Figure : Proposed Dual Action of Exocytosed Mast Cell Granules (The Granule Remnants) of Lipoprotein Metabolism in The Arterial Intima 24 HSCRP 25 26 GM-CSF VCAM-1 MPC-1 Transcription Factors : Endothelial Cell Pro-inflammatory Genes Oxidative Stress NF-xB AP-1 Leucocyte infiltration / activation Plaque Rupture Gibbons, 97 LEUCOCYTE ACTIVATION IN ATHEROGENESIS : IMPLICATIONS FOR ACUTE ISCHEMIC SYNDROMES 27 p38 c-Jun activation Caspases Apoptosis NIK ? ? MEKK1?   CKII IKK complex TNFR-1 TNFR-1 IL-1R Shear stress p65 p50 CBP/p300 Gene activation p65 p50 IB pKAc IB Ub Target genes : - IL-1, IL-8, IL-6, IFN  - TNF, MCP-1 - CSFs, c-myc - VCAM-1, ICAM-1, E-selectin - Tissue factor - Survival factor Thurberg and Collins : Curr Opin Lipidol 9:387-396,1998 Ub Ox-LDL ROIs ??? Lipid peroxides ? H2O2 Ubiquitination and proteosome degradation T R A D D R I P F A D D R I P T R A D D T R A F 2 T R A F 6 28 Visual Medica. 2009 29 Stockley. 2006 Cytokines : IL-6, TNF-α MACROPHAGE FOAM CELL Oxidized LDL CRP CRP Chemokines: MCO-1 Atherosclerotic plaque MONOCYTE Inflammatory Mediators: CRP Prothrombotic factors FCR Receptor 30 POTENTIAL MECHANISM OF CRP Stevens, R. 2005 CRP LDL opsonisation Monocyte infiltration Foam cell formation Increased MCP-1 and CAM EC activation Inflammatory cell recruitment Atherosclerosis plaque formation Complement activation EC sensitisation T-cell attack EC damage Atherosclerotic plaque rupture 31 Rheumatoid arthritis Atherosclerosis Multiple sclerosis Asthma Inflammatory bowel disease Helicobacter pylori-associated gastritis Systemic inflammatory response syndrome NF-KB ACTIVATION INFLAMMATORY DISEASE The Journal of Clinical Investigation, 2001
Slide 32 - 1 Nama : Prof. Dr. H. Djanggan Sargowo, dr., SpPD., SpJP(K), FIHA, FACC, FESC, FCAPC, FASCC Tempat/Tgl lahir : Sragen, 21 September 1947 Alamat : Wilis Indah E-10 Malang, Telp. 0341-552395 Pendidikan : Lulus Dokter dari UGM, tahun 1974 Lulus Cardiologist dari Univ. Indonesia, tahun 1983 Lulus Internist dari Univ. Airlangga, tahun 1986 Lulus Doktor, Univ. Airlangga, tahun 1996 Advanced Cardiology Course, Univ. Hongkong, tahun 1984 Senior Visiting Program, Institut Jantung Negara, Kualalumpur, 1996 Fellow American College of Cardiology (FACC), September 2006. Fellow Collage Asia Pacific Society of Cardiology (FCAPC), Desember 2007 Fellow European Sociaty of Cardiology (FESC), 2008 Fellow Asean Collage of Cardiology (FASCC), 2008 Jabatan : Dosen Pengajar Program Pascasarjana Universitas Brawijaya Ketua MKEK Ikatan Dokter Indonesia Cabang Malang Raya Ketua PERKI Cabang Malang Raya Anggota Kolegium Kardiovaskuler Indonesia Dekan Fak. Kedokteran Univ. Wijaya Kusuma Surabaya Ketua Dewan Pengawas Rumah Sakit Pendidikan Ketua Program Studi Kardiovascular Fak. Kedokteran Univ. Brawijaya Curriculum Vitae 2 Djanggan Sargowo Surabaya, 15 April 2012 INFLAMMATION IN ATHEROSCLEROSIS : FROM BENCH TO BEDSIDE 3 4 RUDOLF VIRCHOW Inflammation-based arterial changes as a mechanism of primary importance in atherogenesis mid 19th century Lamond, B. The American Journal of Pathology. 2008 5 Atherosclerosis Start from very young To Old age ? 6 Atherothrombosis* is aLeading Cause of Death Worldwide1† The World Health Report, 2002, WHO Geneva, 2002 28.7 17.8 12.6 9.1 6 5.1 0 5 10 15 20 25 30 Atherothrombosis* Infectious disease Cancer Injuries Pulmonary disease AIDS Mortality (%) * Ischemic heart disease, cerebrovascular disease, inflammatory heart disease and hypertensive heart disease † Worldwide defined as Member States by WHO Region (Africa, Americas, Eastern Mediterranean, European, South-East Asia and Western Pacific) 7 MAJOR CLINICAL MANIFESTATIONS OF ATHEROTHROMBOSIS Adapted from: Drouet L. Cerebrovasc Dis 2002; 13(suppl 1): 1–6. Transient ischemic attack Angina: Stable Unstable Ischemic stroke Myocardial infarction Peripheral arterial disease: Intermittent claudication Rest Pain Gangrene Necrosis 8  Dyslipidemia  Endothelial dysfunction  Free radicals  Immunologic Atherosclerosis/CAD THEORY AND CONCEPT OF ATHEROSCLEROSIS Inflamation (Sargowo, 1996) 9 Free Radical ATHEROGENESIS (Sargowo, 1996) 10 IDENTIFYING THOSE AT RISK OF ATHEROTHROMBOSIS Yusuf S et al. Circulation 2001; 104: 2746–53. 2. Drouet L. Cerebrovasc Dis 2002;13(suppl 1):1–6. Lifestyle Smoking Diet Lack of exercise Genetic Genetic traits Gender Age Generalized disorders Obesity Diabetes Systemic conditions History of vascular events Hypertension Hyperlipidemia Hypercoagulable states Homocystinemia Local factors Elevated prothrombotic factors: fibrinogen, CRP, PAI-1 Blood flow patterns, vessel diameter, arterial wall structure Atherothrombosis manifestations (myocardial infarction, stroke, vascular death) 11 Arici. 2010 Risk Factors for Atherosclerosis Classic Hypertension, Hyper-lipidemia, DM, Smoking Uremia Related Increase ox-LDL, Free radicals, Uremic toxin Infection Bacterial and viral infection Proinflammatory cytokine release Endothelial dysfunction Systemic inflammatory respones Acute phase response Elevated CRP Binding LDL, cemplement activation, tissue factor secretion Accelerated ATHEROSCLEROSIS 12 LDL CD40L=CD40 ligand; TNF-α=tumor necrosis factor-alpha; IL=interleukin; VCAM=vascular cell adhesion molecule; ICAM=intercellular adhesion molecule. Cockerill GW et al. Arterioscler Thromb Vasc Biol. 1995;15:1987-1994; Andre P et al. Circulation. 2002;106:896-899; Libby P. Circulation. 2001;104:365-372; Libby P et al. Circulation. 2002;105:1135-1143; Ross R. N Engl J Med. 1999;340:115-126. Vessel lumen Monocyte Macrophage Adhesionmolecules (VCAM-1, ICAM-1) Inflammatory mediators (CRP, CD40/CD40L, TNF-α, IL-1, IL-6) Intima Foam cell INFLAMMATION PROMOTES PROGRESSION OF ATHEROSCLEROSIS Endothelium LDL Ox-LDL 13 14 Atherosclerosis is a fibroproliferative and inflammatory process occurring ins response to a variety of vascular insults The insults come from classical risk factors ( HT, dyslipidemia, endothelial dysfunction, smoking, menopause, diabetes etc) and novel risk factors (Hcy, LVH, Lp(a), TG, oxidative stress, fibrinogen etc) Endothelial dysfunction is regarded as the first abnormality leading to atherosclerosis This implies that modulation of endothelial function may be used as strategy to intervene the process. 15 Two theories gain more acceptance: (a) the lipid theory (b) inflammation theory Endothelial dysfunction is now regarded as the first abnormality leading to AS. More novel cardiovascular risk factors are known, e.g.: Fibrinogen b. PAI-1 Homocysteins d. AT-1 e. CRP f. Lp(a) g. small-dense LDL h. infectious agents i. and more are emerging 16 Acute Coronary Syndrome (endocrine viewpoints) atherosclerotic lesions vascular funtions b.1. inflammatory reaction b.2. thrombogeneity b.3. vasoreactivity b.4. plaque stability b.5. shoulder of plaque endothelium balance between c.1. vasodilating, antithrombotic, antiproliferative factors (NO, prostacyclin, C-natriuretic peptide, EDHF) c.2. vasoconstricting, prothrombotic, proliferative factors (ET, superoxide, thromoboxan A2) 17 NATURAL HISTORY OF CORONARY ATHEROSCLEROSIS Chatzizisis et all. JACC. 2007. Asymtomatic Stable Angina Acute Coronary Syndrome Early fibroatheroma Compensatory expansive remodeling Quiescent plaque Contrictive remodeling Stenotic plaque Exessive expansive remodeling Thin cap fibroatheroma Erosion Physiologic coronary artery Local factors, e.g. low ESS Systemic factors, e.g. hyperlipidemia Genetic factors Physiologic ESS Limited inflammation Fibroproliferation Microruptures 18 ATHEROSCLEROSIS IS AN INFLAMMATORY DISEASE Libby P. Circulation. 2001;104:365-372; Ross R. N Engl J Med. 1999;340:115-126. Monocyte LDL-C Adhesion molecule Macrophage Foam cell OxidizedLDL-C Plaque rupture Smooth muscle cells CRP Plaque instability and thrombus Oxidation Inflammation Endothelial dysfunction 19 20 Reverse Cholesterol Transport Monocyte CRP TXA2 PGI2 Thrombin LDL Platelets HDL HDL Ox-LDL MCP-1 Macrophage P-selectin CD 40L PDGF Foam cell MMP T cell E-selectins CD 40L VCAM-1 ICAM-1 IL-1 Reilly, et.all. 2005 21 THE ROLE OF Lp-PLA2 IN CHD LUMEN Monocytes Adhesion Molecules Oxidated LDL INTIMA MEDIA Lp-PLA2 Lyso-PC OxFA Cytokines Plaque Formation Foam Cell Macrophage 22 MC T T FC FC LDL Oxidation Lyso-PC Ox-chol Cytokines Cytokines ? C5a C’ MCP-1 F SMC 23 Intracelluler proteolysis and fusion of LDL Figure : Proposed Dual Action of Exocytosed Mast Cell Granules (The Granule Remnants) of Lipoprotein Metabolism in The Arterial Intima 24 HSCRP 25 26 GM-CSF VCAM-1 MPC-1 Transcription Factors : Endothelial Cell Pro-inflammatory Genes Oxidative Stress NF-xB AP-1 Leucocyte infiltration / activation Plaque Rupture Gibbons, 97 LEUCOCYTE ACTIVATION IN ATHEROGENESIS : IMPLICATIONS FOR ACUTE ISCHEMIC SYNDROMES 27 p38 c-Jun activation Caspases Apoptosis NIK ? ? MEKK1?   CKII IKK complex TNFR-1 TNFR-1 IL-1R Shear stress p65 p50 CBP/p300 Gene activation p65 p50 IB pKAc IB Ub Target genes : - IL-1, IL-8, IL-6, IFN  - TNF, MCP-1 - CSFs, c-myc - VCAM-1, ICAM-1, E-selectin - Tissue factor - Survival factor Thurberg and Collins : Curr Opin Lipidol 9:387-396,1998 Ub Ox-LDL ROIs ??? Lipid peroxides ? H2O2 Ubiquitination and proteosome degradation T R A D D R I P F A D D R I P T R A D D T R A F 2 T R A F 6 28 Visual Medica. 2009 29 Stockley. 2006 Cytokines : IL-6, TNF-α MACROPHAGE FOAM CELL Oxidized LDL CRP CRP Chemokines: MCO-1 Atherosclerotic plaque MONOCYTE Inflammatory Mediators: CRP Prothrombotic factors FCR Receptor 30 POTENTIAL MECHANISM OF CRP Stevens, R. 2005 CRP LDL opsonisation Monocyte infiltration Foam cell formation Increased MCP-1 and CAM EC activation Inflammatory cell recruitment Atherosclerosis plaque formation Complement activation EC sensitisation T-cell attack EC damage Atherosclerotic plaque rupture 31 Rheumatoid arthritis Atherosclerosis Multiple sclerosis Asthma Inflammatory bowel disease Helicobacter pylori-associated gastritis Systemic inflammatory response syndrome NF-KB ACTIVATION INFLAMMATORY DISEASE The Journal of Clinical Investigation, 2001 32 PROTEIN REGULATED BY NF-KB Inflammatory Enzyme Adhesion Molecule Inducible nitric oxide synthase Inducide cylooxigenase-2 5-Lipoxigenase Cytosolic phospolipase A2 ICAM-1 VCAM-1 E-selectin Receptor Interlekin-2 receptor (alpha chain) T-cell receptors (beta chain) NEJM, 1997
Slide 33 - 1 Nama : Prof. Dr. H. Djanggan Sargowo, dr., SpPD., SpJP(K), FIHA, FACC, FESC, FCAPC, FASCC Tempat/Tgl lahir : Sragen, 21 September 1947 Alamat : Wilis Indah E-10 Malang, Telp. 0341-552395 Pendidikan : Lulus Dokter dari UGM, tahun 1974 Lulus Cardiologist dari Univ. Indonesia, tahun 1983 Lulus Internist dari Univ. Airlangga, tahun 1986 Lulus Doktor, Univ. Airlangga, tahun 1996 Advanced Cardiology Course, Univ. Hongkong, tahun 1984 Senior Visiting Program, Institut Jantung Negara, Kualalumpur, 1996 Fellow American College of Cardiology (FACC), September 2006. Fellow Collage Asia Pacific Society of Cardiology (FCAPC), Desember 2007 Fellow European Sociaty of Cardiology (FESC), 2008 Fellow Asean Collage of Cardiology (FASCC), 2008 Jabatan : Dosen Pengajar Program Pascasarjana Universitas Brawijaya Ketua MKEK Ikatan Dokter Indonesia Cabang Malang Raya Ketua PERKI Cabang Malang Raya Anggota Kolegium Kardiovaskuler Indonesia Dekan Fak. Kedokteran Univ. Wijaya Kusuma Surabaya Ketua Dewan Pengawas Rumah Sakit Pendidikan Ketua Program Studi Kardiovascular Fak. Kedokteran Univ. Brawijaya Curriculum Vitae 2 Djanggan Sargowo Surabaya, 15 April 2012 INFLAMMATION IN ATHEROSCLEROSIS : FROM BENCH TO BEDSIDE 3 4 RUDOLF VIRCHOW Inflammation-based arterial changes as a mechanism of primary importance in atherogenesis mid 19th century Lamond, B. The American Journal of Pathology. 2008 5 Atherosclerosis Start from very young To Old age ? 6 Atherothrombosis* is aLeading Cause of Death Worldwide1† The World Health Report, 2002, WHO Geneva, 2002 28.7 17.8 12.6 9.1 6 5.1 0 5 10 15 20 25 30 Atherothrombosis* Infectious disease Cancer Injuries Pulmonary disease AIDS Mortality (%) * Ischemic heart disease, cerebrovascular disease, inflammatory heart disease and hypertensive heart disease † Worldwide defined as Member States by WHO Region (Africa, Americas, Eastern Mediterranean, European, South-East Asia and Western Pacific) 7 MAJOR CLINICAL MANIFESTATIONS OF ATHEROTHROMBOSIS Adapted from: Drouet L. Cerebrovasc Dis 2002; 13(suppl 1): 1–6. Transient ischemic attack Angina: Stable Unstable Ischemic stroke Myocardial infarction Peripheral arterial disease: Intermittent claudication Rest Pain Gangrene Necrosis 8  Dyslipidemia  Endothelial dysfunction  Free radicals  Immunologic Atherosclerosis/CAD THEORY AND CONCEPT OF ATHEROSCLEROSIS Inflamation (Sargowo, 1996) 9 Free Radical ATHEROGENESIS (Sargowo, 1996) 10 IDENTIFYING THOSE AT RISK OF ATHEROTHROMBOSIS Yusuf S et al. Circulation 2001; 104: 2746–53. 2. Drouet L. Cerebrovasc Dis 2002;13(suppl 1):1–6. Lifestyle Smoking Diet Lack of exercise Genetic Genetic traits Gender Age Generalized disorders Obesity Diabetes Systemic conditions History of vascular events Hypertension Hyperlipidemia Hypercoagulable states Homocystinemia Local factors Elevated prothrombotic factors: fibrinogen, CRP, PAI-1 Blood flow patterns, vessel diameter, arterial wall structure Atherothrombosis manifestations (myocardial infarction, stroke, vascular death) 11 Arici. 2010 Risk Factors for Atherosclerosis Classic Hypertension, Hyper-lipidemia, DM, Smoking Uremia Related Increase ox-LDL, Free radicals, Uremic toxin Infection Bacterial and viral infection Proinflammatory cytokine release Endothelial dysfunction Systemic inflammatory respones Acute phase response Elevated CRP Binding LDL, cemplement activation, tissue factor secretion Accelerated ATHEROSCLEROSIS 12 LDL CD40L=CD40 ligand; TNF-α=tumor necrosis factor-alpha; IL=interleukin; VCAM=vascular cell adhesion molecule; ICAM=intercellular adhesion molecule. Cockerill GW et al. Arterioscler Thromb Vasc Biol. 1995;15:1987-1994; Andre P et al. Circulation. 2002;106:896-899; Libby P. Circulation. 2001;104:365-372; Libby P et al. Circulation. 2002;105:1135-1143; Ross R. N Engl J Med. 1999;340:115-126. Vessel lumen Monocyte Macrophage Adhesionmolecules (VCAM-1, ICAM-1) Inflammatory mediators (CRP, CD40/CD40L, TNF-α, IL-1, IL-6) Intima Foam cell INFLAMMATION PROMOTES PROGRESSION OF ATHEROSCLEROSIS Endothelium LDL Ox-LDL 13 14 Atherosclerosis is a fibroproliferative and inflammatory process occurring ins response to a variety of vascular insults The insults come from classical risk factors ( HT, dyslipidemia, endothelial dysfunction, smoking, menopause, diabetes etc) and novel risk factors (Hcy, LVH, Lp(a), TG, oxidative stress, fibrinogen etc) Endothelial dysfunction is regarded as the first abnormality leading to atherosclerosis This implies that modulation of endothelial function may be used as strategy to intervene the process. 15 Two theories gain more acceptance: (a) the lipid theory (b) inflammation theory Endothelial dysfunction is now regarded as the first abnormality leading to AS. More novel cardiovascular risk factors are known, e.g.: Fibrinogen b. PAI-1 Homocysteins d. AT-1 e. CRP f. Lp(a) g. small-dense LDL h. infectious agents i. and more are emerging 16 Acute Coronary Syndrome (endocrine viewpoints) atherosclerotic lesions vascular funtions b.1. inflammatory reaction b.2. thrombogeneity b.3. vasoreactivity b.4. plaque stability b.5. shoulder of plaque endothelium balance between c.1. vasodilating, antithrombotic, antiproliferative factors (NO, prostacyclin, C-natriuretic peptide, EDHF) c.2. vasoconstricting, prothrombotic, proliferative factors (ET, superoxide, thromoboxan A2) 17 NATURAL HISTORY OF CORONARY ATHEROSCLEROSIS Chatzizisis et all. JACC. 2007. Asymtomatic Stable Angina Acute Coronary Syndrome Early fibroatheroma Compensatory expansive remodeling Quiescent plaque Contrictive remodeling Stenotic plaque Exessive expansive remodeling Thin cap fibroatheroma Erosion Physiologic coronary artery Local factors, e.g. low ESS Systemic factors, e.g. hyperlipidemia Genetic factors Physiologic ESS Limited inflammation Fibroproliferation Microruptures 18 ATHEROSCLEROSIS IS AN INFLAMMATORY DISEASE Libby P. Circulation. 2001;104:365-372; Ross R. N Engl J Med. 1999;340:115-126. Monocyte LDL-C Adhesion molecule Macrophage Foam cell OxidizedLDL-C Plaque rupture Smooth muscle cells CRP Plaque instability and thrombus Oxidation Inflammation Endothelial dysfunction 19 20 Reverse Cholesterol Transport Monocyte CRP TXA2 PGI2 Thrombin LDL Platelets HDL HDL Ox-LDL MCP-1 Macrophage P-selectin CD 40L PDGF Foam cell MMP T cell E-selectins CD 40L VCAM-1 ICAM-1 IL-1 Reilly, et.all. 2005 21 THE ROLE OF Lp-PLA2 IN CHD LUMEN Monocytes Adhesion Molecules Oxidated LDL INTIMA MEDIA Lp-PLA2 Lyso-PC OxFA Cytokines Plaque Formation Foam Cell Macrophage 22 MC T T FC FC LDL Oxidation Lyso-PC Ox-chol Cytokines Cytokines ? C5a C’ MCP-1 F SMC 23 Intracelluler proteolysis and fusion of LDL Figure : Proposed Dual Action of Exocytosed Mast Cell Granules (The Granule Remnants) of Lipoprotein Metabolism in The Arterial Intima 24 HSCRP 25 26 GM-CSF VCAM-1 MPC-1 Transcription Factors : Endothelial Cell Pro-inflammatory Genes Oxidative Stress NF-xB AP-1 Leucocyte infiltration / activation Plaque Rupture Gibbons, 97 LEUCOCYTE ACTIVATION IN ATHEROGENESIS : IMPLICATIONS FOR ACUTE ISCHEMIC SYNDROMES 27 p38 c-Jun activation Caspases Apoptosis NIK ? ? MEKK1?   CKII IKK complex TNFR-1 TNFR-1 IL-1R Shear stress p65 p50 CBP/p300 Gene activation p65 p50 IB pKAc IB Ub Target genes : - IL-1, IL-8, IL-6, IFN  - TNF, MCP-1 - CSFs, c-myc - VCAM-1, ICAM-1, E-selectin - Tissue factor - Survival factor Thurberg and Collins : Curr Opin Lipidol 9:387-396,1998 Ub Ox-LDL ROIs ??? Lipid peroxides ? H2O2 Ubiquitination and proteosome degradation T R A D D R I P F A D D R I P T R A D D T R A F 2 T R A F 6 28 Visual Medica. 2009 29 Stockley. 2006 Cytokines : IL-6, TNF-α MACROPHAGE FOAM CELL Oxidized LDL CRP CRP Chemokines: MCO-1 Atherosclerotic plaque MONOCYTE Inflammatory Mediators: CRP Prothrombotic factors FCR Receptor 30 POTENTIAL MECHANISM OF CRP Stevens, R. 2005 CRP LDL opsonisation Monocyte infiltration Foam cell formation Increased MCP-1 and CAM EC activation Inflammatory cell recruitment Atherosclerosis plaque formation Complement activation EC sensitisation T-cell attack EC damage Atherosclerotic plaque rupture 31 Rheumatoid arthritis Atherosclerosis Multiple sclerosis Asthma Inflammatory bowel disease Helicobacter pylori-associated gastritis Systemic inflammatory response syndrome NF-KB ACTIVATION INFLAMMATORY DISEASE The Journal of Clinical Investigation, 2001 32 PROTEIN REGULATED BY NF-KB Inflammatory Enzyme Adhesion Molecule Inducible nitric oxide synthase Inducide cylooxigenase-2 5-Lipoxigenase Cytosolic phospolipase A2 ICAM-1 VCAM-1 E-selectin Receptor Interlekin-2 receptor (alpha chain) T-cell receptors (beta chain) NEJM, 1997 33 BIOMARKERS OF ACTIVITY STUDIED FOR CAD Cytokines (IL-1β, IL-6, IL-8, IL-10, TNF-α, sCD40 ligand, myeloperoxidase) Adhesion molecules (sICAM-1, sVCAM-1, p-selectin) Acute phase reactans (fibrinogen, AAS, CRP) White blood cells Erythrocyte sedimentation rate Neopterin Heat shock proteins Adiponectin Lipoprotein associated phospholipase A2 Placental growth factos Cystatin C Kaski, JC. 2006.
Slide 34 - 1 Nama : Prof. Dr. H. Djanggan Sargowo, dr., SpPD., SpJP(K), FIHA, FACC, FESC, FCAPC, FASCC Tempat/Tgl lahir : Sragen, 21 September 1947 Alamat : Wilis Indah E-10 Malang, Telp. 0341-552395 Pendidikan : Lulus Dokter dari UGM, tahun 1974 Lulus Cardiologist dari Univ. Indonesia, tahun 1983 Lulus Internist dari Univ. Airlangga, tahun 1986 Lulus Doktor, Univ. Airlangga, tahun 1996 Advanced Cardiology Course, Univ. Hongkong, tahun 1984 Senior Visiting Program, Institut Jantung Negara, Kualalumpur, 1996 Fellow American College of Cardiology (FACC), September 2006. Fellow Collage Asia Pacific Society of Cardiology (FCAPC), Desember 2007 Fellow European Sociaty of Cardiology (FESC), 2008 Fellow Asean Collage of Cardiology (FASCC), 2008 Jabatan : Dosen Pengajar Program Pascasarjana Universitas Brawijaya Ketua MKEK Ikatan Dokter Indonesia Cabang Malang Raya Ketua PERKI Cabang Malang Raya Anggota Kolegium Kardiovaskuler Indonesia Dekan Fak. Kedokteran Univ. Wijaya Kusuma Surabaya Ketua Dewan Pengawas Rumah Sakit Pendidikan Ketua Program Studi Kardiovascular Fak. Kedokteran Univ. Brawijaya Curriculum Vitae 2 Djanggan Sargowo Surabaya, 15 April 2012 INFLAMMATION IN ATHEROSCLEROSIS : FROM BENCH TO BEDSIDE 3 4 RUDOLF VIRCHOW Inflammation-based arterial changes as a mechanism of primary importance in atherogenesis mid 19th century Lamond, B. The American Journal of Pathology. 2008 5 Atherosclerosis Start from very young To Old age ? 6 Atherothrombosis* is aLeading Cause of Death Worldwide1† The World Health Report, 2002, WHO Geneva, 2002 28.7 17.8 12.6 9.1 6 5.1 0 5 10 15 20 25 30 Atherothrombosis* Infectious disease Cancer Injuries Pulmonary disease AIDS Mortality (%) * Ischemic heart disease, cerebrovascular disease, inflammatory heart disease and hypertensive heart disease † Worldwide defined as Member States by WHO Region (Africa, Americas, Eastern Mediterranean, European, South-East Asia and Western Pacific) 7 MAJOR CLINICAL MANIFESTATIONS OF ATHEROTHROMBOSIS Adapted from: Drouet L. Cerebrovasc Dis 2002; 13(suppl 1): 1–6. Transient ischemic attack Angina: Stable Unstable Ischemic stroke Myocardial infarction Peripheral arterial disease: Intermittent claudication Rest Pain Gangrene Necrosis 8  Dyslipidemia  Endothelial dysfunction  Free radicals  Immunologic Atherosclerosis/CAD THEORY AND CONCEPT OF ATHEROSCLEROSIS Inflamation (Sargowo, 1996) 9 Free Radical ATHEROGENESIS (Sargowo, 1996) 10 IDENTIFYING THOSE AT RISK OF ATHEROTHROMBOSIS Yusuf S et al. Circulation 2001; 104: 2746–53. 2. Drouet L. Cerebrovasc Dis 2002;13(suppl 1):1–6. Lifestyle Smoking Diet Lack of exercise Genetic Genetic traits Gender Age Generalized disorders Obesity Diabetes Systemic conditions History of vascular events Hypertension Hyperlipidemia Hypercoagulable states Homocystinemia Local factors Elevated prothrombotic factors: fibrinogen, CRP, PAI-1 Blood flow patterns, vessel diameter, arterial wall structure Atherothrombosis manifestations (myocardial infarction, stroke, vascular death) 11 Arici. 2010 Risk Factors for Atherosclerosis Classic Hypertension, Hyper-lipidemia, DM, Smoking Uremia Related Increase ox-LDL, Free radicals, Uremic toxin Infection Bacterial and viral infection Proinflammatory cytokine release Endothelial dysfunction Systemic inflammatory respones Acute phase response Elevated CRP Binding LDL, cemplement activation, tissue factor secretion Accelerated ATHEROSCLEROSIS 12 LDL CD40L=CD40 ligand; TNF-α=tumor necrosis factor-alpha; IL=interleukin; VCAM=vascular cell adhesion molecule; ICAM=intercellular adhesion molecule. Cockerill GW et al. Arterioscler Thromb Vasc Biol. 1995;15:1987-1994; Andre P et al. Circulation. 2002;106:896-899; Libby P. Circulation. 2001;104:365-372; Libby P et al. Circulation. 2002;105:1135-1143; Ross R. N Engl J Med. 1999;340:115-126. Vessel lumen Monocyte Macrophage Adhesionmolecules (VCAM-1, ICAM-1) Inflammatory mediators (CRP, CD40/CD40L, TNF-α, IL-1, IL-6) Intima Foam cell INFLAMMATION PROMOTES PROGRESSION OF ATHEROSCLEROSIS Endothelium LDL Ox-LDL 13 14 Atherosclerosis is a fibroproliferative and inflammatory process occurring ins response to a variety of vascular insults The insults come from classical risk factors ( HT, dyslipidemia, endothelial dysfunction, smoking, menopause, diabetes etc) and novel risk factors (Hcy, LVH, Lp(a), TG, oxidative stress, fibrinogen etc) Endothelial dysfunction is regarded as the first abnormality leading to atherosclerosis This implies that modulation of endothelial function may be used as strategy to intervene the process. 15 Two theories gain more acceptance: (a) the lipid theory (b) inflammation theory Endothelial dysfunction is now regarded as the first abnormality leading to AS. More novel cardiovascular risk factors are known, e.g.: Fibrinogen b. PAI-1 Homocysteins d. AT-1 e. CRP f. Lp(a) g. small-dense LDL h. infectious agents i. and more are emerging 16 Acute Coronary Syndrome (endocrine viewpoints) atherosclerotic lesions vascular funtions b.1. inflammatory reaction b.2. thrombogeneity b.3. vasoreactivity b.4. plaque stability b.5. shoulder of plaque endothelium balance between c.1. vasodilating, antithrombotic, antiproliferative factors (NO, prostacyclin, C-natriuretic peptide, EDHF) c.2. vasoconstricting, prothrombotic, proliferative factors (ET, superoxide, thromoboxan A2) 17 NATURAL HISTORY OF CORONARY ATHEROSCLEROSIS Chatzizisis et all. JACC. 2007. Asymtomatic Stable Angina Acute Coronary Syndrome Early fibroatheroma Compensatory expansive remodeling Quiescent plaque Contrictive remodeling Stenotic plaque Exessive expansive remodeling Thin cap fibroatheroma Erosion Physiologic coronary artery Local factors, e.g. low ESS Systemic factors, e.g. hyperlipidemia Genetic factors Physiologic ESS Limited inflammation Fibroproliferation Microruptures 18 ATHEROSCLEROSIS IS AN INFLAMMATORY DISEASE Libby P. Circulation. 2001;104:365-372; Ross R. N Engl J Med. 1999;340:115-126. Monocyte LDL-C Adhesion molecule Macrophage Foam cell OxidizedLDL-C Plaque rupture Smooth muscle cells CRP Plaque instability and thrombus Oxidation Inflammation Endothelial dysfunction 19 20 Reverse Cholesterol Transport Monocyte CRP TXA2 PGI2 Thrombin LDL Platelets HDL HDL Ox-LDL MCP-1 Macrophage P-selectin CD 40L PDGF Foam cell MMP T cell E-selectins CD 40L VCAM-1 ICAM-1 IL-1 Reilly, et.all. 2005 21 THE ROLE OF Lp-PLA2 IN CHD LUMEN Monocytes Adhesion Molecules Oxidated LDL INTIMA MEDIA Lp-PLA2 Lyso-PC OxFA Cytokines Plaque Formation Foam Cell Macrophage 22 MC T T FC FC LDL Oxidation Lyso-PC Ox-chol Cytokines Cytokines ? C5a C’ MCP-1 F SMC 23 Intracelluler proteolysis and fusion of LDL Figure : Proposed Dual Action of Exocytosed Mast Cell Granules (The Granule Remnants) of Lipoprotein Metabolism in The Arterial Intima 24 HSCRP 25 26 GM-CSF VCAM-1 MPC-1 Transcription Factors : Endothelial Cell Pro-inflammatory Genes Oxidative Stress NF-xB AP-1 Leucocyte infiltration / activation Plaque Rupture Gibbons, 97 LEUCOCYTE ACTIVATION IN ATHEROGENESIS : IMPLICATIONS FOR ACUTE ISCHEMIC SYNDROMES 27 p38 c-Jun activation Caspases Apoptosis NIK ? ? MEKK1?   CKII IKK complex TNFR-1 TNFR-1 IL-1R Shear stress p65 p50 CBP/p300 Gene activation p65 p50 IB pKAc IB Ub Target genes : - IL-1, IL-8, IL-6, IFN  - TNF, MCP-1 - CSFs, c-myc - VCAM-1, ICAM-1, E-selectin - Tissue factor - Survival factor Thurberg and Collins : Curr Opin Lipidol 9:387-396,1998 Ub Ox-LDL ROIs ??? Lipid peroxides ? H2O2 Ubiquitination and proteosome degradation T R A D D R I P F A D D R I P T R A D D T R A F 2 T R A F 6 28 Visual Medica. 2009 29 Stockley. 2006 Cytokines : IL-6, TNF-α MACROPHAGE FOAM CELL Oxidized LDL CRP CRP Chemokines: MCO-1 Atherosclerotic plaque MONOCYTE Inflammatory Mediators: CRP Prothrombotic factors FCR Receptor 30 POTENTIAL MECHANISM OF CRP Stevens, R. 2005 CRP LDL opsonisation Monocyte infiltration Foam cell formation Increased MCP-1 and CAM EC activation Inflammatory cell recruitment Atherosclerosis plaque formation Complement activation EC sensitisation T-cell attack EC damage Atherosclerotic plaque rupture 31 Rheumatoid arthritis Atherosclerosis Multiple sclerosis Asthma Inflammatory bowel disease Helicobacter pylori-associated gastritis Systemic inflammatory response syndrome NF-KB ACTIVATION INFLAMMATORY DISEASE The Journal of Clinical Investigation, 2001 32 PROTEIN REGULATED BY NF-KB Inflammatory Enzyme Adhesion Molecule Inducible nitric oxide synthase Inducide cylooxigenase-2 5-Lipoxigenase Cytosolic phospolipase A2 ICAM-1 VCAM-1 E-selectin Receptor Interlekin-2 receptor (alpha chain) T-cell receptors (beta chain) NEJM, 1997 33 BIOMARKERS OF ACTIVITY STUDIED FOR CAD Cytokines (IL-1β, IL-6, IL-8, IL-10, TNF-α, sCD40 ligand, myeloperoxidase) Adhesion molecules (sICAM-1, sVCAM-1, p-selectin) Acute phase reactans (fibrinogen, AAS, CRP) White blood cells Erythrocyte sedimentation rate Neopterin Heat shock proteins Adiponectin Lipoprotein associated phospholipase A2 Placental growth factos Cystatin C Kaski, JC. 2006. 34 Are you hungry or sleepy ???? Sciences
Slide 35 - 1 Nama : Prof. Dr. H. Djanggan Sargowo, dr., SpPD., SpJP(K), FIHA, FACC, FESC, FCAPC, FASCC Tempat/Tgl lahir : Sragen, 21 September 1947 Alamat : Wilis Indah E-10 Malang, Telp. 0341-552395 Pendidikan : Lulus Dokter dari UGM, tahun 1974 Lulus Cardiologist dari Univ. Indonesia, tahun 1983 Lulus Internist dari Univ. Airlangga, tahun 1986 Lulus Doktor, Univ. Airlangga, tahun 1996 Advanced Cardiology Course, Univ. Hongkong, tahun 1984 Senior Visiting Program, Institut Jantung Negara, Kualalumpur, 1996 Fellow American College of Cardiology (FACC), September 2006. Fellow Collage Asia Pacific Society of Cardiology (FCAPC), Desember 2007 Fellow European Sociaty of Cardiology (FESC), 2008 Fellow Asean Collage of Cardiology (FASCC), 2008 Jabatan : Dosen Pengajar Program Pascasarjana Universitas Brawijaya Ketua MKEK Ikatan Dokter Indonesia Cabang Malang Raya Ketua PERKI Cabang Malang Raya Anggota Kolegium Kardiovaskuler Indonesia Dekan Fak. Kedokteran Univ. Wijaya Kusuma Surabaya Ketua Dewan Pengawas Rumah Sakit Pendidikan Ketua Program Studi Kardiovascular Fak. Kedokteran Univ. Brawijaya Curriculum Vitae 2 Djanggan Sargowo Surabaya, 15 April 2012 INFLAMMATION IN ATHEROSCLEROSIS : FROM BENCH TO BEDSIDE 3 4 RUDOLF VIRCHOW Inflammation-based arterial changes as a mechanism of primary importance in atherogenesis mid 19th century Lamond, B. The American Journal of Pathology. 2008 5 Atherosclerosis Start from very young To Old age ? 6 Atherothrombosis* is aLeading Cause of Death Worldwide1† The World Health Report, 2002, WHO Geneva, 2002 28.7 17.8 12.6 9.1 6 5.1 0 5 10 15 20 25 30 Atherothrombosis* Infectious disease Cancer Injuries Pulmonary disease AIDS Mortality (%) * Ischemic heart disease, cerebrovascular disease, inflammatory heart disease and hypertensive heart disease † Worldwide defined as Member States by WHO Region (Africa, Americas, Eastern Mediterranean, European, South-East Asia and Western Pacific) 7 MAJOR CLINICAL MANIFESTATIONS OF ATHEROTHROMBOSIS Adapted from: Drouet L. Cerebrovasc Dis 2002; 13(suppl 1): 1–6. Transient ischemic attack Angina: Stable Unstable Ischemic stroke Myocardial infarction Peripheral arterial disease: Intermittent claudication Rest Pain Gangrene Necrosis 8  Dyslipidemia  Endothelial dysfunction  Free radicals  Immunologic Atherosclerosis/CAD THEORY AND CONCEPT OF ATHEROSCLEROSIS Inflamation (Sargowo, 1996) 9 Free Radical ATHEROGENESIS (Sargowo, 1996) 10 IDENTIFYING THOSE AT RISK OF ATHEROTHROMBOSIS Yusuf S et al. Circulation 2001; 104: 2746–53. 2. Drouet L. Cerebrovasc Dis 2002;13(suppl 1):1–6. Lifestyle Smoking Diet Lack of exercise Genetic Genetic traits Gender Age Generalized disorders Obesity Diabetes Systemic conditions History of vascular events Hypertension Hyperlipidemia Hypercoagulable states Homocystinemia Local factors Elevated prothrombotic factors: fibrinogen, CRP, PAI-1 Blood flow patterns, vessel diameter, arterial wall structure Atherothrombosis manifestations (myocardial infarction, stroke, vascular death) 11 Arici. 2010 Risk Factors for Atherosclerosis Classic Hypertension, Hyper-lipidemia, DM, Smoking Uremia Related Increase ox-LDL, Free radicals, Uremic toxin Infection Bacterial and viral infection Proinflammatory cytokine release Endothelial dysfunction Systemic inflammatory respones Acute phase response Elevated CRP Binding LDL, cemplement activation, tissue factor secretion Accelerated ATHEROSCLEROSIS 12 LDL CD40L=CD40 ligand; TNF-α=tumor necrosis factor-alpha; IL=interleukin; VCAM=vascular cell adhesion molecule; ICAM=intercellular adhesion molecule. Cockerill GW et al. Arterioscler Thromb Vasc Biol. 1995;15:1987-1994; Andre P et al. Circulation. 2002;106:896-899; Libby P. Circulation. 2001;104:365-372; Libby P et al. Circulation. 2002;105:1135-1143; Ross R. N Engl J Med. 1999;340:115-126. Vessel lumen Monocyte Macrophage Adhesionmolecules (VCAM-1, ICAM-1) Inflammatory mediators (CRP, CD40/CD40L, TNF-α, IL-1, IL-6) Intima Foam cell INFLAMMATION PROMOTES PROGRESSION OF ATHEROSCLEROSIS Endothelium LDL Ox-LDL 13 14 Atherosclerosis is a fibroproliferative and inflammatory process occurring ins response to a variety of vascular insults The insults come from classical risk factors ( HT, dyslipidemia, endothelial dysfunction, smoking, menopause, diabetes etc) and novel risk factors (Hcy, LVH, Lp(a), TG, oxidative stress, fibrinogen etc) Endothelial dysfunction is regarded as the first abnormality leading to atherosclerosis This implies that modulation of endothelial function may be used as strategy to intervene the process. 15 Two theories gain more acceptance: (a) the lipid theory (b) inflammation theory Endothelial dysfunction is now regarded as the first abnormality leading to AS. More novel cardiovascular risk factors are known, e.g.: Fibrinogen b. PAI-1 Homocysteins d. AT-1 e. CRP f. Lp(a) g. small-dense LDL h. infectious agents i. and more are emerging 16 Acute Coronary Syndrome (endocrine viewpoints) atherosclerotic lesions vascular funtions b.1. inflammatory reaction b.2. thrombogeneity b.3. vasoreactivity b.4. plaque stability b.5. shoulder of plaque endothelium balance between c.1. vasodilating, antithrombotic, antiproliferative factors (NO, prostacyclin, C-natriuretic peptide, EDHF) c.2. vasoconstricting, prothrombotic, proliferative factors (ET, superoxide, thromoboxan A2) 17 NATURAL HISTORY OF CORONARY ATHEROSCLEROSIS Chatzizisis et all. JACC. 2007. Asymtomatic Stable Angina Acute Coronary Syndrome Early fibroatheroma Compensatory expansive remodeling Quiescent plaque Contrictive remodeling Stenotic plaque Exessive expansive remodeling Thin cap fibroatheroma Erosion Physiologic coronary artery Local factors, e.g. low ESS Systemic factors, e.g. hyperlipidemia Genetic factors Physiologic ESS Limited inflammation Fibroproliferation Microruptures 18 ATHEROSCLEROSIS IS AN INFLAMMATORY DISEASE Libby P. Circulation. 2001;104:365-372; Ross R. N Engl J Med. 1999;340:115-126. Monocyte LDL-C Adhesion molecule Macrophage Foam cell OxidizedLDL-C Plaque rupture Smooth muscle cells CRP Plaque instability and thrombus Oxidation Inflammation Endothelial dysfunction 19 20 Reverse Cholesterol Transport Monocyte CRP TXA2 PGI2 Thrombin LDL Platelets HDL HDL Ox-LDL MCP-1 Macrophage P-selectin CD 40L PDGF Foam cell MMP T cell E-selectins CD 40L VCAM-1 ICAM-1 IL-1 Reilly, et.all. 2005 21 THE ROLE OF Lp-PLA2 IN CHD LUMEN Monocytes Adhesion Molecules Oxidated LDL INTIMA MEDIA Lp-PLA2 Lyso-PC OxFA Cytokines Plaque Formation Foam Cell Macrophage 22 MC T T FC FC LDL Oxidation Lyso-PC Ox-chol Cytokines Cytokines ? C5a C’ MCP-1 F SMC 23 Intracelluler proteolysis and fusion of LDL Figure : Proposed Dual Action of Exocytosed Mast Cell Granules (The Granule Remnants) of Lipoprotein Metabolism in The Arterial Intima 24 HSCRP 25 26 GM-CSF VCAM-1 MPC-1 Transcription Factors : Endothelial Cell Pro-inflammatory Genes Oxidative Stress NF-xB AP-1 Leucocyte infiltration / activation Plaque Rupture Gibbons, 97 LEUCOCYTE ACTIVATION IN ATHEROGENESIS : IMPLICATIONS FOR ACUTE ISCHEMIC SYNDROMES 27 p38 c-Jun activation Caspases Apoptosis NIK ? ? MEKK1?   CKII IKK complex TNFR-1 TNFR-1 IL-1R Shear stress p65 p50 CBP/p300 Gene activation p65 p50 IB pKAc IB Ub Target genes : - IL-1, IL-8, IL-6, IFN  - TNF, MCP-1 - CSFs, c-myc - VCAM-1, ICAM-1, E-selectin - Tissue factor - Survival factor Thurberg and Collins : Curr Opin Lipidol 9:387-396,1998 Ub Ox-LDL ROIs ??? Lipid peroxides ? H2O2 Ubiquitination and proteosome degradation T R A D D R I P F A D D R I P T R A D D T R A F 2 T R A F 6 28 Visual Medica. 2009 29 Stockley. 2006 Cytokines : IL-6, TNF-α MACROPHAGE FOAM CELL Oxidized LDL CRP CRP Chemokines: MCO-1 Atherosclerotic plaque MONOCYTE Inflammatory Mediators: CRP Prothrombotic factors FCR Receptor 30 POTENTIAL MECHANISM OF CRP Stevens, R. 2005 CRP LDL opsonisation Monocyte infiltration Foam cell formation Increased MCP-1 and CAM EC activation Inflammatory cell recruitment Atherosclerosis plaque formation Complement activation EC sensitisation T-cell attack EC damage Atherosclerotic plaque rupture 31 Rheumatoid arthritis Atherosclerosis Multiple sclerosis Asthma Inflammatory bowel disease Helicobacter pylori-associated gastritis Systemic inflammatory response syndrome NF-KB ACTIVATION INFLAMMATORY DISEASE The Journal of Clinical Investigation, 2001 32 PROTEIN REGULATED BY NF-KB Inflammatory Enzyme Adhesion Molecule Inducible nitric oxide synthase Inducide cylooxigenase-2 5-Lipoxigenase Cytosolic phospolipase A2 ICAM-1 VCAM-1 E-selectin Receptor Interlekin-2 receptor (alpha chain) T-cell receptors (beta chain) NEJM, 1997 33 BIOMARKERS OF ACTIVITY STUDIED FOR CAD Cytokines (IL-1β, IL-6, IL-8, IL-10, TNF-α, sCD40 ligand, myeloperoxidase) Adhesion molecules (sICAM-1, sVCAM-1, p-selectin) Acute phase reactans (fibrinogen, AAS, CRP) White blood cells Erythrocyte sedimentation rate Neopterin Heat shock proteins Adiponectin Lipoprotein associated phospholipase A2 Placental growth factos Cystatin C Kaski, JC. 2006. 34 Are you hungry or sleepy ???? Sciences 35 The inflammatory cascade. IL indicates interleukin; ICAM, intercellular adhesion molecule; and HSP, heat shock protein. (Libby, Ridker; 1999) Pro-Inflammatory Risk Factors Primary Pro-Inflammatory Cytokines (eg. IL-1, TNF-) IL-6 “Mesenger” Cytokine CRP SAA Endothelium and other cells LIVER Circulation
Slide 36 - 1 Nama : Prof. Dr. H. Djanggan Sargowo, dr., SpPD., SpJP(K), FIHA, FACC, FESC, FCAPC, FASCC Tempat/Tgl lahir : Sragen, 21 September 1947 Alamat : Wilis Indah E-10 Malang, Telp. 0341-552395 Pendidikan : Lulus Dokter dari UGM, tahun 1974 Lulus Cardiologist dari Univ. Indonesia, tahun 1983 Lulus Internist dari Univ. Airlangga, tahun 1986 Lulus Doktor, Univ. Airlangga, tahun 1996 Advanced Cardiology Course, Univ. Hongkong, tahun 1984 Senior Visiting Program, Institut Jantung Negara, Kualalumpur, 1996 Fellow American College of Cardiology (FACC), September 2006. Fellow Collage Asia Pacific Society of Cardiology (FCAPC), Desember 2007 Fellow European Sociaty of Cardiology (FESC), 2008 Fellow Asean Collage of Cardiology (FASCC), 2008 Jabatan : Dosen Pengajar Program Pascasarjana Universitas Brawijaya Ketua MKEK Ikatan Dokter Indonesia Cabang Malang Raya Ketua PERKI Cabang Malang Raya Anggota Kolegium Kardiovaskuler Indonesia Dekan Fak. Kedokteran Univ. Wijaya Kusuma Surabaya Ketua Dewan Pengawas Rumah Sakit Pendidikan Ketua Program Studi Kardiovascular Fak. Kedokteran Univ. Brawijaya Curriculum Vitae 2 Djanggan Sargowo Surabaya, 15 April 2012 INFLAMMATION IN ATHEROSCLEROSIS : FROM BENCH TO BEDSIDE 3 4 RUDOLF VIRCHOW Inflammation-based arterial changes as a mechanism of primary importance in atherogenesis mid 19th century Lamond, B. The American Journal of Pathology. 2008 5 Atherosclerosis Start from very young To Old age ? 6 Atherothrombosis* is aLeading Cause of Death Worldwide1† The World Health Report, 2002, WHO Geneva, 2002 28.7 17.8 12.6 9.1 6 5.1 0 5 10 15 20 25 30 Atherothrombosis* Infectious disease Cancer Injuries Pulmonary disease AIDS Mortality (%) * Ischemic heart disease, cerebrovascular disease, inflammatory heart disease and hypertensive heart disease † Worldwide defined as Member States by WHO Region (Africa, Americas, Eastern Mediterranean, European, South-East Asia and Western Pacific) 7 MAJOR CLINICAL MANIFESTATIONS OF ATHEROTHROMBOSIS Adapted from: Drouet L. Cerebrovasc Dis 2002; 13(suppl 1): 1–6. Transient ischemic attack Angina: Stable Unstable Ischemic stroke Myocardial infarction Peripheral arterial disease: Intermittent claudication Rest Pain Gangrene Necrosis 8  Dyslipidemia  Endothelial dysfunction  Free radicals  Immunologic Atherosclerosis/CAD THEORY AND CONCEPT OF ATHEROSCLEROSIS Inflamation (Sargowo, 1996) 9 Free Radical ATHEROGENESIS (Sargowo, 1996) 10 IDENTIFYING THOSE AT RISK OF ATHEROTHROMBOSIS Yusuf S et al. Circulation 2001; 104: 2746–53. 2. Drouet L. Cerebrovasc Dis 2002;13(suppl 1):1–6. Lifestyle Smoking Diet Lack of exercise Genetic Genetic traits Gender Age Generalized disorders Obesity Diabetes Systemic conditions History of vascular events Hypertension Hyperlipidemia Hypercoagulable states Homocystinemia Local factors Elevated prothrombotic factors: fibrinogen, CRP, PAI-1 Blood flow patterns, vessel diameter, arterial wall structure Atherothrombosis manifestations (myocardial infarction, stroke, vascular death) 11 Arici. 2010 Risk Factors for Atherosclerosis Classic Hypertension, Hyper-lipidemia, DM, Smoking Uremia Related Increase ox-LDL, Free radicals, Uremic toxin Infection Bacterial and viral infection Proinflammatory cytokine release Endothelial dysfunction Systemic inflammatory respones Acute phase response Elevated CRP Binding LDL, cemplement activation, tissue factor secretion Accelerated ATHEROSCLEROSIS 12 LDL CD40L=CD40 ligand; TNF-α=tumor necrosis factor-alpha; IL=interleukin; VCAM=vascular cell adhesion molecule; ICAM=intercellular adhesion molecule. Cockerill GW et al. Arterioscler Thromb Vasc Biol. 1995;15:1987-1994; Andre P et al. Circulation. 2002;106:896-899; Libby P. Circulation. 2001;104:365-372; Libby P et al. Circulation. 2002;105:1135-1143; Ross R. N Engl J Med. 1999;340:115-126. Vessel lumen Monocyte Macrophage Adhesionmolecules (VCAM-1, ICAM-1) Inflammatory mediators (CRP, CD40/CD40L, TNF-α, IL-1, IL-6) Intima Foam cell INFLAMMATION PROMOTES PROGRESSION OF ATHEROSCLEROSIS Endothelium LDL Ox-LDL 13 14 Atherosclerosis is a fibroproliferative and inflammatory process occurring ins response to a variety of vascular insults The insults come from classical risk factors ( HT, dyslipidemia, endothelial dysfunction, smoking, menopause, diabetes etc) and novel risk factors (Hcy, LVH, Lp(a), TG, oxidative stress, fibrinogen etc) Endothelial dysfunction is regarded as the first abnormality leading to atherosclerosis This implies that modulation of endothelial function may be used as strategy to intervene the process. 15 Two theories gain more acceptance: (a) the lipid theory (b) inflammation theory Endothelial dysfunction is now regarded as the first abnormality leading to AS. More novel cardiovascular risk factors are known, e.g.: Fibrinogen b. PAI-1 Homocysteins d. AT-1 e. CRP f. Lp(a) g. small-dense LDL h. infectious agents i. and more are emerging 16 Acute Coronary Syndrome (endocrine viewpoints) atherosclerotic lesions vascular funtions b.1. inflammatory reaction b.2. thrombogeneity b.3. vasoreactivity b.4. plaque stability b.5. shoulder of plaque endothelium balance between c.1. vasodilating, antithrombotic, antiproliferative factors (NO, prostacyclin, C-natriuretic peptide, EDHF) c.2. vasoconstricting, prothrombotic, proliferative factors (ET, superoxide, thromoboxan A2) 17 NATURAL HISTORY OF CORONARY ATHEROSCLEROSIS Chatzizisis et all. JACC. 2007. Asymtomatic Stable Angina Acute Coronary Syndrome Early fibroatheroma Compensatory expansive remodeling Quiescent plaque Contrictive remodeling Stenotic plaque Exessive expansive remodeling Thin cap fibroatheroma Erosion Physiologic coronary artery Local factors, e.g. low ESS Systemic factors, e.g. hyperlipidemia Genetic factors Physiologic ESS Limited inflammation Fibroproliferation Microruptures 18 ATHEROSCLEROSIS IS AN INFLAMMATORY DISEASE Libby P. Circulation. 2001;104:365-372; Ross R. N Engl J Med. 1999;340:115-126. Monocyte LDL-C Adhesion molecule Macrophage Foam cell OxidizedLDL-C Plaque rupture Smooth muscle cells CRP Plaque instability and thrombus Oxidation Inflammation Endothelial dysfunction 19 20 Reverse Cholesterol Transport Monocyte CRP TXA2 PGI2 Thrombin LDL Platelets HDL HDL Ox-LDL MCP-1 Macrophage P-selectin CD 40L PDGF Foam cell MMP T cell E-selectins CD 40L VCAM-1 ICAM-1 IL-1 Reilly, et.all. 2005 21 THE ROLE OF Lp-PLA2 IN CHD LUMEN Monocytes Adhesion Molecules Oxidated LDL INTIMA MEDIA Lp-PLA2 Lyso-PC OxFA Cytokines Plaque Formation Foam Cell Macrophage 22 MC T T FC FC LDL Oxidation Lyso-PC Ox-chol Cytokines Cytokines ? C5a C’ MCP-1 F SMC 23 Intracelluler proteolysis and fusion of LDL Figure : Proposed Dual Action of Exocytosed Mast Cell Granules (The Granule Remnants) of Lipoprotein Metabolism in The Arterial Intima 24 HSCRP 25 26 GM-CSF VCAM-1 MPC-1 Transcription Factors : Endothelial Cell Pro-inflammatory Genes Oxidative Stress NF-xB AP-1 Leucocyte infiltration / activation Plaque Rupture Gibbons, 97 LEUCOCYTE ACTIVATION IN ATHEROGENESIS : IMPLICATIONS FOR ACUTE ISCHEMIC SYNDROMES 27 p38 c-Jun activation Caspases Apoptosis NIK ? ? MEKK1?   CKII IKK complex TNFR-1 TNFR-1 IL-1R Shear stress p65 p50 CBP/p300 Gene activation p65 p50 IB pKAc IB Ub Target genes : - IL-1, IL-8, IL-6, IFN  - TNF, MCP-1 - CSFs, c-myc - VCAM-1, ICAM-1, E-selectin - Tissue factor - Survival factor Thurberg and Collins : Curr Opin Lipidol 9:387-396,1998 Ub Ox-LDL ROIs ??? Lipid peroxides ? H2O2 Ubiquitination and proteosome degradation T R A D D R I P F A D D R I P T R A D D T R A F 2 T R A F 6 28 Visual Medica. 2009 29 Stockley. 2006 Cytokines : IL-6, TNF-α MACROPHAGE FOAM CELL Oxidized LDL CRP CRP Chemokines: MCO-1 Atherosclerotic plaque MONOCYTE Inflammatory Mediators: CRP Prothrombotic factors FCR Receptor 30 POTENTIAL MECHANISM OF CRP Stevens, R. 2005 CRP LDL opsonisation Monocyte infiltration Foam cell formation Increased MCP-1 and CAM EC activation Inflammatory cell recruitment Atherosclerosis plaque formation Complement activation EC sensitisation T-cell attack EC damage Atherosclerotic plaque rupture 31 Rheumatoid arthritis Atherosclerosis Multiple sclerosis Asthma Inflammatory bowel disease Helicobacter pylori-associated gastritis Systemic inflammatory response syndrome NF-KB ACTIVATION INFLAMMATORY DISEASE The Journal of Clinical Investigation, 2001 32 PROTEIN REGULATED BY NF-KB Inflammatory Enzyme Adhesion Molecule Inducible nitric oxide synthase Inducide cylooxigenase-2 5-Lipoxigenase Cytosolic phospolipase A2 ICAM-1 VCAM-1 E-selectin Receptor Interlekin-2 receptor (alpha chain) T-cell receptors (beta chain) NEJM, 1997 33 BIOMARKERS OF ACTIVITY STUDIED FOR CAD Cytokines (IL-1β, IL-6, IL-8, IL-10, TNF-α, sCD40 ligand, myeloperoxidase) Adhesion molecules (sICAM-1, sVCAM-1, p-selectin) Acute phase reactans (fibrinogen, AAS, CRP) White blood cells Erythrocyte sedimentation rate Neopterin Heat shock proteins Adiponectin Lipoprotein associated phospholipase A2 Placental growth factos Cystatin C Kaski, JC. 2006. 34 Are you hungry or sleepy ???? Sciences 35 The inflammatory cascade. IL indicates interleukin; ICAM, intercellular adhesion molecule; and HSP, heat shock protein. (Libby, Ridker; 1999) Pro-Inflammatory Risk Factors Primary Pro-Inflammatory Cytokines (eg. IL-1, TNF-) IL-6 “Mesenger” Cytokine CRP SAA Endothelium and other cells LIVER Circulation 36 (Ridker, 2004) MORE THAN A MARKER : DOES CRP PLAY A DIRECT ROLE IN ATHEROTHROMBOSIS ? CRP localizes in atherosclerotic but not normal intima CRP induced Complement activation CRP dependent monocyte recruitment into arterial wall CRP induced production of tissue factor in monocytes CRP based blunting of endothelial vasoreactivity CRP mediated LDL uptake by macrophages CRP triggered oxidation of LDL cholesterol CRP induced PAI-1 expression stabilizes PAI-1 mRNA CRP attenuates NO production and decreases eNOS expression CRP induced production of cell adhesion moleculas MCP-1, ET-1
Slide 37 - 1 Nama : Prof. Dr. H. Djanggan Sargowo, dr., SpPD., SpJP(K), FIHA, FACC, FESC, FCAPC, FASCC Tempat/Tgl lahir : Sragen, 21 September 1947 Alamat : Wilis Indah E-10 Malang, Telp. 0341-552395 Pendidikan : Lulus Dokter dari UGM, tahun 1974 Lulus Cardiologist dari Univ. Indonesia, tahun 1983 Lulus Internist dari Univ. Airlangga, tahun 1986 Lulus Doktor, Univ. Airlangga, tahun 1996 Advanced Cardiology Course, Univ. Hongkong, tahun 1984 Senior Visiting Program, Institut Jantung Negara, Kualalumpur, 1996 Fellow American College of Cardiology (FACC), September 2006. Fellow Collage Asia Pacific Society of Cardiology (FCAPC), Desember 2007 Fellow European Sociaty of Cardiology (FESC), 2008 Fellow Asean Collage of Cardiology (FASCC), 2008 Jabatan : Dosen Pengajar Program Pascasarjana Universitas Brawijaya Ketua MKEK Ikatan Dokter Indonesia Cabang Malang Raya Ketua PERKI Cabang Malang Raya Anggota Kolegium Kardiovaskuler Indonesia Dekan Fak. Kedokteran Univ. Wijaya Kusuma Surabaya Ketua Dewan Pengawas Rumah Sakit Pendidikan Ketua Program Studi Kardiovascular Fak. Kedokteran Univ. Brawijaya Curriculum Vitae 2 Djanggan Sargowo Surabaya, 15 April 2012 INFLAMMATION IN ATHEROSCLEROSIS : FROM BENCH TO BEDSIDE 3 4 RUDOLF VIRCHOW Inflammation-based arterial changes as a mechanism of primary importance in atherogenesis mid 19th century Lamond, B. The American Journal of Pathology. 2008 5 Atherosclerosis Start from very young To Old age ? 6 Atherothrombosis* is aLeading Cause of Death Worldwide1† The World Health Report, 2002, WHO Geneva, 2002 28.7 17.8 12.6 9.1 6 5.1 0 5 10 15 20 25 30 Atherothrombosis* Infectious disease Cancer Injuries Pulmonary disease AIDS Mortality (%) * Ischemic heart disease, cerebrovascular disease, inflammatory heart disease and hypertensive heart disease † Worldwide defined as Member States by WHO Region (Africa, Americas, Eastern Mediterranean, European, South-East Asia and Western Pacific) 7 MAJOR CLINICAL MANIFESTATIONS OF ATHEROTHROMBOSIS Adapted from: Drouet L. Cerebrovasc Dis 2002; 13(suppl 1): 1–6. Transient ischemic attack Angina: Stable Unstable Ischemic stroke Myocardial infarction Peripheral arterial disease: Intermittent claudication Rest Pain Gangrene Necrosis 8  Dyslipidemia  Endothelial dysfunction  Free radicals  Immunologic Atherosclerosis/CAD THEORY AND CONCEPT OF ATHEROSCLEROSIS Inflamation (Sargowo, 1996) 9 Free Radical ATHEROGENESIS (Sargowo, 1996) 10 IDENTIFYING THOSE AT RISK OF ATHEROTHROMBOSIS Yusuf S et al. Circulation 2001; 104: 2746–53. 2. Drouet L. Cerebrovasc Dis 2002;13(suppl 1):1–6. Lifestyle Smoking Diet Lack of exercise Genetic Genetic traits Gender Age Generalized disorders Obesity Diabetes Systemic conditions History of vascular events Hypertension Hyperlipidemia Hypercoagulable states Homocystinemia Local factors Elevated prothrombotic factors: fibrinogen, CRP, PAI-1 Blood flow patterns, vessel diameter, arterial wall structure Atherothrombosis manifestations (myocardial infarction, stroke, vascular death) 11 Arici. 2010 Risk Factors for Atherosclerosis Classic Hypertension, Hyper-lipidemia, DM, Smoking Uremia Related Increase ox-LDL, Free radicals, Uremic toxin Infection Bacterial and viral infection Proinflammatory cytokine release Endothelial dysfunction Systemic inflammatory respones Acute phase response Elevated CRP Binding LDL, cemplement activation, tissue factor secretion Accelerated ATHEROSCLEROSIS 12 LDL CD40L=CD40 ligand; TNF-α=tumor necrosis factor-alpha; IL=interleukin; VCAM=vascular cell adhesion molecule; ICAM=intercellular adhesion molecule. Cockerill GW et al. Arterioscler Thromb Vasc Biol. 1995;15:1987-1994; Andre P et al. Circulation. 2002;106:896-899; Libby P. Circulation. 2001;104:365-372; Libby P et al. Circulation. 2002;105:1135-1143; Ross R. N Engl J Med. 1999;340:115-126. Vessel lumen Monocyte Macrophage Adhesionmolecules (VCAM-1, ICAM-1) Inflammatory mediators (CRP, CD40/CD40L, TNF-α, IL-1, IL-6) Intima Foam cell INFLAMMATION PROMOTES PROGRESSION OF ATHEROSCLEROSIS Endothelium LDL Ox-LDL 13 14 Atherosclerosis is a fibroproliferative and inflammatory process occurring ins response to a variety of vascular insults The insults come from classical risk factors ( HT, dyslipidemia, endothelial dysfunction, smoking, menopause, diabetes etc) and novel risk factors (Hcy, LVH, Lp(a), TG, oxidative stress, fibrinogen etc) Endothelial dysfunction is regarded as the first abnormality leading to atherosclerosis This implies that modulation of endothelial function may be used as strategy to intervene the process. 15 Two theories gain more acceptance: (a) the lipid theory (b) inflammation theory Endothelial dysfunction is now regarded as the first abnormality leading to AS. More novel cardiovascular risk factors are known, e.g.: Fibrinogen b. PAI-1 Homocysteins d. AT-1 e. CRP f. Lp(a) g. small-dense LDL h. infectious agents i. and more are emerging 16 Acute Coronary Syndrome (endocrine viewpoints) atherosclerotic lesions vascular funtions b.1. inflammatory reaction b.2. thrombogeneity b.3. vasoreactivity b.4. plaque stability b.5. shoulder of plaque endothelium balance between c.1. vasodilating, antithrombotic, antiproliferative factors (NO, prostacyclin, C-natriuretic peptide, EDHF) c.2. vasoconstricting, prothrombotic, proliferative factors (ET, superoxide, thromoboxan A2) 17 NATURAL HISTORY OF CORONARY ATHEROSCLEROSIS Chatzizisis et all. JACC. 2007. Asymtomatic Stable Angina Acute Coronary Syndrome Early fibroatheroma Compensatory expansive remodeling Quiescent plaque Contrictive remodeling Stenotic plaque Exessive expansive remodeling Thin cap fibroatheroma Erosion Physiologic coronary artery Local factors, e.g. low ESS Systemic factors, e.g. hyperlipidemia Genetic factors Physiologic ESS Limited inflammation Fibroproliferation Microruptures 18 ATHEROSCLEROSIS IS AN INFLAMMATORY DISEASE Libby P. Circulation. 2001;104:365-372; Ross R. N Engl J Med. 1999;340:115-126. Monocyte LDL-C Adhesion molecule Macrophage Foam cell OxidizedLDL-C Plaque rupture Smooth muscle cells CRP Plaque instability and thrombus Oxidation Inflammation Endothelial dysfunction 19 20 Reverse Cholesterol Transport Monocyte CRP TXA2 PGI2 Thrombin LDL Platelets HDL HDL Ox-LDL MCP-1 Macrophage P-selectin CD 40L PDGF Foam cell MMP T cell E-selectins CD 40L VCAM-1 ICAM-1 IL-1 Reilly, et.all. 2005 21 THE ROLE OF Lp-PLA2 IN CHD LUMEN Monocytes Adhesion Molecules Oxidated LDL INTIMA MEDIA Lp-PLA2 Lyso-PC OxFA Cytokines Plaque Formation Foam Cell Macrophage 22 MC T T FC FC LDL Oxidation Lyso-PC Ox-chol Cytokines Cytokines ? C5a C’ MCP-1 F SMC 23 Intracelluler proteolysis and fusion of LDL Figure : Proposed Dual Action of Exocytosed Mast Cell Granules (The Granule Remnants) of Lipoprotein Metabolism in The Arterial Intima 24 HSCRP 25 26 GM-CSF VCAM-1 MPC-1 Transcription Factors : Endothelial Cell Pro-inflammatory Genes Oxidative Stress NF-xB AP-1 Leucocyte infiltration / activation Plaque Rupture Gibbons, 97 LEUCOCYTE ACTIVATION IN ATHEROGENESIS : IMPLICATIONS FOR ACUTE ISCHEMIC SYNDROMES 27 p38 c-Jun activation Caspases Apoptosis NIK ? ? MEKK1?   CKII IKK complex TNFR-1 TNFR-1 IL-1R Shear stress p65 p50 CBP/p300 Gene activation p65 p50 IB pKAc IB Ub Target genes : - IL-1, IL-8, IL-6, IFN  - TNF, MCP-1 - CSFs, c-myc - VCAM-1, ICAM-1, E-selectin - Tissue factor - Survival factor Thurberg and Collins : Curr Opin Lipidol 9:387-396,1998 Ub Ox-LDL ROIs ??? Lipid peroxides ? H2O2 Ubiquitination and proteosome degradation T R A D D R I P F A D D R I P T R A D D T R A F 2 T R A F 6 28 Visual Medica. 2009 29 Stockley. 2006 Cytokines : IL-6, TNF-α MACROPHAGE FOAM CELL Oxidized LDL CRP CRP Chemokines: MCO-1 Atherosclerotic plaque MONOCYTE Inflammatory Mediators: CRP Prothrombotic factors FCR Receptor 30 POTENTIAL MECHANISM OF CRP Stevens, R. 2005 CRP LDL opsonisation Monocyte infiltration Foam cell formation Increased MCP-1 and CAM EC activation Inflammatory cell recruitment Atherosclerosis plaque formation Complement activation EC sensitisation T-cell attack EC damage Atherosclerotic plaque rupture 31 Rheumatoid arthritis Atherosclerosis Multiple sclerosis Asthma Inflammatory bowel disease Helicobacter pylori-associated gastritis Systemic inflammatory response syndrome NF-KB ACTIVATION INFLAMMATORY DISEASE The Journal of Clinical Investigation, 2001 32 PROTEIN REGULATED BY NF-KB Inflammatory Enzyme Adhesion Molecule Inducible nitric oxide synthase Inducide cylooxigenase-2 5-Lipoxigenase Cytosolic phospolipase A2 ICAM-1 VCAM-1 E-selectin Receptor Interlekin-2 receptor (alpha chain) T-cell receptors (beta chain) NEJM, 1997 33 BIOMARKERS OF ACTIVITY STUDIED FOR CAD Cytokines (IL-1β, IL-6, IL-8, IL-10, TNF-α, sCD40 ligand, myeloperoxidase) Adhesion molecules (sICAM-1, sVCAM-1, p-selectin) Acute phase reactans (fibrinogen, AAS, CRP) White blood cells Erythrocyte sedimentation rate Neopterin Heat shock proteins Adiponectin Lipoprotein associated phospholipase A2 Placental growth factos Cystatin C Kaski, JC. 2006. 34 Are you hungry or sleepy ???? Sciences 35 The inflammatory cascade. IL indicates interleukin; ICAM, intercellular adhesion molecule; and HSP, heat shock protein. (Libby, Ridker; 1999) Pro-Inflammatory Risk Factors Primary Pro-Inflammatory Cytokines (eg. IL-1, TNF-) IL-6 “Mesenger” Cytokine CRP SAA Endothelium and other cells LIVER Circulation 36 (Ridker, 2004) MORE THAN A MARKER : DOES CRP PLAY A DIRECT ROLE IN ATHEROTHROMBOSIS ? CRP localizes in atherosclerotic but not normal intima CRP induced Complement activation CRP dependent monocyte recruitment into arterial wall CRP induced production of tissue factor in monocytes CRP based blunting of endothelial vasoreactivity CRP mediated LDL uptake by macrophages CRP triggered oxidation of LDL cholesterol CRP induced PAI-1 expression stabilizes PAI-1 mRNA CRP attenuates NO production and decreases eNOS expression CRP induced production of cell adhesion moleculas MCP-1, ET-1 37 ROLE OF INFLAMATORY MARKERS Interleukin-6 Total cholesterol LDL-cholesterol siCAM-1 Serum amyloid A Apolipoprotein B Total cholesterol: HDL-cholesterol Hs-CRP Hs-CRP + total cholesterol: HDL-cholesterol 0 1.0 2.0 4.0 6.0 Relative Risk (New England Journal of Medicine)
Slide 38 - 1 Nama : Prof. Dr. H. Djanggan Sargowo, dr., SpPD., SpJP(K), FIHA, FACC, FESC, FCAPC, FASCC Tempat/Tgl lahir : Sragen, 21 September 1947 Alamat : Wilis Indah E-10 Malang, Telp. 0341-552395 Pendidikan : Lulus Dokter dari UGM, tahun 1974 Lulus Cardiologist dari Univ. Indonesia, tahun 1983 Lulus Internist dari Univ. Airlangga, tahun 1986 Lulus Doktor, Univ. Airlangga, tahun 1996 Advanced Cardiology Course, Univ. Hongkong, tahun 1984 Senior Visiting Program, Institut Jantung Negara, Kualalumpur, 1996 Fellow American College of Cardiology (FACC), September 2006. Fellow Collage Asia Pacific Society of Cardiology (FCAPC), Desember 2007 Fellow European Sociaty of Cardiology (FESC), 2008 Fellow Asean Collage of Cardiology (FASCC), 2008 Jabatan : Dosen Pengajar Program Pascasarjana Universitas Brawijaya Ketua MKEK Ikatan Dokter Indonesia Cabang Malang Raya Ketua PERKI Cabang Malang Raya Anggota Kolegium Kardiovaskuler Indonesia Dekan Fak. Kedokteran Univ. Wijaya Kusuma Surabaya Ketua Dewan Pengawas Rumah Sakit Pendidikan Ketua Program Studi Kardiovascular Fak. Kedokteran Univ. Brawijaya Curriculum Vitae 2 Djanggan Sargowo Surabaya, 15 April 2012 INFLAMMATION IN ATHEROSCLEROSIS : FROM BENCH TO BEDSIDE 3 4 RUDOLF VIRCHOW Inflammation-based arterial changes as a mechanism of primary importance in atherogenesis mid 19th century Lamond, B. The American Journal of Pathology. 2008 5 Atherosclerosis Start from very young To Old age ? 6 Atherothrombosis* is aLeading Cause of Death Worldwide1† The World Health Report, 2002, WHO Geneva, 2002 28.7 17.8 12.6 9.1 6 5.1 0 5 10 15 20 25 30 Atherothrombosis* Infectious disease Cancer Injuries Pulmonary disease AIDS Mortality (%) * Ischemic heart disease, cerebrovascular disease, inflammatory heart disease and hypertensive heart disease † Worldwide defined as Member States by WHO Region (Africa, Americas, Eastern Mediterranean, European, South-East Asia and Western Pacific) 7 MAJOR CLINICAL MANIFESTATIONS OF ATHEROTHROMBOSIS Adapted from: Drouet L. Cerebrovasc Dis 2002; 13(suppl 1): 1–6. Transient ischemic attack Angina: Stable Unstable Ischemic stroke Myocardial infarction Peripheral arterial disease: Intermittent claudication Rest Pain Gangrene Necrosis 8  Dyslipidemia  Endothelial dysfunction  Free radicals  Immunologic Atherosclerosis/CAD THEORY AND CONCEPT OF ATHEROSCLEROSIS Inflamation (Sargowo, 1996) 9 Free Radical ATHEROGENESIS (Sargowo, 1996) 10 IDENTIFYING THOSE AT RISK OF ATHEROTHROMBOSIS Yusuf S et al. Circulation 2001; 104: 2746–53. 2. Drouet L. Cerebrovasc Dis 2002;13(suppl 1):1–6. Lifestyle Smoking Diet Lack of exercise Genetic Genetic traits Gender Age Generalized disorders Obesity Diabetes Systemic conditions History of vascular events Hypertension Hyperlipidemia Hypercoagulable states Homocystinemia Local factors Elevated prothrombotic factors: fibrinogen, CRP, PAI-1 Blood flow patterns, vessel diameter, arterial wall structure Atherothrombosis manifestations (myocardial infarction, stroke, vascular death) 11 Arici. 2010 Risk Factors for Atherosclerosis Classic Hypertension, Hyper-lipidemia, DM, Smoking Uremia Related Increase ox-LDL, Free radicals, Uremic toxin Infection Bacterial and viral infection Proinflammatory cytokine release Endothelial dysfunction Systemic inflammatory respones Acute phase response Elevated CRP Binding LDL, cemplement activation, tissue factor secretion Accelerated ATHEROSCLEROSIS 12 LDL CD40L=CD40 ligand; TNF-α=tumor necrosis factor-alpha; IL=interleukin; VCAM=vascular cell adhesion molecule; ICAM=intercellular adhesion molecule. Cockerill GW et al. Arterioscler Thromb Vasc Biol. 1995;15:1987-1994; Andre P et al. Circulation. 2002;106:896-899; Libby P. Circulation. 2001;104:365-372; Libby P et al. Circulation. 2002;105:1135-1143; Ross R. N Engl J Med. 1999;340:115-126. Vessel lumen Monocyte Macrophage Adhesionmolecules (VCAM-1, ICAM-1) Inflammatory mediators (CRP, CD40/CD40L, TNF-α, IL-1, IL-6) Intima Foam cell INFLAMMATION PROMOTES PROGRESSION OF ATHEROSCLEROSIS Endothelium LDL Ox-LDL 13 14 Atherosclerosis is a fibroproliferative and inflammatory process occurring ins response to a variety of vascular insults The insults come from classical risk factors ( HT, dyslipidemia, endothelial dysfunction, smoking, menopause, diabetes etc) and novel risk factors (Hcy, LVH, Lp(a), TG, oxidative stress, fibrinogen etc) Endothelial dysfunction is regarded as the first abnormality leading to atherosclerosis This implies that modulation of endothelial function may be used as strategy to intervene the process. 15 Two theories gain more acceptance: (a) the lipid theory (b) inflammation theory Endothelial dysfunction is now regarded as the first abnormality leading to AS. More novel cardiovascular risk factors are known, e.g.: Fibrinogen b. PAI-1 Homocysteins d. AT-1 e. CRP f. Lp(a) g. small-dense LDL h. infectious agents i. and more are emerging 16 Acute Coronary Syndrome (endocrine viewpoints) atherosclerotic lesions vascular funtions b.1. inflammatory reaction b.2. thrombogeneity b.3. vasoreactivity b.4. plaque stability b.5. shoulder of plaque endothelium balance between c.1. vasodilating, antithrombotic, antiproliferative factors (NO, prostacyclin, C-natriuretic peptide, EDHF) c.2. vasoconstricting, prothrombotic, proliferative factors (ET, superoxide, thromoboxan A2) 17 NATURAL HISTORY OF CORONARY ATHEROSCLEROSIS Chatzizisis et all. JACC. 2007. Asymtomatic Stable Angina Acute Coronary Syndrome Early fibroatheroma Compensatory expansive remodeling Quiescent plaque Contrictive remodeling Stenotic plaque Exessive expansive remodeling Thin cap fibroatheroma Erosion Physiologic coronary artery Local factors, e.g. low ESS Systemic factors, e.g. hyperlipidemia Genetic factors Physiologic ESS Limited inflammation Fibroproliferation Microruptures 18 ATHEROSCLEROSIS IS AN INFLAMMATORY DISEASE Libby P. Circulation. 2001;104:365-372; Ross R. N Engl J Med. 1999;340:115-126. Monocyte LDL-C Adhesion molecule Macrophage Foam cell OxidizedLDL-C Plaque rupture Smooth muscle cells CRP Plaque instability and thrombus Oxidation Inflammation Endothelial dysfunction 19 20 Reverse Cholesterol Transport Monocyte CRP TXA2 PGI2 Thrombin LDL Platelets HDL HDL Ox-LDL MCP-1 Macrophage P-selectin CD 40L PDGF Foam cell MMP T cell E-selectins CD 40L VCAM-1 ICAM-1 IL-1 Reilly, et.all. 2005 21 THE ROLE OF Lp-PLA2 IN CHD LUMEN Monocytes Adhesion Molecules Oxidated LDL INTIMA MEDIA Lp-PLA2 Lyso-PC OxFA Cytokines Plaque Formation Foam Cell Macrophage 22 MC T T FC FC LDL Oxidation Lyso-PC Ox-chol Cytokines Cytokines ? C5a C’ MCP-1 F SMC 23 Intracelluler proteolysis and fusion of LDL Figure : Proposed Dual Action of Exocytosed Mast Cell Granules (The Granule Remnants) of Lipoprotein Metabolism in The Arterial Intima 24 HSCRP 25 26 GM-CSF VCAM-1 MPC-1 Transcription Factors : Endothelial Cell Pro-inflammatory Genes Oxidative Stress NF-xB AP-1 Leucocyte infiltration / activation Plaque Rupture Gibbons, 97 LEUCOCYTE ACTIVATION IN ATHEROGENESIS : IMPLICATIONS FOR ACUTE ISCHEMIC SYNDROMES 27 p38 c-Jun activation Caspases Apoptosis NIK ? ? MEKK1?   CKII IKK complex TNFR-1 TNFR-1 IL-1R Shear stress p65 p50 CBP/p300 Gene activation p65 p50 IB pKAc IB Ub Target genes : - IL-1, IL-8, IL-6, IFN  - TNF, MCP-1 - CSFs, c-myc - VCAM-1, ICAM-1, E-selectin - Tissue factor - Survival factor Thurberg and Collins : Curr Opin Lipidol 9:387-396,1998 Ub Ox-LDL ROIs ??? Lipid peroxides ? H2O2 Ubiquitination and proteosome degradation T R A D D R I P F A D D R I P T R A D D T R A F 2 T R A F 6 28 Visual Medica. 2009 29 Stockley. 2006 Cytokines : IL-6, TNF-α MACROPHAGE FOAM CELL Oxidized LDL CRP CRP Chemokines: MCO-1 Atherosclerotic plaque MONOCYTE Inflammatory Mediators: CRP Prothrombotic factors FCR Receptor 30 POTENTIAL MECHANISM OF CRP Stevens, R. 2005 CRP LDL opsonisation Monocyte infiltration Foam cell formation Increased MCP-1 and CAM EC activation Inflammatory cell recruitment Atherosclerosis plaque formation Complement activation EC sensitisation T-cell attack EC damage Atherosclerotic plaque rupture 31 Rheumatoid arthritis Atherosclerosis Multiple sclerosis Asthma Inflammatory bowel disease Helicobacter pylori-associated gastritis Systemic inflammatory response syndrome NF-KB ACTIVATION INFLAMMATORY DISEASE The Journal of Clinical Investigation, 2001 32 PROTEIN REGULATED BY NF-KB Inflammatory Enzyme Adhesion Molecule Inducible nitric oxide synthase Inducide cylooxigenase-2 5-Lipoxigenase Cytosolic phospolipase A2 ICAM-1 VCAM-1 E-selectin Receptor Interlekin-2 receptor (alpha chain) T-cell receptors (beta chain) NEJM, 1997 33 BIOMARKERS OF ACTIVITY STUDIED FOR CAD Cytokines (IL-1β, IL-6, IL-8, IL-10, TNF-α, sCD40 ligand, myeloperoxidase) Adhesion molecules (sICAM-1, sVCAM-1, p-selectin) Acute phase reactans (fibrinogen, AAS, CRP) White blood cells Erythrocyte sedimentation rate Neopterin Heat shock proteins Adiponectin Lipoprotein associated phospholipase A2 Placental growth factos Cystatin C Kaski, JC. 2006. 34 Are you hungry or sleepy ???? Sciences 35 The inflammatory cascade. IL indicates interleukin; ICAM, intercellular adhesion molecule; and HSP, heat shock protein. (Libby, Ridker; 1999) Pro-Inflammatory Risk Factors Primary Pro-Inflammatory Cytokines (eg. IL-1, TNF-) IL-6 “Mesenger” Cytokine CRP SAA Endothelium and other cells LIVER Circulation 36 (Ridker, 2004) MORE THAN A MARKER : DOES CRP PLAY A DIRECT ROLE IN ATHEROTHROMBOSIS ? CRP localizes in atherosclerotic but not normal intima CRP induced Complement activation CRP dependent monocyte recruitment into arterial wall CRP induced production of tissue factor in monocytes CRP based blunting of endothelial vasoreactivity CRP mediated LDL uptake by macrophages CRP triggered oxidation of LDL cholesterol CRP induced PAI-1 expression stabilizes PAI-1 mRNA CRP attenuates NO production and decreases eNOS expression CRP induced production of cell adhesion moleculas MCP-1, ET-1 37 ROLE OF INFLAMATORY MARKERS Interleukin-6 Total cholesterol LDL-cholesterol siCAM-1 Serum amyloid A Apolipoprotein B Total cholesterol: HDL-cholesterol Hs-CRP Hs-CRP + total cholesterol: HDL-cholesterol 0 1.0 2.0 4.0 6.0 Relative Risk (New England Journal of Medicine) 38
Slide 39 - 1 Nama : Prof. Dr. H. Djanggan Sargowo, dr., SpPD., SpJP(K), FIHA, FACC, FESC, FCAPC, FASCC Tempat/Tgl lahir : Sragen, 21 September 1947 Alamat : Wilis Indah E-10 Malang, Telp. 0341-552395 Pendidikan : Lulus Dokter dari UGM, tahun 1974 Lulus Cardiologist dari Univ. Indonesia, tahun 1983 Lulus Internist dari Univ. Airlangga, tahun 1986 Lulus Doktor, Univ. Airlangga, tahun 1996 Advanced Cardiology Course, Univ. Hongkong, tahun 1984 Senior Visiting Program, Institut Jantung Negara, Kualalumpur, 1996 Fellow American College of Cardiology (FACC), September 2006. Fellow Collage Asia Pacific Society of Cardiology (FCAPC), Desember 2007 Fellow European Sociaty of Cardiology (FESC), 2008 Fellow Asean Collage of Cardiology (FASCC), 2008 Jabatan : Dosen Pengajar Program Pascasarjana Universitas Brawijaya Ketua MKEK Ikatan Dokter Indonesia Cabang Malang Raya Ketua PERKI Cabang Malang Raya Anggota Kolegium Kardiovaskuler Indonesia Dekan Fak. Kedokteran Univ. Wijaya Kusuma Surabaya Ketua Dewan Pengawas Rumah Sakit Pendidikan Ketua Program Studi Kardiovascular Fak. Kedokteran Univ. Brawijaya Curriculum Vitae 2 Djanggan Sargowo Surabaya, 15 April 2012 INFLAMMATION IN ATHEROSCLEROSIS : FROM BENCH TO BEDSIDE 3 4 RUDOLF VIRCHOW Inflammation-based arterial changes as a mechanism of primary importance in atherogenesis mid 19th century Lamond, B. The American Journal of Pathology. 2008 5 Atherosclerosis Start from very young To Old age ? 6 Atherothrombosis* is aLeading Cause of Death Worldwide1† The World Health Report, 2002, WHO Geneva, 2002 28.7 17.8 12.6 9.1 6 5.1 0 5 10 15 20 25 30 Atherothrombosis* Infectious disease Cancer Injuries Pulmonary disease AIDS Mortality (%) * Ischemic heart disease, cerebrovascular disease, inflammatory heart disease and hypertensive heart disease † Worldwide defined as Member States by WHO Region (Africa, Americas, Eastern Mediterranean, European, South-East Asia and Western Pacific) 7 MAJOR CLINICAL MANIFESTATIONS OF ATHEROTHROMBOSIS Adapted from: Drouet L. Cerebrovasc Dis 2002; 13(suppl 1): 1–6. Transient ischemic attack Angina: Stable Unstable Ischemic stroke Myocardial infarction Peripheral arterial disease: Intermittent claudication Rest Pain Gangrene Necrosis 8  Dyslipidemia  Endothelial dysfunction  Free radicals  Immunologic Atherosclerosis/CAD THEORY AND CONCEPT OF ATHEROSCLEROSIS Inflamation (Sargowo, 1996) 9 Free Radical ATHEROGENESIS (Sargowo, 1996) 10 IDENTIFYING THOSE AT RISK OF ATHEROTHROMBOSIS Yusuf S et al. Circulation 2001; 104: 2746–53. 2. Drouet L. Cerebrovasc Dis 2002;13(suppl 1):1–6. Lifestyle Smoking Diet Lack of exercise Genetic Genetic traits Gender Age Generalized disorders Obesity Diabetes Systemic conditions History of vascular events Hypertension Hyperlipidemia Hypercoagulable states Homocystinemia Local factors Elevated prothrombotic factors: fibrinogen, CRP, PAI-1 Blood flow patterns, vessel diameter, arterial wall structure Atherothrombosis manifestations (myocardial infarction, stroke, vascular death) 11 Arici. 2010 Risk Factors for Atherosclerosis Classic Hypertension, Hyper-lipidemia, DM, Smoking Uremia Related Increase ox-LDL, Free radicals, Uremic toxin Infection Bacterial and viral infection Proinflammatory cytokine release Endothelial dysfunction Systemic inflammatory respones Acute phase response Elevated CRP Binding LDL, cemplement activation, tissue factor secretion Accelerated ATHEROSCLEROSIS 12 LDL CD40L=CD40 ligand; TNF-α=tumor necrosis factor-alpha; IL=interleukin; VCAM=vascular cell adhesion molecule; ICAM=intercellular adhesion molecule. Cockerill GW et al. Arterioscler Thromb Vasc Biol. 1995;15:1987-1994; Andre P et al. Circulation. 2002;106:896-899; Libby P. Circulation. 2001;104:365-372; Libby P et al. Circulation. 2002;105:1135-1143; Ross R. N Engl J Med. 1999;340:115-126. Vessel lumen Monocyte Macrophage Adhesionmolecules (VCAM-1, ICAM-1) Inflammatory mediators (CRP, CD40/CD40L, TNF-α, IL-1, IL-6) Intima Foam cell INFLAMMATION PROMOTES PROGRESSION OF ATHEROSCLEROSIS Endothelium LDL Ox-LDL 13 14 Atherosclerosis is a fibroproliferative and inflammatory process occurring ins response to a variety of vascular insults The insults come from classical risk factors ( HT, dyslipidemia, endothelial dysfunction, smoking, menopause, diabetes etc) and novel risk factors (Hcy, LVH, Lp(a), TG, oxidative stress, fibrinogen etc) Endothelial dysfunction is regarded as the first abnormality leading to atherosclerosis This implies that modulation of endothelial function may be used as strategy to intervene the process. 15 Two theories gain more acceptance: (a) the lipid theory (b) inflammation theory Endothelial dysfunction is now regarded as the first abnormality leading to AS. More novel cardiovascular risk factors are known, e.g.: Fibrinogen b. PAI-1 Homocysteins d. AT-1 e. CRP f. Lp(a) g. small-dense LDL h. infectious agents i. and more are emerging 16 Acute Coronary Syndrome (endocrine viewpoints) atherosclerotic lesions vascular funtions b.1. inflammatory reaction b.2. thrombogeneity b.3. vasoreactivity b.4. plaque stability b.5. shoulder of plaque endothelium balance between c.1. vasodilating, antithrombotic, antiproliferative factors (NO, prostacyclin, C-natriuretic peptide, EDHF) c.2. vasoconstricting, prothrombotic, proliferative factors (ET, superoxide, thromoboxan A2) 17 NATURAL HISTORY OF CORONARY ATHEROSCLEROSIS Chatzizisis et all. JACC. 2007. Asymtomatic Stable Angina Acute Coronary Syndrome Early fibroatheroma Compensatory expansive remodeling Quiescent plaque Contrictive remodeling Stenotic plaque Exessive expansive remodeling Thin cap fibroatheroma Erosion Physiologic coronary artery Local factors, e.g. low ESS Systemic factors, e.g. hyperlipidemia Genetic factors Physiologic ESS Limited inflammation Fibroproliferation Microruptures 18 ATHEROSCLEROSIS IS AN INFLAMMATORY DISEASE Libby P. Circulation. 2001;104:365-372; Ross R. N Engl J Med. 1999;340:115-126. Monocyte LDL-C Adhesion molecule Macrophage Foam cell OxidizedLDL-C Plaque rupture Smooth muscle cells CRP Plaque instability and thrombus Oxidation Inflammation Endothelial dysfunction 19 20 Reverse Cholesterol Transport Monocyte CRP TXA2 PGI2 Thrombin LDL Platelets HDL HDL Ox-LDL MCP-1 Macrophage P-selectin CD 40L PDGF Foam cell MMP T cell E-selectins CD 40L VCAM-1 ICAM-1 IL-1 Reilly, et.all. 2005 21 THE ROLE OF Lp-PLA2 IN CHD LUMEN Monocytes Adhesion Molecules Oxidated LDL INTIMA MEDIA Lp-PLA2 Lyso-PC OxFA Cytokines Plaque Formation Foam Cell Macrophage 22 MC T T FC FC LDL Oxidation Lyso-PC Ox-chol Cytokines Cytokines ? C5a C’ MCP-1 F SMC 23 Intracelluler proteolysis and fusion of LDL Figure : Proposed Dual Action of Exocytosed Mast Cell Granules (The Granule Remnants) of Lipoprotein Metabolism in The Arterial Intima 24 HSCRP 25 26 GM-CSF VCAM-1 MPC-1 Transcription Factors : Endothelial Cell Pro-inflammatory Genes Oxidative Stress NF-xB AP-1 Leucocyte infiltration / activation Plaque Rupture Gibbons, 97 LEUCOCYTE ACTIVATION IN ATHEROGENESIS : IMPLICATIONS FOR ACUTE ISCHEMIC SYNDROMES 27 p38 c-Jun activation Caspases Apoptosis NIK ? ? MEKK1?   CKII IKK complex TNFR-1 TNFR-1 IL-1R Shear stress p65 p50 CBP/p300 Gene activation p65 p50 IB pKAc IB Ub Target genes : - IL-1, IL-8, IL-6, IFN  - TNF, MCP-1 - CSFs, c-myc - VCAM-1, ICAM-1, E-selectin - Tissue factor - Survival factor Thurberg and Collins : Curr Opin Lipidol 9:387-396,1998 Ub Ox-LDL ROIs ??? Lipid peroxides ? H2O2 Ubiquitination and proteosome degradation T R A D D R I P F A D D R I P T R A D D T R A F 2 T R A F 6 28 Visual Medica. 2009 29 Stockley. 2006 Cytokines : IL-6, TNF-α MACROPHAGE FOAM CELL Oxidized LDL CRP CRP Chemokines: MCO-1 Atherosclerotic plaque MONOCYTE Inflammatory Mediators: CRP Prothrombotic factors FCR Receptor 30 POTENTIAL MECHANISM OF CRP Stevens, R. 2005 CRP LDL opsonisation Monocyte infiltration Foam cell formation Increased MCP-1 and CAM EC activation Inflammatory cell recruitment Atherosclerosis plaque formation Complement activation EC sensitisation T-cell attack EC damage Atherosclerotic plaque rupture 31 Rheumatoid arthritis Atherosclerosis Multiple sclerosis Asthma Inflammatory bowel disease Helicobacter pylori-associated gastritis Systemic inflammatory response syndrome NF-KB ACTIVATION INFLAMMATORY DISEASE The Journal of Clinical Investigation, 2001 32 PROTEIN REGULATED BY NF-KB Inflammatory Enzyme Adhesion Molecule Inducible nitric oxide synthase Inducide cylooxigenase-2 5-Lipoxigenase Cytosolic phospolipase A2 ICAM-1 VCAM-1 E-selectin Receptor Interlekin-2 receptor (alpha chain) T-cell receptors (beta chain) NEJM, 1997 33 BIOMARKERS OF ACTIVITY STUDIED FOR CAD Cytokines (IL-1β, IL-6, IL-8, IL-10, TNF-α, sCD40 ligand, myeloperoxidase) Adhesion molecules (sICAM-1, sVCAM-1, p-selectin) Acute phase reactans (fibrinogen, AAS, CRP) White blood cells Erythrocyte sedimentation rate Neopterin Heat shock proteins Adiponectin Lipoprotein associated phospholipase A2 Placental growth factos Cystatin C Kaski, JC. 2006. 34 Are you hungry or sleepy ???? Sciences 35 The inflammatory cascade. IL indicates interleukin; ICAM, intercellular adhesion molecule; and HSP, heat shock protein. (Libby, Ridker; 1999) Pro-Inflammatory Risk Factors Primary Pro-Inflammatory Cytokines (eg. IL-1, TNF-) IL-6 “Mesenger” Cytokine CRP SAA Endothelium and other cells LIVER Circulation 36 (Ridker, 2004) MORE THAN A MARKER : DOES CRP PLAY A DIRECT ROLE IN ATHEROTHROMBOSIS ? CRP localizes in atherosclerotic but not normal intima CRP induced Complement activation CRP dependent monocyte recruitment into arterial wall CRP induced production of tissue factor in monocytes CRP based blunting of endothelial vasoreactivity CRP mediated LDL uptake by macrophages CRP triggered oxidation of LDL cholesterol CRP induced PAI-1 expression stabilizes PAI-1 mRNA CRP attenuates NO production and decreases eNOS expression CRP induced production of cell adhesion moleculas MCP-1, ET-1 37 ROLE OF INFLAMATORY MARKERS Interleukin-6 Total cholesterol LDL-cholesterol siCAM-1 Serum amyloid A Apolipoprotein B Total cholesterol: HDL-cholesterol Hs-CRP Hs-CRP + total cholesterol: HDL-cholesterol 0 1.0 2.0 4.0 6.0 Relative Risk (New England Journal of Medicine) 38 39 Weissberg, 1999 Inflammation Repair
Slide 40 - 1 Nama : Prof. Dr. H. Djanggan Sargowo, dr., SpPD., SpJP(K), FIHA, FACC, FESC, FCAPC, FASCC Tempat/Tgl lahir : Sragen, 21 September 1947 Alamat : Wilis Indah E-10 Malang, Telp. 0341-552395 Pendidikan : Lulus Dokter dari UGM, tahun 1974 Lulus Cardiologist dari Univ. Indonesia, tahun 1983 Lulus Internist dari Univ. Airlangga, tahun 1986 Lulus Doktor, Univ. Airlangga, tahun 1996 Advanced Cardiology Course, Univ. Hongkong, tahun 1984 Senior Visiting Program, Institut Jantung Negara, Kualalumpur, 1996 Fellow American College of Cardiology (FACC), September 2006. Fellow Collage Asia Pacific Society of Cardiology (FCAPC), Desember 2007 Fellow European Sociaty of Cardiology (FESC), 2008 Fellow Asean Collage of Cardiology (FASCC), 2008 Jabatan : Dosen Pengajar Program Pascasarjana Universitas Brawijaya Ketua MKEK Ikatan Dokter Indonesia Cabang Malang Raya Ketua PERKI Cabang Malang Raya Anggota Kolegium Kardiovaskuler Indonesia Dekan Fak. Kedokteran Univ. Wijaya Kusuma Surabaya Ketua Dewan Pengawas Rumah Sakit Pendidikan Ketua Program Studi Kardiovascular Fak. Kedokteran Univ. Brawijaya Curriculum Vitae 2 Djanggan Sargowo Surabaya, 15 April 2012 INFLAMMATION IN ATHEROSCLEROSIS : FROM BENCH TO BEDSIDE 3 4 RUDOLF VIRCHOW Inflammation-based arterial changes as a mechanism of primary importance in atherogenesis mid 19th century Lamond, B. The American Journal of Pathology. 2008 5 Atherosclerosis Start from very young To Old age ? 6 Atherothrombosis* is aLeading Cause of Death Worldwide1† The World Health Report, 2002, WHO Geneva, 2002 28.7 17.8 12.6 9.1 6 5.1 0 5 10 15 20 25 30 Atherothrombosis* Infectious disease Cancer Injuries Pulmonary disease AIDS Mortality (%) * Ischemic heart disease, cerebrovascular disease, inflammatory heart disease and hypertensive heart disease † Worldwide defined as Member States by WHO Region (Africa, Americas, Eastern Mediterranean, European, South-East Asia and Western Pacific) 7 MAJOR CLINICAL MANIFESTATIONS OF ATHEROTHROMBOSIS Adapted from: Drouet L. Cerebrovasc Dis 2002; 13(suppl 1): 1–6. Transient ischemic attack Angina: Stable Unstable Ischemic stroke Myocardial infarction Peripheral arterial disease: Intermittent claudication Rest Pain Gangrene Necrosis 8  Dyslipidemia  Endothelial dysfunction  Free radicals  Immunologic Atherosclerosis/CAD THEORY AND CONCEPT OF ATHEROSCLEROSIS Inflamation (Sargowo, 1996) 9 Free Radical ATHEROGENESIS (Sargowo, 1996) 10 IDENTIFYING THOSE AT RISK OF ATHEROTHROMBOSIS Yusuf S et al. Circulation 2001; 104: 2746–53. 2. Drouet L. Cerebrovasc Dis 2002;13(suppl 1):1–6. Lifestyle Smoking Diet Lack of exercise Genetic Genetic traits Gender Age Generalized disorders Obesity Diabetes Systemic conditions History of vascular events Hypertension Hyperlipidemia Hypercoagulable states Homocystinemia Local factors Elevated prothrombotic factors: fibrinogen, CRP, PAI-1 Blood flow patterns, vessel diameter, arterial wall structure Atherothrombosis manifestations (myocardial infarction, stroke, vascular death) 11 Arici. 2010 Risk Factors for Atherosclerosis Classic Hypertension, Hyper-lipidemia, DM, Smoking Uremia Related Increase ox-LDL, Free radicals, Uremic toxin Infection Bacterial and viral infection Proinflammatory cytokine release Endothelial dysfunction Systemic inflammatory respones Acute phase response Elevated CRP Binding LDL, cemplement activation, tissue factor secretion Accelerated ATHEROSCLEROSIS 12 LDL CD40L=CD40 ligand; TNF-α=tumor necrosis factor-alpha; IL=interleukin; VCAM=vascular cell adhesion molecule; ICAM=intercellular adhesion molecule. Cockerill GW et al. Arterioscler Thromb Vasc Biol. 1995;15:1987-1994; Andre P et al. Circulation. 2002;106:896-899; Libby P. Circulation. 2001;104:365-372; Libby P et al. Circulation. 2002;105:1135-1143; Ross R. N Engl J Med. 1999;340:115-126. Vessel lumen Monocyte Macrophage Adhesionmolecules (VCAM-1, ICAM-1) Inflammatory mediators (CRP, CD40/CD40L, TNF-α, IL-1, IL-6) Intima Foam cell INFLAMMATION PROMOTES PROGRESSION OF ATHEROSCLEROSIS Endothelium LDL Ox-LDL 13 14 Atherosclerosis is a fibroproliferative and inflammatory process occurring ins response to a variety of vascular insults The insults come from classical risk factors ( HT, dyslipidemia, endothelial dysfunction, smoking, menopause, diabetes etc) and novel risk factors (Hcy, LVH, Lp(a), TG, oxidative stress, fibrinogen etc) Endothelial dysfunction is regarded as the first abnormality leading to atherosclerosis This implies that modulation of endothelial function may be used as strategy to intervene the process. 15 Two theories gain more acceptance: (a) the lipid theory (b) inflammation theory Endothelial dysfunction is now regarded as the first abnormality leading to AS. More novel cardiovascular risk factors are known, e.g.: Fibrinogen b. PAI-1 Homocysteins d. AT-1 e. CRP f. Lp(a) g. small-dense LDL h. infectious agents i. and more are emerging 16 Acute Coronary Syndrome (endocrine viewpoints) atherosclerotic lesions vascular funtions b.1. inflammatory reaction b.2. thrombogeneity b.3. vasoreactivity b.4. plaque stability b.5. shoulder of plaque endothelium balance between c.1. vasodilating, antithrombotic, antiproliferative factors (NO, prostacyclin, C-natriuretic peptide, EDHF) c.2. vasoconstricting, prothrombotic, proliferative factors (ET, superoxide, thromoboxan A2) 17 NATURAL HISTORY OF CORONARY ATHEROSCLEROSIS Chatzizisis et all. JACC. 2007. Asymtomatic Stable Angina Acute Coronary Syndrome Early fibroatheroma Compensatory expansive remodeling Quiescent plaque Contrictive remodeling Stenotic plaque Exessive expansive remodeling Thin cap fibroatheroma Erosion Physiologic coronary artery Local factors, e.g. low ESS Systemic factors, e.g. hyperlipidemia Genetic factors Physiologic ESS Limited inflammation Fibroproliferation Microruptures 18 ATHEROSCLEROSIS IS AN INFLAMMATORY DISEASE Libby P. Circulation. 2001;104:365-372; Ross R. N Engl J Med. 1999;340:115-126. Monocyte LDL-C Adhesion molecule Macrophage Foam cell OxidizedLDL-C Plaque rupture Smooth muscle cells CRP Plaque instability and thrombus Oxidation Inflammation Endothelial dysfunction 19 20 Reverse Cholesterol Transport Monocyte CRP TXA2 PGI2 Thrombin LDL Platelets HDL HDL Ox-LDL MCP-1 Macrophage P-selectin CD 40L PDGF Foam cell MMP T cell E-selectins CD 40L VCAM-1 ICAM-1 IL-1 Reilly, et.all. 2005 21 THE ROLE OF Lp-PLA2 IN CHD LUMEN Monocytes Adhesion Molecules Oxidated LDL INTIMA MEDIA Lp-PLA2 Lyso-PC OxFA Cytokines Plaque Formation Foam Cell Macrophage 22 MC T T FC FC LDL Oxidation Lyso-PC Ox-chol Cytokines Cytokines ? C5a C’ MCP-1 F SMC 23 Intracelluler proteolysis and fusion of LDL Figure : Proposed Dual Action of Exocytosed Mast Cell Granules (The Granule Remnants) of Lipoprotein Metabolism in The Arterial Intima 24 HSCRP 25 26 GM-CSF VCAM-1 MPC-1 Transcription Factors : Endothelial Cell Pro-inflammatory Genes Oxidative Stress NF-xB AP-1 Leucocyte infiltration / activation Plaque Rupture Gibbons, 97 LEUCOCYTE ACTIVATION IN ATHEROGENESIS : IMPLICATIONS FOR ACUTE ISCHEMIC SYNDROMES 27 p38 c-Jun activation Caspases Apoptosis NIK ? ? MEKK1?   CKII IKK complex TNFR-1 TNFR-1 IL-1R Shear stress p65 p50 CBP/p300 Gene activation p65 p50 IB pKAc IB Ub Target genes : - IL-1, IL-8, IL-6, IFN  - TNF, MCP-1 - CSFs, c-myc - VCAM-1, ICAM-1, E-selectin - Tissue factor - Survival factor Thurberg and Collins : Curr Opin Lipidol 9:387-396,1998 Ub Ox-LDL ROIs ??? Lipid peroxides ? H2O2 Ubiquitination and proteosome degradation T R A D D R I P F A D D R I P T R A D D T R A F 2 T R A F 6 28 Visual Medica. 2009 29 Stockley. 2006 Cytokines : IL-6, TNF-α MACROPHAGE FOAM CELL Oxidized LDL CRP CRP Chemokines: MCO-1 Atherosclerotic plaque MONOCYTE Inflammatory Mediators: CRP Prothrombotic factors FCR Receptor 30 POTENTIAL MECHANISM OF CRP Stevens, R. 2005 CRP LDL opsonisation Monocyte infiltration Foam cell formation Increased MCP-1 and CAM EC activation Inflammatory cell recruitment Atherosclerosis plaque formation Complement activation EC sensitisation T-cell attack EC damage Atherosclerotic plaque rupture 31 Rheumatoid arthritis Atherosclerosis Multiple sclerosis Asthma Inflammatory bowel disease Helicobacter pylori-associated gastritis Systemic inflammatory response syndrome NF-KB ACTIVATION INFLAMMATORY DISEASE The Journal of Clinical Investigation, 2001 32 PROTEIN REGULATED BY NF-KB Inflammatory Enzyme Adhesion Molecule Inducible nitric oxide synthase Inducide cylooxigenase-2 5-Lipoxigenase Cytosolic phospolipase A2 ICAM-1 VCAM-1 E-selectin Receptor Interlekin-2 receptor (alpha chain) T-cell receptors (beta chain) NEJM, 1997 33 BIOMARKERS OF ACTIVITY STUDIED FOR CAD Cytokines (IL-1β, IL-6, IL-8, IL-10, TNF-α, sCD40 ligand, myeloperoxidase) Adhesion molecules (sICAM-1, sVCAM-1, p-selectin) Acute phase reactans (fibrinogen, AAS, CRP) White blood cells Erythrocyte sedimentation rate Neopterin Heat shock proteins Adiponectin Lipoprotein associated phospholipase A2 Placental growth factos Cystatin C Kaski, JC. 2006. 34 Are you hungry or sleepy ???? Sciences 35 The inflammatory cascade. IL indicates interleukin; ICAM, intercellular adhesion molecule; and HSP, heat shock protein. (Libby, Ridker; 1999) Pro-Inflammatory Risk Factors Primary Pro-Inflammatory Cytokines (eg. IL-1, TNF-) IL-6 “Mesenger” Cytokine CRP SAA Endothelium and other cells LIVER Circulation 36 (Ridker, 2004) MORE THAN A MARKER : DOES CRP PLAY A DIRECT ROLE IN ATHEROTHROMBOSIS ? CRP localizes in atherosclerotic but not normal intima CRP induced Complement activation CRP dependent monocyte recruitment into arterial wall CRP induced production of tissue factor in monocytes CRP based blunting of endothelial vasoreactivity CRP mediated LDL uptake by macrophages CRP triggered oxidation of LDL cholesterol CRP induced PAI-1 expression stabilizes PAI-1 mRNA CRP attenuates NO production and decreases eNOS expression CRP induced production of cell adhesion moleculas MCP-1, ET-1 37 ROLE OF INFLAMATORY MARKERS Interleukin-6 Total cholesterol LDL-cholesterol siCAM-1 Serum amyloid A Apolipoprotein B Total cholesterol: HDL-cholesterol Hs-CRP Hs-CRP + total cholesterol: HDL-cholesterol 0 1.0 2.0 4.0 6.0 Relative Risk (New England Journal of Medicine) 38 39 Weissberg, 1999 Inflammation Repair 40 REDOX REGULATION OF ENDOTHELIAL DYSFUNCTION & ACTIVATION O2– OH H2O2  NO Activity  G-Protein Function  Protein Kinase C Oxidation Endothelial Dysfunction (D. Sargowo)
Slide 41 - 1 Nama : Prof. Dr. H. Djanggan Sargowo, dr., SpPD., SpJP(K), FIHA, FACC, FESC, FCAPC, FASCC Tempat/Tgl lahir : Sragen, 21 September 1947 Alamat : Wilis Indah E-10 Malang, Telp. 0341-552395 Pendidikan : Lulus Dokter dari UGM, tahun 1974 Lulus Cardiologist dari Univ. Indonesia, tahun 1983 Lulus Internist dari Univ. Airlangga, tahun 1986 Lulus Doktor, Univ. Airlangga, tahun 1996 Advanced Cardiology Course, Univ. Hongkong, tahun 1984 Senior Visiting Program, Institut Jantung Negara, Kualalumpur, 1996 Fellow American College of Cardiology (FACC), September 2006. Fellow Collage Asia Pacific Society of Cardiology (FCAPC), Desember 2007 Fellow European Sociaty of Cardiology (FESC), 2008 Fellow Asean Collage of Cardiology (FASCC), 2008 Jabatan : Dosen Pengajar Program Pascasarjana Universitas Brawijaya Ketua MKEK Ikatan Dokter Indonesia Cabang Malang Raya Ketua PERKI Cabang Malang Raya Anggota Kolegium Kardiovaskuler Indonesia Dekan Fak. Kedokteran Univ. Wijaya Kusuma Surabaya Ketua Dewan Pengawas Rumah Sakit Pendidikan Ketua Program Studi Kardiovascular Fak. Kedokteran Univ. Brawijaya Curriculum Vitae 2 Djanggan Sargowo Surabaya, 15 April 2012 INFLAMMATION IN ATHEROSCLEROSIS : FROM BENCH TO BEDSIDE 3 4 RUDOLF VIRCHOW Inflammation-based arterial changes as a mechanism of primary importance in atherogenesis mid 19th century Lamond, B. The American Journal of Pathology. 2008 5 Atherosclerosis Start from very young To Old age ? 6 Atherothrombosis* is aLeading Cause of Death Worldwide1† The World Health Report, 2002, WHO Geneva, 2002 28.7 17.8 12.6 9.1 6 5.1 0 5 10 15 20 25 30 Atherothrombosis* Infectious disease Cancer Injuries Pulmonary disease AIDS Mortality (%) * Ischemic heart disease, cerebrovascular disease, inflammatory heart disease and hypertensive heart disease † Worldwide defined as Member States by WHO Region (Africa, Americas, Eastern Mediterranean, European, South-East Asia and Western Pacific) 7 MAJOR CLINICAL MANIFESTATIONS OF ATHEROTHROMBOSIS Adapted from: Drouet L. Cerebrovasc Dis 2002; 13(suppl 1): 1–6. Transient ischemic attack Angina: Stable Unstable Ischemic stroke Myocardial infarction Peripheral arterial disease: Intermittent claudication Rest Pain Gangrene Necrosis 8  Dyslipidemia  Endothelial dysfunction  Free radicals  Immunologic Atherosclerosis/CAD THEORY AND CONCEPT OF ATHEROSCLEROSIS Inflamation (Sargowo, 1996) 9 Free Radical ATHEROGENESIS (Sargowo, 1996) 10 IDENTIFYING THOSE AT RISK OF ATHEROTHROMBOSIS Yusuf S et al. Circulation 2001; 104: 2746–53. 2. Drouet L. Cerebrovasc Dis 2002;13(suppl 1):1–6. Lifestyle Smoking Diet Lack of exercise Genetic Genetic traits Gender Age Generalized disorders Obesity Diabetes Systemic conditions History of vascular events Hypertension Hyperlipidemia Hypercoagulable states Homocystinemia Local factors Elevated prothrombotic factors: fibrinogen, CRP, PAI-1 Blood flow patterns, vessel diameter, arterial wall structure Atherothrombosis manifestations (myocardial infarction, stroke, vascular death) 11 Arici. 2010 Risk Factors for Atherosclerosis Classic Hypertension, Hyper-lipidemia, DM, Smoking Uremia Related Increase ox-LDL, Free radicals, Uremic toxin Infection Bacterial and viral infection Proinflammatory cytokine release Endothelial dysfunction Systemic inflammatory respones Acute phase response Elevated CRP Binding LDL, cemplement activation, tissue factor secretion Accelerated ATHEROSCLEROSIS 12 LDL CD40L=CD40 ligand; TNF-α=tumor necrosis factor-alpha; IL=interleukin; VCAM=vascular cell adhesion molecule; ICAM=intercellular adhesion molecule. Cockerill GW et al. Arterioscler Thromb Vasc Biol. 1995;15:1987-1994; Andre P et al. Circulation. 2002;106:896-899; Libby P. Circulation. 2001;104:365-372; Libby P et al. Circulation. 2002;105:1135-1143; Ross R. N Engl J Med. 1999;340:115-126. Vessel lumen Monocyte Macrophage Adhesionmolecules (VCAM-1, ICAM-1) Inflammatory mediators (CRP, CD40/CD40L, TNF-α, IL-1, IL-6) Intima Foam cell INFLAMMATION PROMOTES PROGRESSION OF ATHEROSCLEROSIS Endothelium LDL Ox-LDL 13 14 Atherosclerosis is a fibroproliferative and inflammatory process occurring ins response to a variety of vascular insults The insults come from classical risk factors ( HT, dyslipidemia, endothelial dysfunction, smoking, menopause, diabetes etc) and novel risk factors (Hcy, LVH, Lp(a), TG, oxidative stress, fibrinogen etc) Endothelial dysfunction is regarded as the first abnormality leading to atherosclerosis This implies that modulation of endothelial function may be used as strategy to intervene the process. 15 Two theories gain more acceptance: (a) the lipid theory (b) inflammation theory Endothelial dysfunction is now regarded as the first abnormality leading to AS. More novel cardiovascular risk factors are known, e.g.: Fibrinogen b. PAI-1 Homocysteins d. AT-1 e. CRP f. Lp(a) g. small-dense LDL h. infectious agents i. and more are emerging 16 Acute Coronary Syndrome (endocrine viewpoints) atherosclerotic lesions vascular funtions b.1. inflammatory reaction b.2. thrombogeneity b.3. vasoreactivity b.4. plaque stability b.5. shoulder of plaque endothelium balance between c.1. vasodilating, antithrombotic, antiproliferative factors (NO, prostacyclin, C-natriuretic peptide, EDHF) c.2. vasoconstricting, prothrombotic, proliferative factors (ET, superoxide, thromoboxan A2) 17 NATURAL HISTORY OF CORONARY ATHEROSCLEROSIS Chatzizisis et all. JACC. 2007. Asymtomatic Stable Angina Acute Coronary Syndrome Early fibroatheroma Compensatory expansive remodeling Quiescent plaque Contrictive remodeling Stenotic plaque Exessive expansive remodeling Thin cap fibroatheroma Erosion Physiologic coronary artery Local factors, e.g. low ESS Systemic factors, e.g. hyperlipidemia Genetic factors Physiologic ESS Limited inflammation Fibroproliferation Microruptures 18 ATHEROSCLEROSIS IS AN INFLAMMATORY DISEASE Libby P. Circulation. 2001;104:365-372; Ross R. N Engl J Med. 1999;340:115-126. Monocyte LDL-C Adhesion molecule Macrophage Foam cell OxidizedLDL-C Plaque rupture Smooth muscle cells CRP Plaque instability and thrombus Oxidation Inflammation Endothelial dysfunction 19 20 Reverse Cholesterol Transport Monocyte CRP TXA2 PGI2 Thrombin LDL Platelets HDL HDL Ox-LDL MCP-1 Macrophage P-selectin CD 40L PDGF Foam cell MMP T cell E-selectins CD 40L VCAM-1 ICAM-1 IL-1 Reilly, et.all. 2005 21 THE ROLE OF Lp-PLA2 IN CHD LUMEN Monocytes Adhesion Molecules Oxidated LDL INTIMA MEDIA Lp-PLA2 Lyso-PC OxFA Cytokines Plaque Formation Foam Cell Macrophage 22 MC T T FC FC LDL Oxidation Lyso-PC Ox-chol Cytokines Cytokines ? C5a C’ MCP-1 F SMC 23 Intracelluler proteolysis and fusion of LDL Figure : Proposed Dual Action of Exocytosed Mast Cell Granules (The Granule Remnants) of Lipoprotein Metabolism in The Arterial Intima 24 HSCRP 25 26 GM-CSF VCAM-1 MPC-1 Transcription Factors : Endothelial Cell Pro-inflammatory Genes Oxidative Stress NF-xB AP-1 Leucocyte infiltration / activation Plaque Rupture Gibbons, 97 LEUCOCYTE ACTIVATION IN ATHEROGENESIS : IMPLICATIONS FOR ACUTE ISCHEMIC SYNDROMES 27 p38 c-Jun activation Caspases Apoptosis NIK ? ? MEKK1?   CKII IKK complex TNFR-1 TNFR-1 IL-1R Shear stress p65 p50 CBP/p300 Gene activation p65 p50 IB pKAc IB Ub Target genes : - IL-1, IL-8, IL-6, IFN  - TNF, MCP-1 - CSFs, c-myc - VCAM-1, ICAM-1, E-selectin - Tissue factor - Survival factor Thurberg and Collins : Curr Opin Lipidol 9:387-396,1998 Ub Ox-LDL ROIs ??? Lipid peroxides ? H2O2 Ubiquitination and proteosome degradation T R A D D R I P F A D D R I P T R A D D T R A F 2 T R A F 6 28 Visual Medica. 2009 29 Stockley. 2006 Cytokines : IL-6, TNF-α MACROPHAGE FOAM CELL Oxidized LDL CRP CRP Chemokines: MCO-1 Atherosclerotic plaque MONOCYTE Inflammatory Mediators: CRP Prothrombotic factors FCR Receptor 30 POTENTIAL MECHANISM OF CRP Stevens, R. 2005 CRP LDL opsonisation Monocyte infiltration Foam cell formation Increased MCP-1 and CAM EC activation Inflammatory cell recruitment Atherosclerosis plaque formation Complement activation EC sensitisation T-cell attack EC damage Atherosclerotic plaque rupture 31 Rheumatoid arthritis Atherosclerosis Multiple sclerosis Asthma Inflammatory bowel disease Helicobacter pylori-associated gastritis Systemic inflammatory response syndrome NF-KB ACTIVATION INFLAMMATORY DISEASE The Journal of Clinical Investigation, 2001 32 PROTEIN REGULATED BY NF-KB Inflammatory Enzyme Adhesion Molecule Inducible nitric oxide synthase Inducide cylooxigenase-2 5-Lipoxigenase Cytosolic phospolipase A2 ICAM-1 VCAM-1 E-selectin Receptor Interlekin-2 receptor (alpha chain) T-cell receptors (beta chain) NEJM, 1997 33 BIOMARKERS OF ACTIVITY STUDIED FOR CAD Cytokines (IL-1β, IL-6, IL-8, IL-10, TNF-α, sCD40 ligand, myeloperoxidase) Adhesion molecules (sICAM-1, sVCAM-1, p-selectin) Acute phase reactans (fibrinogen, AAS, CRP) White blood cells Erythrocyte sedimentation rate Neopterin Heat shock proteins Adiponectin Lipoprotein associated phospholipase A2 Placental growth factos Cystatin C Kaski, JC. 2006. 34 Are you hungry or sleepy ???? Sciences 35 The inflammatory cascade. IL indicates interleukin; ICAM, intercellular adhesion molecule; and HSP, heat shock protein. (Libby, Ridker; 1999) Pro-Inflammatory Risk Factors Primary Pro-Inflammatory Cytokines (eg. IL-1, TNF-) IL-6 “Mesenger” Cytokine CRP SAA Endothelium and other cells LIVER Circulation 36 (Ridker, 2004) MORE THAN A MARKER : DOES CRP PLAY A DIRECT ROLE IN ATHEROTHROMBOSIS ? CRP localizes in atherosclerotic but not normal intima CRP induced Complement activation CRP dependent monocyte recruitment into arterial wall CRP induced production of tissue factor in monocytes CRP based blunting of endothelial vasoreactivity CRP mediated LDL uptake by macrophages CRP triggered oxidation of LDL cholesterol CRP induced PAI-1 expression stabilizes PAI-1 mRNA CRP attenuates NO production and decreases eNOS expression CRP induced production of cell adhesion moleculas MCP-1, ET-1 37 ROLE OF INFLAMATORY MARKERS Interleukin-6 Total cholesterol LDL-cholesterol siCAM-1 Serum amyloid A Apolipoprotein B Total cholesterol: HDL-cholesterol Hs-CRP Hs-CRP + total cholesterol: HDL-cholesterol 0 1.0 2.0 4.0 6.0 Relative Risk (New England Journal of Medicine) 38 39 Weissberg, 1999 Inflammation Repair 40 REDOX REGULATION OF ENDOTHELIAL DYSFUNCTION & ACTIVATION O2– OH H2O2  NO Activity  G-Protein Function  Protein Kinase C Oxidation Endothelial Dysfunction (D. Sargowo) 41 ENDOTHELIAL DYSFUNCTION AND ACUTE CORONARY SYNDROMES Vasoconstriction Platelet Aggregation SMC Proliferation Leukocyte Adhesion LDL Oxidation Activation of MMPs Endothelial Dysfunction Plaque Rupture Thrombosis Matrix Remodeling (D. Sargowo)
Slide 42 - 1 Nama : Prof. Dr. H. Djanggan Sargowo, dr., SpPD., SpJP(K), FIHA, FACC, FESC, FCAPC, FASCC Tempat/Tgl lahir : Sragen, 21 September 1947 Alamat : Wilis Indah E-10 Malang, Telp. 0341-552395 Pendidikan : Lulus Dokter dari UGM, tahun 1974 Lulus Cardiologist dari Univ. Indonesia, tahun 1983 Lulus Internist dari Univ. Airlangga, tahun 1986 Lulus Doktor, Univ. Airlangga, tahun 1996 Advanced Cardiology Course, Univ. Hongkong, tahun 1984 Senior Visiting Program, Institut Jantung Negara, Kualalumpur, 1996 Fellow American College of Cardiology (FACC), September 2006. Fellow Collage Asia Pacific Society of Cardiology (FCAPC), Desember 2007 Fellow European Sociaty of Cardiology (FESC), 2008 Fellow Asean Collage of Cardiology (FASCC), 2008 Jabatan : Dosen Pengajar Program Pascasarjana Universitas Brawijaya Ketua MKEK Ikatan Dokter Indonesia Cabang Malang Raya Ketua PERKI Cabang Malang Raya Anggota Kolegium Kardiovaskuler Indonesia Dekan Fak. Kedokteran Univ. Wijaya Kusuma Surabaya Ketua Dewan Pengawas Rumah Sakit Pendidikan Ketua Program Studi Kardiovascular Fak. Kedokteran Univ. Brawijaya Curriculum Vitae 2 Djanggan Sargowo Surabaya, 15 April 2012 INFLAMMATION IN ATHEROSCLEROSIS : FROM BENCH TO BEDSIDE 3 4 RUDOLF VIRCHOW Inflammation-based arterial changes as a mechanism of primary importance in atherogenesis mid 19th century Lamond, B. The American Journal of Pathology. 2008 5 Atherosclerosis Start from very young To Old age ? 6 Atherothrombosis* is aLeading Cause of Death Worldwide1† The World Health Report, 2002, WHO Geneva, 2002 28.7 17.8 12.6 9.1 6 5.1 0 5 10 15 20 25 30 Atherothrombosis* Infectious disease Cancer Injuries Pulmonary disease AIDS Mortality (%) * Ischemic heart disease, cerebrovascular disease, inflammatory heart disease and hypertensive heart disease † Worldwide defined as Member States by WHO Region (Africa, Americas, Eastern Mediterranean, European, South-East Asia and Western Pacific) 7 MAJOR CLINICAL MANIFESTATIONS OF ATHEROTHROMBOSIS Adapted from: Drouet L. Cerebrovasc Dis 2002; 13(suppl 1): 1–6. Transient ischemic attack Angina: Stable Unstable Ischemic stroke Myocardial infarction Peripheral arterial disease: Intermittent claudication Rest Pain Gangrene Necrosis 8  Dyslipidemia  Endothelial dysfunction  Free radicals  Immunologic Atherosclerosis/CAD THEORY AND CONCEPT OF ATHEROSCLEROSIS Inflamation (Sargowo, 1996) 9 Free Radical ATHEROGENESIS (Sargowo, 1996) 10 IDENTIFYING THOSE AT RISK OF ATHEROTHROMBOSIS Yusuf S et al. Circulation 2001; 104: 2746–53. 2. Drouet L. Cerebrovasc Dis 2002;13(suppl 1):1–6. Lifestyle Smoking Diet Lack of exercise Genetic Genetic traits Gender Age Generalized disorders Obesity Diabetes Systemic conditions History of vascular events Hypertension Hyperlipidemia Hypercoagulable states Homocystinemia Local factors Elevated prothrombotic factors: fibrinogen, CRP, PAI-1 Blood flow patterns, vessel diameter, arterial wall structure Atherothrombosis manifestations (myocardial infarction, stroke, vascular death) 11 Arici. 2010 Risk Factors for Atherosclerosis Classic Hypertension, Hyper-lipidemia, DM, Smoking Uremia Related Increase ox-LDL, Free radicals, Uremic toxin Infection Bacterial and viral infection Proinflammatory cytokine release Endothelial dysfunction Systemic inflammatory respones Acute phase response Elevated CRP Binding LDL, cemplement activation, tissue factor secretion Accelerated ATHEROSCLEROSIS 12 LDL CD40L=CD40 ligand; TNF-α=tumor necrosis factor-alpha; IL=interleukin; VCAM=vascular cell adhesion molecule; ICAM=intercellular adhesion molecule. Cockerill GW et al. Arterioscler Thromb Vasc Biol. 1995;15:1987-1994; Andre P et al. Circulation. 2002;106:896-899; Libby P. Circulation. 2001;104:365-372; Libby P et al. Circulation. 2002;105:1135-1143; Ross R. N Engl J Med. 1999;340:115-126. Vessel lumen Monocyte Macrophage Adhesionmolecules (VCAM-1, ICAM-1) Inflammatory mediators (CRP, CD40/CD40L, TNF-α, IL-1, IL-6) Intima Foam cell INFLAMMATION PROMOTES PROGRESSION OF ATHEROSCLEROSIS Endothelium LDL Ox-LDL 13 14 Atherosclerosis is a fibroproliferative and inflammatory process occurring ins response to a variety of vascular insults The insults come from classical risk factors ( HT, dyslipidemia, endothelial dysfunction, smoking, menopause, diabetes etc) and novel risk factors (Hcy, LVH, Lp(a), TG, oxidative stress, fibrinogen etc) Endothelial dysfunction is regarded as the first abnormality leading to atherosclerosis This implies that modulation of endothelial function may be used as strategy to intervene the process. 15 Two theories gain more acceptance: (a) the lipid theory (b) inflammation theory Endothelial dysfunction is now regarded as the first abnormality leading to AS. More novel cardiovascular risk factors are known, e.g.: Fibrinogen b. PAI-1 Homocysteins d. AT-1 e. CRP f. Lp(a) g. small-dense LDL h. infectious agents i. and more are emerging 16 Acute Coronary Syndrome (endocrine viewpoints) atherosclerotic lesions vascular funtions b.1. inflammatory reaction b.2. thrombogeneity b.3. vasoreactivity b.4. plaque stability b.5. shoulder of plaque endothelium balance between c.1. vasodilating, antithrombotic, antiproliferative factors (NO, prostacyclin, C-natriuretic peptide, EDHF) c.2. vasoconstricting, prothrombotic, proliferative factors (ET, superoxide, thromoboxan A2) 17 NATURAL HISTORY OF CORONARY ATHEROSCLEROSIS Chatzizisis et all. JACC. 2007. Asymtomatic Stable Angina Acute Coronary Syndrome Early fibroatheroma Compensatory expansive remodeling Quiescent plaque Contrictive remodeling Stenotic plaque Exessive expansive remodeling Thin cap fibroatheroma Erosion Physiologic coronary artery Local factors, e.g. low ESS Systemic factors, e.g. hyperlipidemia Genetic factors Physiologic ESS Limited inflammation Fibroproliferation Microruptures 18 ATHEROSCLEROSIS IS AN INFLAMMATORY DISEASE Libby P. Circulation. 2001;104:365-372; Ross R. N Engl J Med. 1999;340:115-126. Monocyte LDL-C Adhesion molecule Macrophage Foam cell OxidizedLDL-C Plaque rupture Smooth muscle cells CRP Plaque instability and thrombus Oxidation Inflammation Endothelial dysfunction 19 20 Reverse Cholesterol Transport Monocyte CRP TXA2 PGI2 Thrombin LDL Platelets HDL HDL Ox-LDL MCP-1 Macrophage P-selectin CD 40L PDGF Foam cell MMP T cell E-selectins CD 40L VCAM-1 ICAM-1 IL-1 Reilly, et.all. 2005 21 THE ROLE OF Lp-PLA2 IN CHD LUMEN Monocytes Adhesion Molecules Oxidated LDL INTIMA MEDIA Lp-PLA2 Lyso-PC OxFA Cytokines Plaque Formation Foam Cell Macrophage 22 MC T T FC FC LDL Oxidation Lyso-PC Ox-chol Cytokines Cytokines ? C5a C’ MCP-1 F SMC 23 Intracelluler proteolysis and fusion of LDL Figure : Proposed Dual Action of Exocytosed Mast Cell Granules (The Granule Remnants) of Lipoprotein Metabolism in The Arterial Intima 24 HSCRP 25 26 GM-CSF VCAM-1 MPC-1 Transcription Factors : Endothelial Cell Pro-inflammatory Genes Oxidative Stress NF-xB AP-1 Leucocyte infiltration / activation Plaque Rupture Gibbons, 97 LEUCOCYTE ACTIVATION IN ATHEROGENESIS : IMPLICATIONS FOR ACUTE ISCHEMIC SYNDROMES 27 p38 c-Jun activation Caspases Apoptosis NIK ? ? MEKK1?   CKII IKK complex TNFR-1 TNFR-1 IL-1R Shear stress p65 p50 CBP/p300 Gene activation p65 p50 IB pKAc IB Ub Target genes : - IL-1, IL-8, IL-6, IFN  - TNF, MCP-1 - CSFs, c-myc - VCAM-1, ICAM-1, E-selectin - Tissue factor - Survival factor Thurberg and Collins : Curr Opin Lipidol 9:387-396,1998 Ub Ox-LDL ROIs ??? Lipid peroxides ? H2O2 Ubiquitination and proteosome degradation T R A D D R I P F A D D R I P T R A D D T R A F 2 T R A F 6 28 Visual Medica. 2009 29 Stockley. 2006 Cytokines : IL-6, TNF-α MACROPHAGE FOAM CELL Oxidized LDL CRP CRP Chemokines: MCO-1 Atherosclerotic plaque MONOCYTE Inflammatory Mediators: CRP Prothrombotic factors FCR Receptor 30 POTENTIAL MECHANISM OF CRP Stevens, R. 2005 CRP LDL opsonisation Monocyte infiltration Foam cell formation Increased MCP-1 and CAM EC activation Inflammatory cell recruitment Atherosclerosis plaque formation Complement activation EC sensitisation T-cell attack EC damage Atherosclerotic plaque rupture 31 Rheumatoid arthritis Atherosclerosis Multiple sclerosis Asthma Inflammatory bowel disease Helicobacter pylori-associated gastritis Systemic inflammatory response syndrome NF-KB ACTIVATION INFLAMMATORY DISEASE The Journal of Clinical Investigation, 2001 32 PROTEIN REGULATED BY NF-KB Inflammatory Enzyme Adhesion Molecule Inducible nitric oxide synthase Inducide cylooxigenase-2 5-Lipoxigenase Cytosolic phospolipase A2 ICAM-1 VCAM-1 E-selectin Receptor Interlekin-2 receptor (alpha chain) T-cell receptors (beta chain) NEJM, 1997 33 BIOMARKERS OF ACTIVITY STUDIED FOR CAD Cytokines (IL-1β, IL-6, IL-8, IL-10, TNF-α, sCD40 ligand, myeloperoxidase) Adhesion molecules (sICAM-1, sVCAM-1, p-selectin) Acute phase reactans (fibrinogen, AAS, CRP) White blood cells Erythrocyte sedimentation rate Neopterin Heat shock proteins Adiponectin Lipoprotein associated phospholipase A2 Placental growth factos Cystatin C Kaski, JC. 2006. 34 Are you hungry or sleepy ???? Sciences 35 The inflammatory cascade. IL indicates interleukin; ICAM, intercellular adhesion molecule; and HSP, heat shock protein. (Libby, Ridker; 1999) Pro-Inflammatory Risk Factors Primary Pro-Inflammatory Cytokines (eg. IL-1, TNF-) IL-6 “Mesenger” Cytokine CRP SAA Endothelium and other cells LIVER Circulation 36 (Ridker, 2004) MORE THAN A MARKER : DOES CRP PLAY A DIRECT ROLE IN ATHEROTHROMBOSIS ? CRP localizes in atherosclerotic but not normal intima CRP induced Complement activation CRP dependent monocyte recruitment into arterial wall CRP induced production of tissue factor in monocytes CRP based blunting of endothelial vasoreactivity CRP mediated LDL uptake by macrophages CRP triggered oxidation of LDL cholesterol CRP induced PAI-1 expression stabilizes PAI-1 mRNA CRP attenuates NO production and decreases eNOS expression CRP induced production of cell adhesion moleculas MCP-1, ET-1 37 ROLE OF INFLAMATORY MARKERS Interleukin-6 Total cholesterol LDL-cholesterol siCAM-1 Serum amyloid A Apolipoprotein B Total cholesterol: HDL-cholesterol Hs-CRP Hs-CRP + total cholesterol: HDL-cholesterol 0 1.0 2.0 4.0 6.0 Relative Risk (New England Journal of Medicine) 38 39 Weissberg, 1999 Inflammation Repair 40 REDOX REGULATION OF ENDOTHELIAL DYSFUNCTION & ACTIVATION O2– OH H2O2  NO Activity  G-Protein Function  Protein Kinase C Oxidation Endothelial Dysfunction (D. Sargowo) 41 ENDOTHELIAL DYSFUNCTION AND ACUTE CORONARY SYNDROMES Vasoconstriction Platelet Aggregation SMC Proliferation Leukocyte Adhesion LDL Oxidation Activation of MMPs Endothelial Dysfunction Plaque Rupture Thrombosis Matrix Remodeling (D. Sargowo) 42 ENDOTHELIAL DYSFUNCTION AND ACUTE CORONARY SYNDROMES Vasospasm Plaque Rupture Thrombosis Matrix Remodeling ACUTE CORONARY SYNDROMES (D. Sargowo)
Slide 43 - 1 Nama : Prof. Dr. H. Djanggan Sargowo, dr., SpPD., SpJP(K), FIHA, FACC, FESC, FCAPC, FASCC Tempat/Tgl lahir : Sragen, 21 September 1947 Alamat : Wilis Indah E-10 Malang, Telp. 0341-552395 Pendidikan : Lulus Dokter dari UGM, tahun 1974 Lulus Cardiologist dari Univ. Indonesia, tahun 1983 Lulus Internist dari Univ. Airlangga, tahun 1986 Lulus Doktor, Univ. Airlangga, tahun 1996 Advanced Cardiology Course, Univ. Hongkong, tahun 1984 Senior Visiting Program, Institut Jantung Negara, Kualalumpur, 1996 Fellow American College of Cardiology (FACC), September 2006. Fellow Collage Asia Pacific Society of Cardiology (FCAPC), Desember 2007 Fellow European Sociaty of Cardiology (FESC), 2008 Fellow Asean Collage of Cardiology (FASCC), 2008 Jabatan : Dosen Pengajar Program Pascasarjana Universitas Brawijaya Ketua MKEK Ikatan Dokter Indonesia Cabang Malang Raya Ketua PERKI Cabang Malang Raya Anggota Kolegium Kardiovaskuler Indonesia Dekan Fak. Kedokteran Univ. Wijaya Kusuma Surabaya Ketua Dewan Pengawas Rumah Sakit Pendidikan Ketua Program Studi Kardiovascular Fak. Kedokteran Univ. Brawijaya Curriculum Vitae 2 Djanggan Sargowo Surabaya, 15 April 2012 INFLAMMATION IN ATHEROSCLEROSIS : FROM BENCH TO BEDSIDE 3 4 RUDOLF VIRCHOW Inflammation-based arterial changes as a mechanism of primary importance in atherogenesis mid 19th century Lamond, B. The American Journal of Pathology. 2008 5 Atherosclerosis Start from very young To Old age ? 6 Atherothrombosis* is aLeading Cause of Death Worldwide1† The World Health Report, 2002, WHO Geneva, 2002 28.7 17.8 12.6 9.1 6 5.1 0 5 10 15 20 25 30 Atherothrombosis* Infectious disease Cancer Injuries Pulmonary disease AIDS Mortality (%) * Ischemic heart disease, cerebrovascular disease, inflammatory heart disease and hypertensive heart disease † Worldwide defined as Member States by WHO Region (Africa, Americas, Eastern Mediterranean, European, South-East Asia and Western Pacific) 7 MAJOR CLINICAL MANIFESTATIONS OF ATHEROTHROMBOSIS Adapted from: Drouet L. Cerebrovasc Dis 2002; 13(suppl 1): 1–6. Transient ischemic attack Angina: Stable Unstable Ischemic stroke Myocardial infarction Peripheral arterial disease: Intermittent claudication Rest Pain Gangrene Necrosis 8  Dyslipidemia  Endothelial dysfunction  Free radicals  Immunologic Atherosclerosis/CAD THEORY AND CONCEPT OF ATHEROSCLEROSIS Inflamation (Sargowo, 1996) 9 Free Radical ATHEROGENESIS (Sargowo, 1996) 10 IDENTIFYING THOSE AT RISK OF ATHEROTHROMBOSIS Yusuf S et al. Circulation 2001; 104: 2746–53. 2. Drouet L. Cerebrovasc Dis 2002;13(suppl 1):1–6. Lifestyle Smoking Diet Lack of exercise Genetic Genetic traits Gender Age Generalized disorders Obesity Diabetes Systemic conditions History of vascular events Hypertension Hyperlipidemia Hypercoagulable states Homocystinemia Local factors Elevated prothrombotic factors: fibrinogen, CRP, PAI-1 Blood flow patterns, vessel diameter, arterial wall structure Atherothrombosis manifestations (myocardial infarction, stroke, vascular death) 11 Arici. 2010 Risk Factors for Atherosclerosis Classic Hypertension, Hyper-lipidemia, DM, Smoking Uremia Related Increase ox-LDL, Free radicals, Uremic toxin Infection Bacterial and viral infection Proinflammatory cytokine release Endothelial dysfunction Systemic inflammatory respones Acute phase response Elevated CRP Binding LDL, cemplement activation, tissue factor secretion Accelerated ATHEROSCLEROSIS 12 LDL CD40L=CD40 ligand; TNF-α=tumor necrosis factor-alpha; IL=interleukin; VCAM=vascular cell adhesion molecule; ICAM=intercellular adhesion molecule. Cockerill GW et al. Arterioscler Thromb Vasc Biol. 1995;15:1987-1994; Andre P et al. Circulation. 2002;106:896-899; Libby P. Circulation. 2001;104:365-372; Libby P et al. Circulation. 2002;105:1135-1143; Ross R. N Engl J Med. 1999;340:115-126. Vessel lumen Monocyte Macrophage Adhesionmolecules (VCAM-1, ICAM-1) Inflammatory mediators (CRP, CD40/CD40L, TNF-α, IL-1, IL-6) Intima Foam cell INFLAMMATION PROMOTES PROGRESSION OF ATHEROSCLEROSIS Endothelium LDL Ox-LDL 13 14 Atherosclerosis is a fibroproliferative and inflammatory process occurring ins response to a variety of vascular insults The insults come from classical risk factors ( HT, dyslipidemia, endothelial dysfunction, smoking, menopause, diabetes etc) and novel risk factors (Hcy, LVH, Lp(a), TG, oxidative stress, fibrinogen etc) Endothelial dysfunction is regarded as the first abnormality leading to atherosclerosis This implies that modulation of endothelial function may be used as strategy to intervene the process. 15 Two theories gain more acceptance: (a) the lipid theory (b) inflammation theory Endothelial dysfunction is now regarded as the first abnormality leading to AS. More novel cardiovascular risk factors are known, e.g.: Fibrinogen b. PAI-1 Homocysteins d. AT-1 e. CRP f. Lp(a) g. small-dense LDL h. infectious agents i. and more are emerging 16 Acute Coronary Syndrome (endocrine viewpoints) atherosclerotic lesions vascular funtions b.1. inflammatory reaction b.2. thrombogeneity b.3. vasoreactivity b.4. plaque stability b.5. shoulder of plaque endothelium balance between c.1. vasodilating, antithrombotic, antiproliferative factors (NO, prostacyclin, C-natriuretic peptide, EDHF) c.2. vasoconstricting, prothrombotic, proliferative factors (ET, superoxide, thromoboxan A2) 17 NATURAL HISTORY OF CORONARY ATHEROSCLEROSIS Chatzizisis et all. JACC. 2007. Asymtomatic Stable Angina Acute Coronary Syndrome Early fibroatheroma Compensatory expansive remodeling Quiescent plaque Contrictive remodeling Stenotic plaque Exessive expansive remodeling Thin cap fibroatheroma Erosion Physiologic coronary artery Local factors, e.g. low ESS Systemic factors, e.g. hyperlipidemia Genetic factors Physiologic ESS Limited inflammation Fibroproliferation Microruptures 18 ATHEROSCLEROSIS IS AN INFLAMMATORY DISEASE Libby P. Circulation. 2001;104:365-372; Ross R. N Engl J Med. 1999;340:115-126. Monocyte LDL-C Adhesion molecule Macrophage Foam cell OxidizedLDL-C Plaque rupture Smooth muscle cells CRP Plaque instability and thrombus Oxidation Inflammation Endothelial dysfunction 19 20 Reverse Cholesterol Transport Monocyte CRP TXA2 PGI2 Thrombin LDL Platelets HDL HDL Ox-LDL MCP-1 Macrophage P-selectin CD 40L PDGF Foam cell MMP T cell E-selectins CD 40L VCAM-1 ICAM-1 IL-1 Reilly, et.all. 2005 21 THE ROLE OF Lp-PLA2 IN CHD LUMEN Monocytes Adhesion Molecules Oxidated LDL INTIMA MEDIA Lp-PLA2 Lyso-PC OxFA Cytokines Plaque Formation Foam Cell Macrophage 22 MC T T FC FC LDL Oxidation Lyso-PC Ox-chol Cytokines Cytokines ? C5a C’ MCP-1 F SMC 23 Intracelluler proteolysis and fusion of LDL Figure : Proposed Dual Action of Exocytosed Mast Cell Granules (The Granule Remnants) of Lipoprotein Metabolism in The Arterial Intima 24 HSCRP 25 26 GM-CSF VCAM-1 MPC-1 Transcription Factors : Endothelial Cell Pro-inflammatory Genes Oxidative Stress NF-xB AP-1 Leucocyte infiltration / activation Plaque Rupture Gibbons, 97 LEUCOCYTE ACTIVATION IN ATHEROGENESIS : IMPLICATIONS FOR ACUTE ISCHEMIC SYNDROMES 27 p38 c-Jun activation Caspases Apoptosis NIK ? ? MEKK1?   CKII IKK complex TNFR-1 TNFR-1 IL-1R Shear stress p65 p50 CBP/p300 Gene activation p65 p50 IB pKAc IB Ub Target genes : - IL-1, IL-8, IL-6, IFN  - TNF, MCP-1 - CSFs, c-myc - VCAM-1, ICAM-1, E-selectin - Tissue factor - Survival factor Thurberg and Collins : Curr Opin Lipidol 9:387-396,1998 Ub Ox-LDL ROIs ??? Lipid peroxides ? H2O2 Ubiquitination and proteosome degradation T R A D D R I P F A D D R I P T R A D D T R A F 2 T R A F 6 28 Visual Medica. 2009 29 Stockley. 2006 Cytokines : IL-6, TNF-α MACROPHAGE FOAM CELL Oxidized LDL CRP CRP Chemokines: MCO-1 Atherosclerotic plaque MONOCYTE Inflammatory Mediators: CRP Prothrombotic factors FCR Receptor 30 POTENTIAL MECHANISM OF CRP Stevens, R. 2005 CRP LDL opsonisation Monocyte infiltration Foam cell formation Increased MCP-1 and CAM EC activation Inflammatory cell recruitment Atherosclerosis plaque formation Complement activation EC sensitisation T-cell attack EC damage Atherosclerotic plaque rupture 31 Rheumatoid arthritis Atherosclerosis Multiple sclerosis Asthma Inflammatory bowel disease Helicobacter pylori-associated gastritis Systemic inflammatory response syndrome NF-KB ACTIVATION INFLAMMATORY DISEASE The Journal of Clinical Investigation, 2001 32 PROTEIN REGULATED BY NF-KB Inflammatory Enzyme Adhesion Molecule Inducible nitric oxide synthase Inducide cylooxigenase-2 5-Lipoxigenase Cytosolic phospolipase A2 ICAM-1 VCAM-1 E-selectin Receptor Interlekin-2 receptor (alpha chain) T-cell receptors (beta chain) NEJM, 1997 33 BIOMARKERS OF ACTIVITY STUDIED FOR CAD Cytokines (IL-1β, IL-6, IL-8, IL-10, TNF-α, sCD40 ligand, myeloperoxidase) Adhesion molecules (sICAM-1, sVCAM-1, p-selectin) Acute phase reactans (fibrinogen, AAS, CRP) White blood cells Erythrocyte sedimentation rate Neopterin Heat shock proteins Adiponectin Lipoprotein associated phospholipase A2 Placental growth factos Cystatin C Kaski, JC. 2006. 34 Are you hungry or sleepy ???? Sciences 35 The inflammatory cascade. IL indicates interleukin; ICAM, intercellular adhesion molecule; and HSP, heat shock protein. (Libby, Ridker; 1999) Pro-Inflammatory Risk Factors Primary Pro-Inflammatory Cytokines (eg. IL-1, TNF-) IL-6 “Mesenger” Cytokine CRP SAA Endothelium and other cells LIVER Circulation 36 (Ridker, 2004) MORE THAN A MARKER : DOES CRP PLAY A DIRECT ROLE IN ATHEROTHROMBOSIS ? CRP localizes in atherosclerotic but not normal intima CRP induced Complement activation CRP dependent monocyte recruitment into arterial wall CRP induced production of tissue factor in monocytes CRP based blunting of endothelial vasoreactivity CRP mediated LDL uptake by macrophages CRP triggered oxidation of LDL cholesterol CRP induced PAI-1 expression stabilizes PAI-1 mRNA CRP attenuates NO production and decreases eNOS expression CRP induced production of cell adhesion moleculas MCP-1, ET-1 37 ROLE OF INFLAMATORY MARKERS Interleukin-6 Total cholesterol LDL-cholesterol siCAM-1 Serum amyloid A Apolipoprotein B Total cholesterol: HDL-cholesterol Hs-CRP Hs-CRP + total cholesterol: HDL-cholesterol 0 1.0 2.0 4.0 6.0 Relative Risk (New England Journal of Medicine) 38 39 Weissberg, 1999 Inflammation Repair 40 REDOX REGULATION OF ENDOTHELIAL DYSFUNCTION & ACTIVATION O2– OH H2O2  NO Activity  G-Protein Function  Protein Kinase C Oxidation Endothelial Dysfunction (D. Sargowo) 41 ENDOTHELIAL DYSFUNCTION AND ACUTE CORONARY SYNDROMES Vasoconstriction Platelet Aggregation SMC Proliferation Leukocyte Adhesion LDL Oxidation Activation of MMPs Endothelial Dysfunction Plaque Rupture Thrombosis Matrix Remodeling (D. Sargowo) 42 ENDOTHELIAL DYSFUNCTION AND ACUTE CORONARY SYNDROMES Vasospasm Plaque Rupture Thrombosis Matrix Remodeling ACUTE CORONARY SYNDROMES (D. Sargowo) 43
Slide 44 - 1 Nama : Prof. Dr. H. Djanggan Sargowo, dr., SpPD., SpJP(K), FIHA, FACC, FESC, FCAPC, FASCC Tempat/Tgl lahir : Sragen, 21 September 1947 Alamat : Wilis Indah E-10 Malang, Telp. 0341-552395 Pendidikan : Lulus Dokter dari UGM, tahun 1974 Lulus Cardiologist dari Univ. Indonesia, tahun 1983 Lulus Internist dari Univ. Airlangga, tahun 1986 Lulus Doktor, Univ. Airlangga, tahun 1996 Advanced Cardiology Course, Univ. Hongkong, tahun 1984 Senior Visiting Program, Institut Jantung Negara, Kualalumpur, 1996 Fellow American College of Cardiology (FACC), September 2006. Fellow Collage Asia Pacific Society of Cardiology (FCAPC), Desember 2007 Fellow European Sociaty of Cardiology (FESC), 2008 Fellow Asean Collage of Cardiology (FASCC), 2008 Jabatan : Dosen Pengajar Program Pascasarjana Universitas Brawijaya Ketua MKEK Ikatan Dokter Indonesia Cabang Malang Raya Ketua PERKI Cabang Malang Raya Anggota Kolegium Kardiovaskuler Indonesia Dekan Fak. Kedokteran Univ. Wijaya Kusuma Surabaya Ketua Dewan Pengawas Rumah Sakit Pendidikan Ketua Program Studi Kardiovascular Fak. Kedokteran Univ. Brawijaya Curriculum Vitae 2 Djanggan Sargowo Surabaya, 15 April 2012 INFLAMMATION IN ATHEROSCLEROSIS : FROM BENCH TO BEDSIDE 3 4 RUDOLF VIRCHOW Inflammation-based arterial changes as a mechanism of primary importance in atherogenesis mid 19th century Lamond, B. The American Journal of Pathology. 2008 5 Atherosclerosis Start from very young To Old age ? 6 Atherothrombosis* is aLeading Cause of Death Worldwide1† The World Health Report, 2002, WHO Geneva, 2002 28.7 17.8 12.6 9.1 6 5.1 0 5 10 15 20 25 30 Atherothrombosis* Infectious disease Cancer Injuries Pulmonary disease AIDS Mortality (%) * Ischemic heart disease, cerebrovascular disease, inflammatory heart disease and hypertensive heart disease † Worldwide defined as Member States by WHO Region (Africa, Americas, Eastern Mediterranean, European, South-East Asia and Western Pacific) 7 MAJOR CLINICAL MANIFESTATIONS OF ATHEROTHROMBOSIS Adapted from: Drouet L. Cerebrovasc Dis 2002; 13(suppl 1): 1–6. Transient ischemic attack Angina: Stable Unstable Ischemic stroke Myocardial infarction Peripheral arterial disease: Intermittent claudication Rest Pain Gangrene Necrosis 8  Dyslipidemia  Endothelial dysfunction  Free radicals  Immunologic Atherosclerosis/CAD THEORY AND CONCEPT OF ATHEROSCLEROSIS Inflamation (Sargowo, 1996) 9 Free Radical ATHEROGENESIS (Sargowo, 1996) 10 IDENTIFYING THOSE AT RISK OF ATHEROTHROMBOSIS Yusuf S et al. Circulation 2001; 104: 2746–53. 2. Drouet L. Cerebrovasc Dis 2002;13(suppl 1):1–6. Lifestyle Smoking Diet Lack of exercise Genetic Genetic traits Gender Age Generalized disorders Obesity Diabetes Systemic conditions History of vascular events Hypertension Hyperlipidemia Hypercoagulable states Homocystinemia Local factors Elevated prothrombotic factors: fibrinogen, CRP, PAI-1 Blood flow patterns, vessel diameter, arterial wall structure Atherothrombosis manifestations (myocardial infarction, stroke, vascular death) 11 Arici. 2010 Risk Factors for Atherosclerosis Classic Hypertension, Hyper-lipidemia, DM, Smoking Uremia Related Increase ox-LDL, Free radicals, Uremic toxin Infection Bacterial and viral infection Proinflammatory cytokine release Endothelial dysfunction Systemic inflammatory respones Acute phase response Elevated CRP Binding LDL, cemplement activation, tissue factor secretion Accelerated ATHEROSCLEROSIS 12 LDL CD40L=CD40 ligand; TNF-α=tumor necrosis factor-alpha; IL=interleukin; VCAM=vascular cell adhesion molecule; ICAM=intercellular adhesion molecule. Cockerill GW et al. Arterioscler Thromb Vasc Biol. 1995;15:1987-1994; Andre P et al. Circulation. 2002;106:896-899; Libby P. Circulation. 2001;104:365-372; Libby P et al. Circulation. 2002;105:1135-1143; Ross R. N Engl J Med. 1999;340:115-126. Vessel lumen Monocyte Macrophage Adhesionmolecules (VCAM-1, ICAM-1) Inflammatory mediators (CRP, CD40/CD40L, TNF-α, IL-1, IL-6) Intima Foam cell INFLAMMATION PROMOTES PROGRESSION OF ATHEROSCLEROSIS Endothelium LDL Ox-LDL 13 14 Atherosclerosis is a fibroproliferative and inflammatory process occurring ins response to a variety of vascular insults The insults come from classical risk factors ( HT, dyslipidemia, endothelial dysfunction, smoking, menopause, diabetes etc) and novel risk factors (Hcy, LVH, Lp(a), TG, oxidative stress, fibrinogen etc) Endothelial dysfunction is regarded as the first abnormality leading to atherosclerosis This implies that modulation of endothelial function may be used as strategy to intervene the process. 15 Two theories gain more acceptance: (a) the lipid theory (b) inflammation theory Endothelial dysfunction is now regarded as the first abnormality leading to AS. More novel cardiovascular risk factors are known, e.g.: Fibrinogen b. PAI-1 Homocysteins d. AT-1 e. CRP f. Lp(a) g. small-dense LDL h. infectious agents i. and more are emerging 16 Acute Coronary Syndrome (endocrine viewpoints) atherosclerotic lesions vascular funtions b.1. inflammatory reaction b.2. thrombogeneity b.3. vasoreactivity b.4. plaque stability b.5. shoulder of plaque endothelium balance between c.1. vasodilating, antithrombotic, antiproliferative factors (NO, prostacyclin, C-natriuretic peptide, EDHF) c.2. vasoconstricting, prothrombotic, proliferative factors (ET, superoxide, thromoboxan A2) 17 NATURAL HISTORY OF CORONARY ATHEROSCLEROSIS Chatzizisis et all. JACC. 2007. Asymtomatic Stable Angina Acute Coronary Syndrome Early fibroatheroma Compensatory expansive remodeling Quiescent plaque Contrictive remodeling Stenotic plaque Exessive expansive remodeling Thin cap fibroatheroma Erosion Physiologic coronary artery Local factors, e.g. low ESS Systemic factors, e.g. hyperlipidemia Genetic factors Physiologic ESS Limited inflammation Fibroproliferation Microruptures 18 ATHEROSCLEROSIS IS AN INFLAMMATORY DISEASE Libby P. Circulation. 2001;104:365-372; Ross R. N Engl J Med. 1999;340:115-126. Monocyte LDL-C Adhesion molecule Macrophage Foam cell OxidizedLDL-C Plaque rupture Smooth muscle cells CRP Plaque instability and thrombus Oxidation Inflammation Endothelial dysfunction 19 20 Reverse Cholesterol Transport Monocyte CRP TXA2 PGI2 Thrombin LDL Platelets HDL HDL Ox-LDL MCP-1 Macrophage P-selectin CD 40L PDGF Foam cell MMP T cell E-selectins CD 40L VCAM-1 ICAM-1 IL-1 Reilly, et.all. 2005 21 THE ROLE OF Lp-PLA2 IN CHD LUMEN Monocytes Adhesion Molecules Oxidated LDL INTIMA MEDIA Lp-PLA2 Lyso-PC OxFA Cytokines Plaque Formation Foam Cell Macrophage 22 MC T T FC FC LDL Oxidation Lyso-PC Ox-chol Cytokines Cytokines ? C5a C’ MCP-1 F SMC 23 Intracelluler proteolysis and fusion of LDL Figure : Proposed Dual Action of Exocytosed Mast Cell Granules (The Granule Remnants) of Lipoprotein Metabolism in The Arterial Intima 24 HSCRP 25 26 GM-CSF VCAM-1 MPC-1 Transcription Factors : Endothelial Cell Pro-inflammatory Genes Oxidative Stress NF-xB AP-1 Leucocyte infiltration / activation Plaque Rupture Gibbons, 97 LEUCOCYTE ACTIVATION IN ATHEROGENESIS : IMPLICATIONS FOR ACUTE ISCHEMIC SYNDROMES 27 p38 c-Jun activation Caspases Apoptosis NIK ? ? MEKK1?   CKII IKK complex TNFR-1 TNFR-1 IL-1R Shear stress p65 p50 CBP/p300 Gene activation p65 p50 IB pKAc IB Ub Target genes : - IL-1, IL-8, IL-6, IFN  - TNF, MCP-1 - CSFs, c-myc - VCAM-1, ICAM-1, E-selectin - Tissue factor - Survival factor Thurberg and Collins : Curr Opin Lipidol 9:387-396,1998 Ub Ox-LDL ROIs ??? Lipid peroxides ? H2O2 Ubiquitination and proteosome degradation T R A D D R I P F A D D R I P T R A D D T R A F 2 T R A F 6 28 Visual Medica. 2009 29 Stockley. 2006 Cytokines : IL-6, TNF-α MACROPHAGE FOAM CELL Oxidized LDL CRP CRP Chemokines: MCO-1 Atherosclerotic plaque MONOCYTE Inflammatory Mediators: CRP Prothrombotic factors FCR Receptor 30 POTENTIAL MECHANISM OF CRP Stevens, R. 2005 CRP LDL opsonisation Monocyte infiltration Foam cell formation Increased MCP-1 and CAM EC activation Inflammatory cell recruitment Atherosclerosis plaque formation Complement activation EC sensitisation T-cell attack EC damage Atherosclerotic plaque rupture 31 Rheumatoid arthritis Atherosclerosis Multiple sclerosis Asthma Inflammatory bowel disease Helicobacter pylori-associated gastritis Systemic inflammatory response syndrome NF-KB ACTIVATION INFLAMMATORY DISEASE The Journal of Clinical Investigation, 2001 32 PROTEIN REGULATED BY NF-KB Inflammatory Enzyme Adhesion Molecule Inducible nitric oxide synthase Inducide cylooxigenase-2 5-Lipoxigenase Cytosolic phospolipase A2 ICAM-1 VCAM-1 E-selectin Receptor Interlekin-2 receptor (alpha chain) T-cell receptors (beta chain) NEJM, 1997 33 BIOMARKERS OF ACTIVITY STUDIED FOR CAD Cytokines (IL-1β, IL-6, IL-8, IL-10, TNF-α, sCD40 ligand, myeloperoxidase) Adhesion molecules (sICAM-1, sVCAM-1, p-selectin) Acute phase reactans (fibrinogen, AAS, CRP) White blood cells Erythrocyte sedimentation rate Neopterin Heat shock proteins Adiponectin Lipoprotein associated phospholipase A2 Placental growth factos Cystatin C Kaski, JC. 2006. 34 Are you hungry or sleepy ???? Sciences 35 The inflammatory cascade. IL indicates interleukin; ICAM, intercellular adhesion molecule; and HSP, heat shock protein. (Libby, Ridker; 1999) Pro-Inflammatory Risk Factors Primary Pro-Inflammatory Cytokines (eg. IL-1, TNF-) IL-6 “Mesenger” Cytokine CRP SAA Endothelium and other cells LIVER Circulation 36 (Ridker, 2004) MORE THAN A MARKER : DOES CRP PLAY A DIRECT ROLE IN ATHEROTHROMBOSIS ? CRP localizes in atherosclerotic but not normal intima CRP induced Complement activation CRP dependent monocyte recruitment into arterial wall CRP induced production of tissue factor in monocytes CRP based blunting of endothelial vasoreactivity CRP mediated LDL uptake by macrophages CRP triggered oxidation of LDL cholesterol CRP induced PAI-1 expression stabilizes PAI-1 mRNA CRP attenuates NO production and decreases eNOS expression CRP induced production of cell adhesion moleculas MCP-1, ET-1 37 ROLE OF INFLAMATORY MARKERS Interleukin-6 Total cholesterol LDL-cholesterol siCAM-1 Serum amyloid A Apolipoprotein B Total cholesterol: HDL-cholesterol Hs-CRP Hs-CRP + total cholesterol: HDL-cholesterol 0 1.0 2.0 4.0 6.0 Relative Risk (New England Journal of Medicine) 38 39 Weissberg, 1999 Inflammation Repair 40 REDOX REGULATION OF ENDOTHELIAL DYSFUNCTION & ACTIVATION O2– OH H2O2  NO Activity  G-Protein Function  Protein Kinase C Oxidation Endothelial Dysfunction (D. Sargowo) 41 ENDOTHELIAL DYSFUNCTION AND ACUTE CORONARY SYNDROMES Vasoconstriction Platelet Aggregation SMC Proliferation Leukocyte Adhesion LDL Oxidation Activation of MMPs Endothelial Dysfunction Plaque Rupture Thrombosis Matrix Remodeling (D. Sargowo) 42 ENDOTHELIAL DYSFUNCTION AND ACUTE CORONARY SYNDROMES Vasospasm Plaque Rupture Thrombosis Matrix Remodeling ACUTE CORONARY SYNDROMES (D. Sargowo) 43 44 Diabetes Smoking AII Oxidative Stress Endothelial Dysfunction and Smooth Muscle Activation Growth FactorsCytokinesMatrix Proteolysis Inflammation VCAM/1CAMCytokines EndothelinCatecholamines BP LDL  NO • ∆ Local Mediators •  Tissue ACE, AII PAI-1, Platelet Aggregation, Tissue Factor Vasoconstriction Thrombosis Inflammation Plaque Rupture Vascular Lesion and Remodeling Clinical Sequelae Risk Factors Reprinted with permission from Dzau VJ. Hypertension. 2001;37:1047–1052.
Slide 45 - 1 Nama : Prof. Dr. H. Djanggan Sargowo, dr., SpPD., SpJP(K), FIHA, FACC, FESC, FCAPC, FASCC Tempat/Tgl lahir : Sragen, 21 September 1947 Alamat : Wilis Indah E-10 Malang, Telp. 0341-552395 Pendidikan : Lulus Dokter dari UGM, tahun 1974 Lulus Cardiologist dari Univ. Indonesia, tahun 1983 Lulus Internist dari Univ. Airlangga, tahun 1986 Lulus Doktor, Univ. Airlangga, tahun 1996 Advanced Cardiology Course, Univ. Hongkong, tahun 1984 Senior Visiting Program, Institut Jantung Negara, Kualalumpur, 1996 Fellow American College of Cardiology (FACC), September 2006. Fellow Collage Asia Pacific Society of Cardiology (FCAPC), Desember 2007 Fellow European Sociaty of Cardiology (FESC), 2008 Fellow Asean Collage of Cardiology (FASCC), 2008 Jabatan : Dosen Pengajar Program Pascasarjana Universitas Brawijaya Ketua MKEK Ikatan Dokter Indonesia Cabang Malang Raya Ketua PERKI Cabang Malang Raya Anggota Kolegium Kardiovaskuler Indonesia Dekan Fak. Kedokteran Univ. Wijaya Kusuma Surabaya Ketua Dewan Pengawas Rumah Sakit Pendidikan Ketua Program Studi Kardiovascular Fak. Kedokteran Univ. Brawijaya Curriculum Vitae 2 Djanggan Sargowo Surabaya, 15 April 2012 INFLAMMATION IN ATHEROSCLEROSIS : FROM BENCH TO BEDSIDE 3 4 RUDOLF VIRCHOW Inflammation-based arterial changes as a mechanism of primary importance in atherogenesis mid 19th century Lamond, B. The American Journal of Pathology. 2008 5 Atherosclerosis Start from very young To Old age ? 6 Atherothrombosis* is aLeading Cause of Death Worldwide1† The World Health Report, 2002, WHO Geneva, 2002 28.7 17.8 12.6 9.1 6 5.1 0 5 10 15 20 25 30 Atherothrombosis* Infectious disease Cancer Injuries Pulmonary disease AIDS Mortality (%) * Ischemic heart disease, cerebrovascular disease, inflammatory heart disease and hypertensive heart disease † Worldwide defined as Member States by WHO Region (Africa, Americas, Eastern Mediterranean, European, South-East Asia and Western Pacific) 7 MAJOR CLINICAL MANIFESTATIONS OF ATHEROTHROMBOSIS Adapted from: Drouet L. Cerebrovasc Dis 2002; 13(suppl 1): 1–6. Transient ischemic attack Angina: Stable Unstable Ischemic stroke Myocardial infarction Peripheral arterial disease: Intermittent claudication Rest Pain Gangrene Necrosis 8  Dyslipidemia  Endothelial dysfunction  Free radicals  Immunologic Atherosclerosis/CAD THEORY AND CONCEPT OF ATHEROSCLEROSIS Inflamation (Sargowo, 1996) 9 Free Radical ATHEROGENESIS (Sargowo, 1996) 10 IDENTIFYING THOSE AT RISK OF ATHEROTHROMBOSIS Yusuf S et al. Circulation 2001; 104: 2746–53. 2. Drouet L. Cerebrovasc Dis 2002;13(suppl 1):1–6. Lifestyle Smoking Diet Lack of exercise Genetic Genetic traits Gender Age Generalized disorders Obesity Diabetes Systemic conditions History of vascular events Hypertension Hyperlipidemia Hypercoagulable states Homocystinemia Local factors Elevated prothrombotic factors: fibrinogen, CRP, PAI-1 Blood flow patterns, vessel diameter, arterial wall structure Atherothrombosis manifestations (myocardial infarction, stroke, vascular death) 11 Arici. 2010 Risk Factors for Atherosclerosis Classic Hypertension, Hyper-lipidemia, DM, Smoking Uremia Related Increase ox-LDL, Free radicals, Uremic toxin Infection Bacterial and viral infection Proinflammatory cytokine release Endothelial dysfunction Systemic inflammatory respones Acute phase response Elevated CRP Binding LDL, cemplement activation, tissue factor secretion Accelerated ATHEROSCLEROSIS 12 LDL CD40L=CD40 ligand; TNF-α=tumor necrosis factor-alpha; IL=interleukin; VCAM=vascular cell adhesion molecule; ICAM=intercellular adhesion molecule. Cockerill GW et al. Arterioscler Thromb Vasc Biol. 1995;15:1987-1994; Andre P et al. Circulation. 2002;106:896-899; Libby P. Circulation. 2001;104:365-372; Libby P et al. Circulation. 2002;105:1135-1143; Ross R. N Engl J Med. 1999;340:115-126. Vessel lumen Monocyte Macrophage Adhesionmolecules (VCAM-1, ICAM-1) Inflammatory mediators (CRP, CD40/CD40L, TNF-α, IL-1, IL-6) Intima Foam cell INFLAMMATION PROMOTES PROGRESSION OF ATHEROSCLEROSIS Endothelium LDL Ox-LDL 13 14 Atherosclerosis is a fibroproliferative and inflammatory process occurring ins response to a variety of vascular insults The insults come from classical risk factors ( HT, dyslipidemia, endothelial dysfunction, smoking, menopause, diabetes etc) and novel risk factors (Hcy, LVH, Lp(a), TG, oxidative stress, fibrinogen etc) Endothelial dysfunction is regarded as the first abnormality leading to atherosclerosis This implies that modulation of endothelial function may be used as strategy to intervene the process. 15 Two theories gain more acceptance: (a) the lipid theory (b) inflammation theory Endothelial dysfunction is now regarded as the first abnormality leading to AS. More novel cardiovascular risk factors are known, e.g.: Fibrinogen b. PAI-1 Homocysteins d. AT-1 e. CRP f. Lp(a) g. small-dense LDL h. infectious agents i. and more are emerging 16 Acute Coronary Syndrome (endocrine viewpoints) atherosclerotic lesions vascular funtions b.1. inflammatory reaction b.2. thrombogeneity b.3. vasoreactivity b.4. plaque stability b.5. shoulder of plaque endothelium balance between c.1. vasodilating, antithrombotic, antiproliferative factors (NO, prostacyclin, C-natriuretic peptide, EDHF) c.2. vasoconstricting, prothrombotic, proliferative factors (ET, superoxide, thromoboxan A2) 17 NATURAL HISTORY OF CORONARY ATHEROSCLEROSIS Chatzizisis et all. JACC. 2007. Asymtomatic Stable Angina Acute Coronary Syndrome Early fibroatheroma Compensatory expansive remodeling Quiescent plaque Contrictive remodeling Stenotic plaque Exessive expansive remodeling Thin cap fibroatheroma Erosion Physiologic coronary artery Local factors, e.g. low ESS Systemic factors, e.g. hyperlipidemia Genetic factors Physiologic ESS Limited inflammation Fibroproliferation Microruptures 18 ATHEROSCLEROSIS IS AN INFLAMMATORY DISEASE Libby P. Circulation. 2001;104:365-372; Ross R. N Engl J Med. 1999;340:115-126. Monocyte LDL-C Adhesion molecule Macrophage Foam cell OxidizedLDL-C Plaque rupture Smooth muscle cells CRP Plaque instability and thrombus Oxidation Inflammation Endothelial dysfunction 19 20 Reverse Cholesterol Transport Monocyte CRP TXA2 PGI2 Thrombin LDL Platelets HDL HDL Ox-LDL MCP-1 Macrophage P-selectin CD 40L PDGF Foam cell MMP T cell E-selectins CD 40L VCAM-1 ICAM-1 IL-1 Reilly, et.all. 2005 21 THE ROLE OF Lp-PLA2 IN CHD LUMEN Monocytes Adhesion Molecules Oxidated LDL INTIMA MEDIA Lp-PLA2 Lyso-PC OxFA Cytokines Plaque Formation Foam Cell Macrophage 22 MC T T FC FC LDL Oxidation Lyso-PC Ox-chol Cytokines Cytokines ? C5a C’ MCP-1 F SMC 23 Intracelluler proteolysis and fusion of LDL Figure : Proposed Dual Action of Exocytosed Mast Cell Granules (The Granule Remnants) of Lipoprotein Metabolism in The Arterial Intima 24 HSCRP 25 26 GM-CSF VCAM-1 MPC-1 Transcription Factors : Endothelial Cell Pro-inflammatory Genes Oxidative Stress NF-xB AP-1 Leucocyte infiltration / activation Plaque Rupture Gibbons, 97 LEUCOCYTE ACTIVATION IN ATHEROGENESIS : IMPLICATIONS FOR ACUTE ISCHEMIC SYNDROMES 27 p38 c-Jun activation Caspases Apoptosis NIK ? ? MEKK1?   CKII IKK complex TNFR-1 TNFR-1 IL-1R Shear stress p65 p50 CBP/p300 Gene activation p65 p50 IB pKAc IB Ub Target genes : - IL-1, IL-8, IL-6, IFN  - TNF, MCP-1 - CSFs, c-myc - VCAM-1, ICAM-1, E-selectin - Tissue factor - Survival factor Thurberg and Collins : Curr Opin Lipidol 9:387-396,1998 Ub Ox-LDL ROIs ??? Lipid peroxides ? H2O2 Ubiquitination and proteosome degradation T R A D D R I P F A D D R I P T R A D D T R A F 2 T R A F 6 28 Visual Medica. 2009 29 Stockley. 2006 Cytokines : IL-6, TNF-α MACROPHAGE FOAM CELL Oxidized LDL CRP CRP Chemokines: MCO-1 Atherosclerotic plaque MONOCYTE Inflammatory Mediators: CRP Prothrombotic factors FCR Receptor 30 POTENTIAL MECHANISM OF CRP Stevens, R. 2005 CRP LDL opsonisation Monocyte infiltration Foam cell formation Increased MCP-1 and CAM EC activation Inflammatory cell recruitment Atherosclerosis plaque formation Complement activation EC sensitisation T-cell attack EC damage Atherosclerotic plaque rupture 31 Rheumatoid arthritis Atherosclerosis Multiple sclerosis Asthma Inflammatory bowel disease Helicobacter pylori-associated gastritis Systemic inflammatory response syndrome NF-KB ACTIVATION INFLAMMATORY DISEASE The Journal of Clinical Investigation, 2001 32 PROTEIN REGULATED BY NF-KB Inflammatory Enzyme Adhesion Molecule Inducible nitric oxide synthase Inducide cylooxigenase-2 5-Lipoxigenase Cytosolic phospolipase A2 ICAM-1 VCAM-1 E-selectin Receptor Interlekin-2 receptor (alpha chain) T-cell receptors (beta chain) NEJM, 1997 33 BIOMARKERS OF ACTIVITY STUDIED FOR CAD Cytokines (IL-1β, IL-6, IL-8, IL-10, TNF-α, sCD40 ligand, myeloperoxidase) Adhesion molecules (sICAM-1, sVCAM-1, p-selectin) Acute phase reactans (fibrinogen, AAS, CRP) White blood cells Erythrocyte sedimentation rate Neopterin Heat shock proteins Adiponectin Lipoprotein associated phospholipase A2 Placental growth factos Cystatin C Kaski, JC. 2006. 34 Are you hungry or sleepy ???? Sciences 35 The inflammatory cascade. IL indicates interleukin; ICAM, intercellular adhesion molecule; and HSP, heat shock protein. (Libby, Ridker; 1999) Pro-Inflammatory Risk Factors Primary Pro-Inflammatory Cytokines (eg. IL-1, TNF-) IL-6 “Mesenger” Cytokine CRP SAA Endothelium and other cells LIVER Circulation 36 (Ridker, 2004) MORE THAN A MARKER : DOES CRP PLAY A DIRECT ROLE IN ATHEROTHROMBOSIS ? CRP localizes in atherosclerotic but not normal intima CRP induced Complement activation CRP dependent monocyte recruitment into arterial wall CRP induced production of tissue factor in monocytes CRP based blunting of endothelial vasoreactivity CRP mediated LDL uptake by macrophages CRP triggered oxidation of LDL cholesterol CRP induced PAI-1 expression stabilizes PAI-1 mRNA CRP attenuates NO production and decreases eNOS expression CRP induced production of cell adhesion moleculas MCP-1, ET-1 37 ROLE OF INFLAMATORY MARKERS Interleukin-6 Total cholesterol LDL-cholesterol siCAM-1 Serum amyloid A Apolipoprotein B Total cholesterol: HDL-cholesterol Hs-CRP Hs-CRP + total cholesterol: HDL-cholesterol 0 1.0 2.0 4.0 6.0 Relative Risk (New England Journal of Medicine) 38 39 Weissberg, 1999 Inflammation Repair 40 REDOX REGULATION OF ENDOTHELIAL DYSFUNCTION & ACTIVATION O2– OH H2O2  NO Activity  G-Protein Function  Protein Kinase C Oxidation Endothelial Dysfunction (D. Sargowo) 41 ENDOTHELIAL DYSFUNCTION AND ACUTE CORONARY SYNDROMES Vasoconstriction Platelet Aggregation SMC Proliferation Leukocyte Adhesion LDL Oxidation Activation of MMPs Endothelial Dysfunction Plaque Rupture Thrombosis Matrix Remodeling (D. Sargowo) 42 ENDOTHELIAL DYSFUNCTION AND ACUTE CORONARY SYNDROMES Vasospasm Plaque Rupture Thrombosis Matrix Remodeling ACUTE CORONARY SYNDROMES (D. Sargowo) 43 44 Diabetes Smoking AII Oxidative Stress Endothelial Dysfunction and Smooth Muscle Activation Growth FactorsCytokinesMatrix Proteolysis Inflammation VCAM/1CAMCytokines EndothelinCatecholamines BP LDL  NO • ∆ Local Mediators •  Tissue ACE, AII PAI-1, Platelet Aggregation, Tissue Factor Vasoconstriction Thrombosis Inflammation Plaque Rupture Vascular Lesion and Remodeling Clinical Sequelae Risk Factors Reprinted with permission from Dzau VJ. Hypertension. 2001;37:1047–1052. 45 THERAPEUTICS : WHERE DO WE STAND TODAY ? Lipid lowering drugs ACEI / ARB Peroxisome proliferators-activated receptor (PPAR) Chemokine receptor antagonist TNF Inhibitor MMP Inhibitor
Slide 46 - 1 Nama : Prof. Dr. H. Djanggan Sargowo, dr., SpPD., SpJP(K), FIHA, FACC, FESC, FCAPC, FASCC Tempat/Tgl lahir : Sragen, 21 September 1947 Alamat : Wilis Indah E-10 Malang, Telp. 0341-552395 Pendidikan : Lulus Dokter dari UGM, tahun 1974 Lulus Cardiologist dari Univ. Indonesia, tahun 1983 Lulus Internist dari Univ. Airlangga, tahun 1986 Lulus Doktor, Univ. Airlangga, tahun 1996 Advanced Cardiology Course, Univ. Hongkong, tahun 1984 Senior Visiting Program, Institut Jantung Negara, Kualalumpur, 1996 Fellow American College of Cardiology (FACC), September 2006. Fellow Collage Asia Pacific Society of Cardiology (FCAPC), Desember 2007 Fellow European Sociaty of Cardiology (FESC), 2008 Fellow Asean Collage of Cardiology (FASCC), 2008 Jabatan : Dosen Pengajar Program Pascasarjana Universitas Brawijaya Ketua MKEK Ikatan Dokter Indonesia Cabang Malang Raya Ketua PERKI Cabang Malang Raya Anggota Kolegium Kardiovaskuler Indonesia Dekan Fak. Kedokteran Univ. Wijaya Kusuma Surabaya Ketua Dewan Pengawas Rumah Sakit Pendidikan Ketua Program Studi Kardiovascular Fak. Kedokteran Univ. Brawijaya Curriculum Vitae 2 Djanggan Sargowo Surabaya, 15 April 2012 INFLAMMATION IN ATHEROSCLEROSIS : FROM BENCH TO BEDSIDE 3 4 RUDOLF VIRCHOW Inflammation-based arterial changes as a mechanism of primary importance in atherogenesis mid 19th century Lamond, B. The American Journal of Pathology. 2008 5 Atherosclerosis Start from very young To Old age ? 6 Atherothrombosis* is aLeading Cause of Death Worldwide1† The World Health Report, 2002, WHO Geneva, 2002 28.7 17.8 12.6 9.1 6 5.1 0 5 10 15 20 25 30 Atherothrombosis* Infectious disease Cancer Injuries Pulmonary disease AIDS Mortality (%) * Ischemic heart disease, cerebrovascular disease, inflammatory heart disease and hypertensive heart disease † Worldwide defined as Member States by WHO Region (Africa, Americas, Eastern Mediterranean, European, South-East Asia and Western Pacific) 7 MAJOR CLINICAL MANIFESTATIONS OF ATHEROTHROMBOSIS Adapted from: Drouet L. Cerebrovasc Dis 2002; 13(suppl 1): 1–6. Transient ischemic attack Angina: Stable Unstable Ischemic stroke Myocardial infarction Peripheral arterial disease: Intermittent claudication Rest Pain Gangrene Necrosis 8  Dyslipidemia  Endothelial dysfunction  Free radicals  Immunologic Atherosclerosis/CAD THEORY AND CONCEPT OF ATHEROSCLEROSIS Inflamation (Sargowo, 1996) 9 Free Radical ATHEROGENESIS (Sargowo, 1996) 10 IDENTIFYING THOSE AT RISK OF ATHEROTHROMBOSIS Yusuf S et al. Circulation 2001; 104: 2746–53. 2. Drouet L. Cerebrovasc Dis 2002;13(suppl 1):1–6. Lifestyle Smoking Diet Lack of exercise Genetic Genetic traits Gender Age Generalized disorders Obesity Diabetes Systemic conditions History of vascular events Hypertension Hyperlipidemia Hypercoagulable states Homocystinemia Local factors Elevated prothrombotic factors: fibrinogen, CRP, PAI-1 Blood flow patterns, vessel diameter, arterial wall structure Atherothrombosis manifestations (myocardial infarction, stroke, vascular death) 11 Arici. 2010 Risk Factors for Atherosclerosis Classic Hypertension, Hyper-lipidemia, DM, Smoking Uremia Related Increase ox-LDL, Free radicals, Uremic toxin Infection Bacterial and viral infection Proinflammatory cytokine release Endothelial dysfunction Systemic inflammatory respones Acute phase response Elevated CRP Binding LDL, cemplement activation, tissue factor secretion Accelerated ATHEROSCLEROSIS 12 LDL CD40L=CD40 ligand; TNF-α=tumor necrosis factor-alpha; IL=interleukin; VCAM=vascular cell adhesion molecule; ICAM=intercellular adhesion molecule. Cockerill GW et al. Arterioscler Thromb Vasc Biol. 1995;15:1987-1994; Andre P et al. Circulation. 2002;106:896-899; Libby P. Circulation. 2001;104:365-372; Libby P et al. Circulation. 2002;105:1135-1143; Ross R. N Engl J Med. 1999;340:115-126. Vessel lumen Monocyte Macrophage Adhesionmolecules (VCAM-1, ICAM-1) Inflammatory mediators (CRP, CD40/CD40L, TNF-α, IL-1, IL-6) Intima Foam cell INFLAMMATION PROMOTES PROGRESSION OF ATHEROSCLEROSIS Endothelium LDL Ox-LDL 13 14 Atherosclerosis is a fibroproliferative and inflammatory process occurring ins response to a variety of vascular insults The insults come from classical risk factors ( HT, dyslipidemia, endothelial dysfunction, smoking, menopause, diabetes etc) and novel risk factors (Hcy, LVH, Lp(a), TG, oxidative stress, fibrinogen etc) Endothelial dysfunction is regarded as the first abnormality leading to atherosclerosis This implies that modulation of endothelial function may be used as strategy to intervene the process. 15 Two theories gain more acceptance: (a) the lipid theory (b) inflammation theory Endothelial dysfunction is now regarded as the first abnormality leading to AS. More novel cardiovascular risk factors are known, e.g.: Fibrinogen b. PAI-1 Homocysteins d. AT-1 e. CRP f. Lp(a) g. small-dense LDL h. infectious agents i. and more are emerging 16 Acute Coronary Syndrome (endocrine viewpoints) atherosclerotic lesions vascular funtions b.1. inflammatory reaction b.2. thrombogeneity b.3. vasoreactivity b.4. plaque stability b.5. shoulder of plaque endothelium balance between c.1. vasodilating, antithrombotic, antiproliferative factors (NO, prostacyclin, C-natriuretic peptide, EDHF) c.2. vasoconstricting, prothrombotic, proliferative factors (ET, superoxide, thromoboxan A2) 17 NATURAL HISTORY OF CORONARY ATHEROSCLEROSIS Chatzizisis et all. JACC. 2007. Asymtomatic Stable Angina Acute Coronary Syndrome Early fibroatheroma Compensatory expansive remodeling Quiescent plaque Contrictive remodeling Stenotic plaque Exessive expansive remodeling Thin cap fibroatheroma Erosion Physiologic coronary artery Local factors, e.g. low ESS Systemic factors, e.g. hyperlipidemia Genetic factors Physiologic ESS Limited inflammation Fibroproliferation Microruptures 18 ATHEROSCLEROSIS IS AN INFLAMMATORY DISEASE Libby P. Circulation. 2001;104:365-372; Ross R. N Engl J Med. 1999;340:115-126. Monocyte LDL-C Adhesion molecule Macrophage Foam cell OxidizedLDL-C Plaque rupture Smooth muscle cells CRP Plaque instability and thrombus Oxidation Inflammation Endothelial dysfunction 19 20 Reverse Cholesterol Transport Monocyte CRP TXA2 PGI2 Thrombin LDL Platelets HDL HDL Ox-LDL MCP-1 Macrophage P-selectin CD 40L PDGF Foam cell MMP T cell E-selectins CD 40L VCAM-1 ICAM-1 IL-1 Reilly, et.all. 2005 21 THE ROLE OF Lp-PLA2 IN CHD LUMEN Monocytes Adhesion Molecules Oxidated LDL INTIMA MEDIA Lp-PLA2 Lyso-PC OxFA Cytokines Plaque Formation Foam Cell Macrophage 22 MC T T FC FC LDL Oxidation Lyso-PC Ox-chol Cytokines Cytokines ? C5a C’ MCP-1 F SMC 23 Intracelluler proteolysis and fusion of LDL Figure : Proposed Dual Action of Exocytosed Mast Cell Granules (The Granule Remnants) of Lipoprotein Metabolism in The Arterial Intima 24 HSCRP 25 26 GM-CSF VCAM-1 MPC-1 Transcription Factors : Endothelial Cell Pro-inflammatory Genes Oxidative Stress NF-xB AP-1 Leucocyte infiltration / activation Plaque Rupture Gibbons, 97 LEUCOCYTE ACTIVATION IN ATHEROGENESIS : IMPLICATIONS FOR ACUTE ISCHEMIC SYNDROMES 27 p38 c-Jun activation Caspases Apoptosis NIK ? ? MEKK1?   CKII IKK complex TNFR-1 TNFR-1 IL-1R Shear stress p65 p50 CBP/p300 Gene activation p65 p50 IB pKAc IB Ub Target genes : - IL-1, IL-8, IL-6, IFN  - TNF, MCP-1 - CSFs, c-myc - VCAM-1, ICAM-1, E-selectin - Tissue factor - Survival factor Thurberg and Collins : Curr Opin Lipidol 9:387-396,1998 Ub Ox-LDL ROIs ??? Lipid peroxides ? H2O2 Ubiquitination and proteosome degradation T R A D D R I P F A D D R I P T R A D D T R A F 2 T R A F 6 28 Visual Medica. 2009 29 Stockley. 2006 Cytokines : IL-6, TNF-α MACROPHAGE FOAM CELL Oxidized LDL CRP CRP Chemokines: MCO-1 Atherosclerotic plaque MONOCYTE Inflammatory Mediators: CRP Prothrombotic factors FCR Receptor 30 POTENTIAL MECHANISM OF CRP Stevens, R. 2005 CRP LDL opsonisation Monocyte infiltration Foam cell formation Increased MCP-1 and CAM EC activation Inflammatory cell recruitment Atherosclerosis plaque formation Complement activation EC sensitisation T-cell attack EC damage Atherosclerotic plaque rupture 31 Rheumatoid arthritis Atherosclerosis Multiple sclerosis Asthma Inflammatory bowel disease Helicobacter pylori-associated gastritis Systemic inflammatory response syndrome NF-KB ACTIVATION INFLAMMATORY DISEASE The Journal of Clinical Investigation, 2001 32 PROTEIN REGULATED BY NF-KB Inflammatory Enzyme Adhesion Molecule Inducible nitric oxide synthase Inducide cylooxigenase-2 5-Lipoxigenase Cytosolic phospolipase A2 ICAM-1 VCAM-1 E-selectin Receptor Interlekin-2 receptor (alpha chain) T-cell receptors (beta chain) NEJM, 1997 33 BIOMARKERS OF ACTIVITY STUDIED FOR CAD Cytokines (IL-1β, IL-6, IL-8, IL-10, TNF-α, sCD40 ligand, myeloperoxidase) Adhesion molecules (sICAM-1, sVCAM-1, p-selectin) Acute phase reactans (fibrinogen, AAS, CRP) White blood cells Erythrocyte sedimentation rate Neopterin Heat shock proteins Adiponectin Lipoprotein associated phospholipase A2 Placental growth factos Cystatin C Kaski, JC. 2006. 34 Are you hungry or sleepy ???? Sciences 35 The inflammatory cascade. IL indicates interleukin; ICAM, intercellular adhesion molecule; and HSP, heat shock protein. (Libby, Ridker; 1999) Pro-Inflammatory Risk Factors Primary Pro-Inflammatory Cytokines (eg. IL-1, TNF-) IL-6 “Mesenger” Cytokine CRP SAA Endothelium and other cells LIVER Circulation 36 (Ridker, 2004) MORE THAN A MARKER : DOES CRP PLAY A DIRECT ROLE IN ATHEROTHROMBOSIS ? CRP localizes in atherosclerotic but not normal intima CRP induced Complement activation CRP dependent monocyte recruitment into arterial wall CRP induced production of tissue factor in monocytes CRP based blunting of endothelial vasoreactivity CRP mediated LDL uptake by macrophages CRP triggered oxidation of LDL cholesterol CRP induced PAI-1 expression stabilizes PAI-1 mRNA CRP attenuates NO production and decreases eNOS expression CRP induced production of cell adhesion moleculas MCP-1, ET-1 37 ROLE OF INFLAMATORY MARKERS Interleukin-6 Total cholesterol LDL-cholesterol siCAM-1 Serum amyloid A Apolipoprotein B Total cholesterol: HDL-cholesterol Hs-CRP Hs-CRP + total cholesterol: HDL-cholesterol 0 1.0 2.0 4.0 6.0 Relative Risk (New England Journal of Medicine) 38 39 Weissberg, 1999 Inflammation Repair 40 REDOX REGULATION OF ENDOTHELIAL DYSFUNCTION & ACTIVATION O2– OH H2O2  NO Activity  G-Protein Function  Protein Kinase C Oxidation Endothelial Dysfunction (D. Sargowo) 41 ENDOTHELIAL DYSFUNCTION AND ACUTE CORONARY SYNDROMES Vasoconstriction Platelet Aggregation SMC Proliferation Leukocyte Adhesion LDL Oxidation Activation of MMPs Endothelial Dysfunction Plaque Rupture Thrombosis Matrix Remodeling (D. Sargowo) 42 ENDOTHELIAL DYSFUNCTION AND ACUTE CORONARY SYNDROMES Vasospasm Plaque Rupture Thrombosis Matrix Remodeling ACUTE CORONARY SYNDROMES (D. Sargowo) 43 44 Diabetes Smoking AII Oxidative Stress Endothelial Dysfunction and Smooth Muscle Activation Growth FactorsCytokinesMatrix Proteolysis Inflammation VCAM/1CAMCytokines EndothelinCatecholamines BP LDL  NO • ∆ Local Mediators •  Tissue ACE, AII PAI-1, Platelet Aggregation, Tissue Factor Vasoconstriction Thrombosis Inflammation Plaque Rupture Vascular Lesion and Remodeling Clinical Sequelae Risk Factors Reprinted with permission from Dzau VJ. Hypertension. 2001;37:1047–1052. 45 THERAPEUTICS : WHERE DO WE STAND TODAY ? Lipid lowering drugs ACEI / ARB Peroxisome proliferators-activated receptor (PPAR) Chemokine receptor antagonist TNF Inhibitor MMP Inhibitor 46 BIOCHEMICAL PARAMETER FOR ENDOTHELIAL DYSFUNCTION - vWF - Thrombomodulin - E-Selection - ICAM-1 - VCAM-1 - NO - Microalbuminuria - PAI-1 (D. Sargowo) - Ox LDL – MDA – F2 - Isoprostane - LP – PLA2 - Lyso-PC OxFA BIOCHEMICAL PARAMETER FOR ENDOTHELIAL DYSFUNCTION - vWF - Thrombomodulin - E-Selection - NO - Microalbuminuria - PAI-1 - Ox LDL – MDA – F2 - Isoprostane - LP – PLA2 - Lyso-PC OxFA
Slide 47 - 1 Nama : Prof. Dr. H. Djanggan Sargowo, dr., SpPD., SpJP(K), FIHA, FACC, FESC, FCAPC, FASCC Tempat/Tgl lahir : Sragen, 21 September 1947 Alamat : Wilis Indah E-10 Malang, Telp. 0341-552395 Pendidikan : Lulus Dokter dari UGM, tahun 1974 Lulus Cardiologist dari Univ. Indonesia, tahun 1983 Lulus Internist dari Univ. Airlangga, tahun 1986 Lulus Doktor, Univ. Airlangga, tahun 1996 Advanced Cardiology Course, Univ. Hongkong, tahun 1984 Senior Visiting Program, Institut Jantung Negara, Kualalumpur, 1996 Fellow American College of Cardiology (FACC), September 2006. Fellow Collage Asia Pacific Society of Cardiology (FCAPC), Desember 2007 Fellow European Sociaty of Cardiology (FESC), 2008 Fellow Asean Collage of Cardiology (FASCC), 2008 Jabatan : Dosen Pengajar Program Pascasarjana Universitas Brawijaya Ketua MKEK Ikatan Dokter Indonesia Cabang Malang Raya Ketua PERKI Cabang Malang Raya Anggota Kolegium Kardiovaskuler Indonesia Dekan Fak. Kedokteran Univ. Wijaya Kusuma Surabaya Ketua Dewan Pengawas Rumah Sakit Pendidikan Ketua Program Studi Kardiovascular Fak. Kedokteran Univ. Brawijaya Curriculum Vitae 2 Djanggan Sargowo Surabaya, 15 April 2012 INFLAMMATION IN ATHEROSCLEROSIS : FROM BENCH TO BEDSIDE 3 4 RUDOLF VIRCHOW Inflammation-based arterial changes as a mechanism of primary importance in atherogenesis mid 19th century Lamond, B. The American Journal of Pathology. 2008 5 Atherosclerosis Start from very young To Old age ? 6 Atherothrombosis* is aLeading Cause of Death Worldwide1† The World Health Report, 2002, WHO Geneva, 2002 28.7 17.8 12.6 9.1 6 5.1 0 5 10 15 20 25 30 Atherothrombosis* Infectious disease Cancer Injuries Pulmonary disease AIDS Mortality (%) * Ischemic heart disease, cerebrovascular disease, inflammatory heart disease and hypertensive heart disease † Worldwide defined as Member States by WHO Region (Africa, Americas, Eastern Mediterranean, European, South-East Asia and Western Pacific) 7 MAJOR CLINICAL MANIFESTATIONS OF ATHEROTHROMBOSIS Adapted from: Drouet L. Cerebrovasc Dis 2002; 13(suppl 1): 1–6. Transient ischemic attack Angina: Stable Unstable Ischemic stroke Myocardial infarction Peripheral arterial disease: Intermittent claudication Rest Pain Gangrene Necrosis 8  Dyslipidemia  Endothelial dysfunction  Free radicals  Immunologic Atherosclerosis/CAD THEORY AND CONCEPT OF ATHEROSCLEROSIS Inflamation (Sargowo, 1996) 9 Free Radical ATHEROGENESIS (Sargowo, 1996) 10 IDENTIFYING THOSE AT RISK OF ATHEROTHROMBOSIS Yusuf S et al. Circulation 2001; 104: 2746–53. 2. Drouet L. Cerebrovasc Dis 2002;13(suppl 1):1–6. Lifestyle Smoking Diet Lack of exercise Genetic Genetic traits Gender Age Generalized disorders Obesity Diabetes Systemic conditions History of vascular events Hypertension Hyperlipidemia Hypercoagulable states Homocystinemia Local factors Elevated prothrombotic factors: fibrinogen, CRP, PAI-1 Blood flow patterns, vessel diameter, arterial wall structure Atherothrombosis manifestations (myocardial infarction, stroke, vascular death) 11 Arici. 2010 Risk Factors for Atherosclerosis Classic Hypertension, Hyper-lipidemia, DM, Smoking Uremia Related Increase ox-LDL, Free radicals, Uremic toxin Infection Bacterial and viral infection Proinflammatory cytokine release Endothelial dysfunction Systemic inflammatory respones Acute phase response Elevated CRP Binding LDL, cemplement activation, tissue factor secretion Accelerated ATHEROSCLEROSIS 12 LDL CD40L=CD40 ligand; TNF-α=tumor necrosis factor-alpha; IL=interleukin; VCAM=vascular cell adhesion molecule; ICAM=intercellular adhesion molecule. Cockerill GW et al. Arterioscler Thromb Vasc Biol. 1995;15:1987-1994; Andre P et al. Circulation. 2002;106:896-899; Libby P. Circulation. 2001;104:365-372; Libby P et al. Circulation. 2002;105:1135-1143; Ross R. N Engl J Med. 1999;340:115-126. Vessel lumen Monocyte Macrophage Adhesionmolecules (VCAM-1, ICAM-1) Inflammatory mediators (CRP, CD40/CD40L, TNF-α, IL-1, IL-6) Intima Foam cell INFLAMMATION PROMOTES PROGRESSION OF ATHEROSCLEROSIS Endothelium LDL Ox-LDL 13 14 Atherosclerosis is a fibroproliferative and inflammatory process occurring ins response to a variety of vascular insults The insults come from classical risk factors ( HT, dyslipidemia, endothelial dysfunction, smoking, menopause, diabetes etc) and novel risk factors (Hcy, LVH, Lp(a), TG, oxidative stress, fibrinogen etc) Endothelial dysfunction is regarded as the first abnormality leading to atherosclerosis This implies that modulation of endothelial function may be used as strategy to intervene the process. 15 Two theories gain more acceptance: (a) the lipid theory (b) inflammation theory Endothelial dysfunction is now regarded as the first abnormality leading to AS. More novel cardiovascular risk factors are known, e.g.: Fibrinogen b. PAI-1 Homocysteins d. AT-1 e. CRP f. Lp(a) g. small-dense LDL h. infectious agents i. and more are emerging 16 Acute Coronary Syndrome (endocrine viewpoints) atherosclerotic lesions vascular funtions b.1. inflammatory reaction b.2. thrombogeneity b.3. vasoreactivity b.4. plaque stability b.5. shoulder of plaque endothelium balance between c.1. vasodilating, antithrombotic, antiproliferative factors (NO, prostacyclin, C-natriuretic peptide, EDHF) c.2. vasoconstricting, prothrombotic, proliferative factors (ET, superoxide, thromoboxan A2) 17 NATURAL HISTORY OF CORONARY ATHEROSCLEROSIS Chatzizisis et all. JACC. 2007. Asymtomatic Stable Angina Acute Coronary Syndrome Early fibroatheroma Compensatory expansive remodeling Quiescent plaque Contrictive remodeling Stenotic plaque Exessive expansive remodeling Thin cap fibroatheroma Erosion Physiologic coronary artery Local factors, e.g. low ESS Systemic factors, e.g. hyperlipidemia Genetic factors Physiologic ESS Limited inflammation Fibroproliferation Microruptures 18 ATHEROSCLEROSIS IS AN INFLAMMATORY DISEASE Libby P. Circulation. 2001;104:365-372; Ross R. N Engl J Med. 1999;340:115-126. Monocyte LDL-C Adhesion molecule Macrophage Foam cell OxidizedLDL-C Plaque rupture Smooth muscle cells CRP Plaque instability and thrombus Oxidation Inflammation Endothelial dysfunction 19 20 Reverse Cholesterol Transport Monocyte CRP TXA2 PGI2 Thrombin LDL Platelets HDL HDL Ox-LDL MCP-1 Macrophage P-selectin CD 40L PDGF Foam cell MMP T cell E-selectins CD 40L VCAM-1 ICAM-1 IL-1 Reilly, et.all. 2005 21 THE ROLE OF Lp-PLA2 IN CHD LUMEN Monocytes Adhesion Molecules Oxidated LDL INTIMA MEDIA Lp-PLA2 Lyso-PC OxFA Cytokines Plaque Formation Foam Cell Macrophage 22 MC T T FC FC LDL Oxidation Lyso-PC Ox-chol Cytokines Cytokines ? C5a C’ MCP-1 F SMC 23 Intracelluler proteolysis and fusion of LDL Figure : Proposed Dual Action of Exocytosed Mast Cell Granules (The Granule Remnants) of Lipoprotein Metabolism in The Arterial Intima 24 HSCRP 25 26 GM-CSF VCAM-1 MPC-1 Transcription Factors : Endothelial Cell Pro-inflammatory Genes Oxidative Stress NF-xB AP-1 Leucocyte infiltration / activation Plaque Rupture Gibbons, 97 LEUCOCYTE ACTIVATION IN ATHEROGENESIS : IMPLICATIONS FOR ACUTE ISCHEMIC SYNDROMES 27 p38 c-Jun activation Caspases Apoptosis NIK ? ? MEKK1?   CKII IKK complex TNFR-1 TNFR-1 IL-1R Shear stress p65 p50 CBP/p300 Gene activation p65 p50 IB pKAc IB Ub Target genes : - IL-1, IL-8, IL-6, IFN  - TNF, MCP-1 - CSFs, c-myc - VCAM-1, ICAM-1, E-selectin - Tissue factor - Survival factor Thurberg and Collins : Curr Opin Lipidol 9:387-396,1998 Ub Ox-LDL ROIs ??? Lipid peroxides ? H2O2 Ubiquitination and proteosome degradation T R A D D R I P F A D D R I P T R A D D T R A F 2 T R A F 6 28 Visual Medica. 2009 29 Stockley. 2006 Cytokines : IL-6, TNF-α MACROPHAGE FOAM CELL Oxidized LDL CRP CRP Chemokines: MCO-1 Atherosclerotic plaque MONOCYTE Inflammatory Mediators: CRP Prothrombotic factors FCR Receptor 30 POTENTIAL MECHANISM OF CRP Stevens, R. 2005 CRP LDL opsonisation Monocyte infiltration Foam cell formation Increased MCP-1 and CAM EC activation Inflammatory cell recruitment Atherosclerosis plaque formation Complement activation EC sensitisation T-cell attack EC damage Atherosclerotic plaque rupture 31 Rheumatoid arthritis Atherosclerosis Multiple sclerosis Asthma Inflammatory bowel disease Helicobacter pylori-associated gastritis Systemic inflammatory response syndrome NF-KB ACTIVATION INFLAMMATORY DISEASE The Journal of Clinical Investigation, 2001 32 PROTEIN REGULATED BY NF-KB Inflammatory Enzyme Adhesion Molecule Inducible nitric oxide synthase Inducide cylooxigenase-2 5-Lipoxigenase Cytosolic phospolipase A2 ICAM-1 VCAM-1 E-selectin Receptor Interlekin-2 receptor (alpha chain) T-cell receptors (beta chain) NEJM, 1997 33 BIOMARKERS OF ACTIVITY STUDIED FOR CAD Cytokines (IL-1β, IL-6, IL-8, IL-10, TNF-α, sCD40 ligand, myeloperoxidase) Adhesion molecules (sICAM-1, sVCAM-1, p-selectin) Acute phase reactans (fibrinogen, AAS, CRP) White blood cells Erythrocyte sedimentation rate Neopterin Heat shock proteins Adiponectin Lipoprotein associated phospholipase A2 Placental growth factos Cystatin C Kaski, JC. 2006. 34 Are you hungry or sleepy ???? Sciences 35 The inflammatory cascade. IL indicates interleukin; ICAM, intercellular adhesion molecule; and HSP, heat shock protein. (Libby, Ridker; 1999) Pro-Inflammatory Risk Factors Primary Pro-Inflammatory Cytokines (eg. IL-1, TNF-) IL-6 “Mesenger” Cytokine CRP SAA Endothelium and other cells LIVER Circulation 36 (Ridker, 2004) MORE THAN A MARKER : DOES CRP PLAY A DIRECT ROLE IN ATHEROTHROMBOSIS ? CRP localizes in atherosclerotic but not normal intima CRP induced Complement activation CRP dependent monocyte recruitment into arterial wall CRP induced production of tissue factor in monocytes CRP based blunting of endothelial vasoreactivity CRP mediated LDL uptake by macrophages CRP triggered oxidation of LDL cholesterol CRP induced PAI-1 expression stabilizes PAI-1 mRNA CRP attenuates NO production and decreases eNOS expression CRP induced production of cell adhesion moleculas MCP-1, ET-1 37 ROLE OF INFLAMATORY MARKERS Interleukin-6 Total cholesterol LDL-cholesterol siCAM-1 Serum amyloid A Apolipoprotein B Total cholesterol: HDL-cholesterol Hs-CRP Hs-CRP + total cholesterol: HDL-cholesterol 0 1.0 2.0 4.0 6.0 Relative Risk (New England Journal of Medicine) 38 39 Weissberg, 1999 Inflammation Repair 40 REDOX REGULATION OF ENDOTHELIAL DYSFUNCTION & ACTIVATION O2– OH H2O2  NO Activity  G-Protein Function  Protein Kinase C Oxidation Endothelial Dysfunction (D. Sargowo) 41 ENDOTHELIAL DYSFUNCTION AND ACUTE CORONARY SYNDROMES Vasoconstriction Platelet Aggregation SMC Proliferation Leukocyte Adhesion LDL Oxidation Activation of MMPs Endothelial Dysfunction Plaque Rupture Thrombosis Matrix Remodeling (D. Sargowo) 42 ENDOTHELIAL DYSFUNCTION AND ACUTE CORONARY SYNDROMES Vasospasm Plaque Rupture Thrombosis Matrix Remodeling ACUTE CORONARY SYNDROMES (D. Sargowo) 43 44 Diabetes Smoking AII Oxidative Stress Endothelial Dysfunction and Smooth Muscle Activation Growth FactorsCytokinesMatrix Proteolysis Inflammation VCAM/1CAMCytokines EndothelinCatecholamines BP LDL  NO • ∆ Local Mediators •  Tissue ACE, AII PAI-1, Platelet Aggregation, Tissue Factor Vasoconstriction Thrombosis Inflammation Plaque Rupture Vascular Lesion and Remodeling Clinical Sequelae Risk Factors Reprinted with permission from Dzau VJ. Hypertension. 2001;37:1047–1052. 45 THERAPEUTICS : WHERE DO WE STAND TODAY ? Lipid lowering drugs ACEI / ARB Peroxisome proliferators-activated receptor (PPAR) Chemokine receptor antagonist TNF Inhibitor MMP Inhibitor 46 BIOCHEMICAL PARAMETER FOR ENDOTHELIAL DYSFUNCTION - vWF - Thrombomodulin - E-Selection - ICAM-1 - VCAM-1 - NO - Microalbuminuria - PAI-1 (D. Sargowo) - Ox LDL – MDA – F2 - Isoprostane - LP – PLA2 - Lyso-PC OxFA BIOCHEMICAL PARAMETER FOR ENDOTHELIAL DYSFUNCTION - vWF - Thrombomodulin - E-Selection - NO - Microalbuminuria - PAI-1 - Ox LDL – MDA – F2 - Isoprostane - LP – PLA2 - Lyso-PC OxFA 47 INFLAMMATORY MARKERS FOR CONSIDERATION AS PREDICTORS OF CARDIOVASCULAR RISK Adhesion molecules Cytokines Acute-phase reactants Fibrinogen SAA CRP WBC count Other (eg, erytrocyte sedimentation rate) (Pearson et al, 2003)
Slide 48 - 1 Nama : Prof. Dr. H. Djanggan Sargowo, dr., SpPD., SpJP(K), FIHA, FACC, FESC, FCAPC, FASCC Tempat/Tgl lahir : Sragen, 21 September 1947 Alamat : Wilis Indah E-10 Malang, Telp. 0341-552395 Pendidikan : Lulus Dokter dari UGM, tahun 1974 Lulus Cardiologist dari Univ. Indonesia, tahun 1983 Lulus Internist dari Univ. Airlangga, tahun 1986 Lulus Doktor, Univ. Airlangga, tahun 1996 Advanced Cardiology Course, Univ. Hongkong, tahun 1984 Senior Visiting Program, Institut Jantung Negara, Kualalumpur, 1996 Fellow American College of Cardiology (FACC), September 2006. Fellow Collage Asia Pacific Society of Cardiology (FCAPC), Desember 2007 Fellow European Sociaty of Cardiology (FESC), 2008 Fellow Asean Collage of Cardiology (FASCC), 2008 Jabatan : Dosen Pengajar Program Pascasarjana Universitas Brawijaya Ketua MKEK Ikatan Dokter Indonesia Cabang Malang Raya Ketua PERKI Cabang Malang Raya Anggota Kolegium Kardiovaskuler Indonesia Dekan Fak. Kedokteran Univ. Wijaya Kusuma Surabaya Ketua Dewan Pengawas Rumah Sakit Pendidikan Ketua Program Studi Kardiovascular Fak. Kedokteran Univ. Brawijaya Curriculum Vitae 2 Djanggan Sargowo Surabaya, 15 April 2012 INFLAMMATION IN ATHEROSCLEROSIS : FROM BENCH TO BEDSIDE 3 4 RUDOLF VIRCHOW Inflammation-based arterial changes as a mechanism of primary importance in atherogenesis mid 19th century Lamond, B. The American Journal of Pathology. 2008 5 Atherosclerosis Start from very young To Old age ? 6 Atherothrombosis* is aLeading Cause of Death Worldwide1† The World Health Report, 2002, WHO Geneva, 2002 28.7 17.8 12.6 9.1 6 5.1 0 5 10 15 20 25 30 Atherothrombosis* Infectious disease Cancer Injuries Pulmonary disease AIDS Mortality (%) * Ischemic heart disease, cerebrovascular disease, inflammatory heart disease and hypertensive heart disease † Worldwide defined as Member States by WHO Region (Africa, Americas, Eastern Mediterranean, European, South-East Asia and Western Pacific) 7 MAJOR CLINICAL MANIFESTATIONS OF ATHEROTHROMBOSIS Adapted from: Drouet L. Cerebrovasc Dis 2002; 13(suppl 1): 1–6. Transient ischemic attack Angina: Stable Unstable Ischemic stroke Myocardial infarction Peripheral arterial disease: Intermittent claudication Rest Pain Gangrene Necrosis 8  Dyslipidemia  Endothelial dysfunction  Free radicals  Immunologic Atherosclerosis/CAD THEORY AND CONCEPT OF ATHEROSCLEROSIS Inflamation (Sargowo, 1996) 9 Free Radical ATHEROGENESIS (Sargowo, 1996) 10 IDENTIFYING THOSE AT RISK OF ATHEROTHROMBOSIS Yusuf S et al. Circulation 2001; 104: 2746–53. 2. Drouet L. Cerebrovasc Dis 2002;13(suppl 1):1–6. Lifestyle Smoking Diet Lack of exercise Genetic Genetic traits Gender Age Generalized disorders Obesity Diabetes Systemic conditions History of vascular events Hypertension Hyperlipidemia Hypercoagulable states Homocystinemia Local factors Elevated prothrombotic factors: fibrinogen, CRP, PAI-1 Blood flow patterns, vessel diameter, arterial wall structure Atherothrombosis manifestations (myocardial infarction, stroke, vascular death) 11 Arici. 2010 Risk Factors for Atherosclerosis Classic Hypertension, Hyper-lipidemia, DM, Smoking Uremia Related Increase ox-LDL, Free radicals, Uremic toxin Infection Bacterial and viral infection Proinflammatory cytokine release Endothelial dysfunction Systemic inflammatory respones Acute phase response Elevated CRP Binding LDL, cemplement activation, tissue factor secretion Accelerated ATHEROSCLEROSIS 12 LDL CD40L=CD40 ligand; TNF-α=tumor necrosis factor-alpha; IL=interleukin; VCAM=vascular cell adhesion molecule; ICAM=intercellular adhesion molecule. Cockerill GW et al. Arterioscler Thromb Vasc Biol. 1995;15:1987-1994; Andre P et al. Circulation. 2002;106:896-899; Libby P. Circulation. 2001;104:365-372; Libby P et al. Circulation. 2002;105:1135-1143; Ross R. N Engl J Med. 1999;340:115-126. Vessel lumen Monocyte Macrophage Adhesionmolecules (VCAM-1, ICAM-1) Inflammatory mediators (CRP, CD40/CD40L, TNF-α, IL-1, IL-6) Intima Foam cell INFLAMMATION PROMOTES PROGRESSION OF ATHEROSCLEROSIS Endothelium LDL Ox-LDL 13 14 Atherosclerosis is a fibroproliferative and inflammatory process occurring ins response to a variety of vascular insults The insults come from classical risk factors ( HT, dyslipidemia, endothelial dysfunction, smoking, menopause, diabetes etc) and novel risk factors (Hcy, LVH, Lp(a), TG, oxidative stress, fibrinogen etc) Endothelial dysfunction is regarded as the first abnormality leading to atherosclerosis This implies that modulation of endothelial function may be used as strategy to intervene the process. 15 Two theories gain more acceptance: (a) the lipid theory (b) inflammation theory Endothelial dysfunction is now regarded as the first abnormality leading to AS. More novel cardiovascular risk factors are known, e.g.: Fibrinogen b. PAI-1 Homocysteins d. AT-1 e. CRP f. Lp(a) g. small-dense LDL h. infectious agents i. and more are emerging 16 Acute Coronary Syndrome (endocrine viewpoints) atherosclerotic lesions vascular funtions b.1. inflammatory reaction b.2. thrombogeneity b.3. vasoreactivity b.4. plaque stability b.5. shoulder of plaque endothelium balance between c.1. vasodilating, antithrombotic, antiproliferative factors (NO, prostacyclin, C-natriuretic peptide, EDHF) c.2. vasoconstricting, prothrombotic, proliferative factors (ET, superoxide, thromoboxan A2) 17 NATURAL HISTORY OF CORONARY ATHEROSCLEROSIS Chatzizisis et all. JACC. 2007. Asymtomatic Stable Angina Acute Coronary Syndrome Early fibroatheroma Compensatory expansive remodeling Quiescent plaque Contrictive remodeling Stenotic plaque Exessive expansive remodeling Thin cap fibroatheroma Erosion Physiologic coronary artery Local factors, e.g. low ESS Systemic factors, e.g. hyperlipidemia Genetic factors Physiologic ESS Limited inflammation Fibroproliferation Microruptures 18 ATHEROSCLEROSIS IS AN INFLAMMATORY DISEASE Libby P. Circulation. 2001;104:365-372; Ross R. N Engl J Med. 1999;340:115-126. Monocyte LDL-C Adhesion molecule Macrophage Foam cell OxidizedLDL-C Plaque rupture Smooth muscle cells CRP Plaque instability and thrombus Oxidation Inflammation Endothelial dysfunction 19 20 Reverse Cholesterol Transport Monocyte CRP TXA2 PGI2 Thrombin LDL Platelets HDL HDL Ox-LDL MCP-1 Macrophage P-selectin CD 40L PDGF Foam cell MMP T cell E-selectins CD 40L VCAM-1 ICAM-1 IL-1 Reilly, et.all. 2005 21 THE ROLE OF Lp-PLA2 IN CHD LUMEN Monocytes Adhesion Molecules Oxidated LDL INTIMA MEDIA Lp-PLA2 Lyso-PC OxFA Cytokines Plaque Formation Foam Cell Macrophage 22 MC T T FC FC LDL Oxidation Lyso-PC Ox-chol Cytokines Cytokines ? C5a C’ MCP-1 F SMC 23 Intracelluler proteolysis and fusion of LDL Figure : Proposed Dual Action of Exocytosed Mast Cell Granules (The Granule Remnants) of Lipoprotein Metabolism in The Arterial Intima 24 HSCRP 25 26 GM-CSF VCAM-1 MPC-1 Transcription Factors : Endothelial Cell Pro-inflammatory Genes Oxidative Stress NF-xB AP-1 Leucocyte infiltration / activation Plaque Rupture Gibbons, 97 LEUCOCYTE ACTIVATION IN ATHEROGENESIS : IMPLICATIONS FOR ACUTE ISCHEMIC SYNDROMES 27 p38 c-Jun activation Caspases Apoptosis NIK ? ? MEKK1?   CKII IKK complex TNFR-1 TNFR-1 IL-1R Shear stress p65 p50 CBP/p300 Gene activation p65 p50 IB pKAc IB Ub Target genes : - IL-1, IL-8, IL-6, IFN  - TNF, MCP-1 - CSFs, c-myc - VCAM-1, ICAM-1, E-selectin - Tissue factor - Survival factor Thurberg and Collins : Curr Opin Lipidol 9:387-396,1998 Ub Ox-LDL ROIs ??? Lipid peroxides ? H2O2 Ubiquitination and proteosome degradation T R A D D R I P F A D D R I P T R A D D T R A F 2 T R A F 6 28 Visual Medica. 2009 29 Stockley. 2006 Cytokines : IL-6, TNF-α MACROPHAGE FOAM CELL Oxidized LDL CRP CRP Chemokines: MCO-1 Atherosclerotic plaque MONOCYTE Inflammatory Mediators: CRP Prothrombotic factors FCR Receptor 30 POTENTIAL MECHANISM OF CRP Stevens, R. 2005 CRP LDL opsonisation Monocyte infiltration Foam cell formation Increased MCP-1 and CAM EC activation Inflammatory cell recruitment Atherosclerosis plaque formation Complement activation EC sensitisation T-cell attack EC damage Atherosclerotic plaque rupture 31 Rheumatoid arthritis Atherosclerosis Multiple sclerosis Asthma Inflammatory bowel disease Helicobacter pylori-associated gastritis Systemic inflammatory response syndrome NF-KB ACTIVATION INFLAMMATORY DISEASE The Journal of Clinical Investigation, 2001 32 PROTEIN REGULATED BY NF-KB Inflammatory Enzyme Adhesion Molecule Inducible nitric oxide synthase Inducide cylooxigenase-2 5-Lipoxigenase Cytosolic phospolipase A2 ICAM-1 VCAM-1 E-selectin Receptor Interlekin-2 receptor (alpha chain) T-cell receptors (beta chain) NEJM, 1997 33 BIOMARKERS OF ACTIVITY STUDIED FOR CAD Cytokines (IL-1β, IL-6, IL-8, IL-10, TNF-α, sCD40 ligand, myeloperoxidase) Adhesion molecules (sICAM-1, sVCAM-1, p-selectin) Acute phase reactans (fibrinogen, AAS, CRP) White blood cells Erythrocyte sedimentation rate Neopterin Heat shock proteins Adiponectin Lipoprotein associated phospholipase A2 Placental growth factos Cystatin C Kaski, JC. 2006. 34 Are you hungry or sleepy ???? Sciences 35 The inflammatory cascade. IL indicates interleukin; ICAM, intercellular adhesion molecule; and HSP, heat shock protein. (Libby, Ridker; 1999) Pro-Inflammatory Risk Factors Primary Pro-Inflammatory Cytokines (eg. IL-1, TNF-) IL-6 “Mesenger” Cytokine CRP SAA Endothelium and other cells LIVER Circulation 36 (Ridker, 2004) MORE THAN A MARKER : DOES CRP PLAY A DIRECT ROLE IN ATHEROTHROMBOSIS ? CRP localizes in atherosclerotic but not normal intima CRP induced Complement activation CRP dependent monocyte recruitment into arterial wall CRP induced production of tissue factor in monocytes CRP based blunting of endothelial vasoreactivity CRP mediated LDL uptake by macrophages CRP triggered oxidation of LDL cholesterol CRP induced PAI-1 expression stabilizes PAI-1 mRNA CRP attenuates NO production and decreases eNOS expression CRP induced production of cell adhesion moleculas MCP-1, ET-1 37 ROLE OF INFLAMATORY MARKERS Interleukin-6 Total cholesterol LDL-cholesterol siCAM-1 Serum amyloid A Apolipoprotein B Total cholesterol: HDL-cholesterol Hs-CRP Hs-CRP + total cholesterol: HDL-cholesterol 0 1.0 2.0 4.0 6.0 Relative Risk (New England Journal of Medicine) 38 39 Weissberg, 1999 Inflammation Repair 40 REDOX REGULATION OF ENDOTHELIAL DYSFUNCTION & ACTIVATION O2– OH H2O2  NO Activity  G-Protein Function  Protein Kinase C Oxidation Endothelial Dysfunction (D. Sargowo) 41 ENDOTHELIAL DYSFUNCTION AND ACUTE CORONARY SYNDROMES Vasoconstriction Platelet Aggregation SMC Proliferation Leukocyte Adhesion LDL Oxidation Activation of MMPs Endothelial Dysfunction Plaque Rupture Thrombosis Matrix Remodeling (D. Sargowo) 42 ENDOTHELIAL DYSFUNCTION AND ACUTE CORONARY SYNDROMES Vasospasm Plaque Rupture Thrombosis Matrix Remodeling ACUTE CORONARY SYNDROMES (D. Sargowo) 43 44 Diabetes Smoking AII Oxidative Stress Endothelial Dysfunction and Smooth Muscle Activation Growth FactorsCytokinesMatrix Proteolysis Inflammation VCAM/1CAMCytokines EndothelinCatecholamines BP LDL  NO • ∆ Local Mediators •  Tissue ACE, AII PAI-1, Platelet Aggregation, Tissue Factor Vasoconstriction Thrombosis Inflammation Plaque Rupture Vascular Lesion and Remodeling Clinical Sequelae Risk Factors Reprinted with permission from Dzau VJ. Hypertension. 2001;37:1047–1052. 45 THERAPEUTICS : WHERE DO WE STAND TODAY ? Lipid lowering drugs ACEI / ARB Peroxisome proliferators-activated receptor (PPAR) Chemokine receptor antagonist TNF Inhibitor MMP Inhibitor 46 BIOCHEMICAL PARAMETER FOR ENDOTHELIAL DYSFUNCTION - vWF - Thrombomodulin - E-Selection - ICAM-1 - VCAM-1 - NO - Microalbuminuria - PAI-1 (D. Sargowo) - Ox LDL – MDA – F2 - Isoprostane - LP – PLA2 - Lyso-PC OxFA BIOCHEMICAL PARAMETER FOR ENDOTHELIAL DYSFUNCTION - vWF - Thrombomodulin - E-Selection - NO - Microalbuminuria - PAI-1 - Ox LDL – MDA – F2 - Isoprostane - LP – PLA2 - Lyso-PC OxFA 47 INFLAMMATORY MARKERS FOR CONSIDERATION AS PREDICTORS OF CARDIOVASCULAR RISK Adhesion molecules Cytokines Acute-phase reactants Fibrinogen SAA CRP WBC count Other (eg, erytrocyte sedimentation rate) (Pearson et al, 2003) 48 SURREGATE BIOMARKERS FOR ACS HS CRP MMP Stromelysin Kalogenase Elastase INFj, TNF, IL1 Gelatinase LDH CPK MBCK Troponin T-I Fibrinogen Albuminuri D. Sargowo
Slide 49 - 1 Nama : Prof. Dr. H. Djanggan Sargowo, dr., SpPD., SpJP(K), FIHA, FACC, FESC, FCAPC, FASCC Tempat/Tgl lahir : Sragen, 21 September 1947 Alamat : Wilis Indah E-10 Malang, Telp. 0341-552395 Pendidikan : Lulus Dokter dari UGM, tahun 1974 Lulus Cardiologist dari Univ. Indonesia, tahun 1983 Lulus Internist dari Univ. Airlangga, tahun 1986 Lulus Doktor, Univ. Airlangga, tahun 1996 Advanced Cardiology Course, Univ. Hongkong, tahun 1984 Senior Visiting Program, Institut Jantung Negara, Kualalumpur, 1996 Fellow American College of Cardiology (FACC), September 2006. Fellow Collage Asia Pacific Society of Cardiology (FCAPC), Desember 2007 Fellow European Sociaty of Cardiology (FESC), 2008 Fellow Asean Collage of Cardiology (FASCC), 2008 Jabatan : Dosen Pengajar Program Pascasarjana Universitas Brawijaya Ketua MKEK Ikatan Dokter Indonesia Cabang Malang Raya Ketua PERKI Cabang Malang Raya Anggota Kolegium Kardiovaskuler Indonesia Dekan Fak. Kedokteran Univ. Wijaya Kusuma Surabaya Ketua Dewan Pengawas Rumah Sakit Pendidikan Ketua Program Studi Kardiovascular Fak. Kedokteran Univ. Brawijaya Curriculum Vitae 2 Djanggan Sargowo Surabaya, 15 April 2012 INFLAMMATION IN ATHEROSCLEROSIS : FROM BENCH TO BEDSIDE 3 4 RUDOLF VIRCHOW Inflammation-based arterial changes as a mechanism of primary importance in atherogenesis mid 19th century Lamond, B. The American Journal of Pathology. 2008 5 Atherosclerosis Start from very young To Old age ? 6 Atherothrombosis* is aLeading Cause of Death Worldwide1† The World Health Report, 2002, WHO Geneva, 2002 28.7 17.8 12.6 9.1 6 5.1 0 5 10 15 20 25 30 Atherothrombosis* Infectious disease Cancer Injuries Pulmonary disease AIDS Mortality (%) * Ischemic heart disease, cerebrovascular disease, inflammatory heart disease and hypertensive heart disease † Worldwide defined as Member States by WHO Region (Africa, Americas, Eastern Mediterranean, European, South-East Asia and Western Pacific) 7 MAJOR CLINICAL MANIFESTATIONS OF ATHEROTHROMBOSIS Adapted from: Drouet L. Cerebrovasc Dis 2002; 13(suppl 1): 1–6. Transient ischemic attack Angina: Stable Unstable Ischemic stroke Myocardial infarction Peripheral arterial disease: Intermittent claudication Rest Pain Gangrene Necrosis 8  Dyslipidemia  Endothelial dysfunction  Free radicals  Immunologic Atherosclerosis/CAD THEORY AND CONCEPT OF ATHEROSCLEROSIS Inflamation (Sargowo, 1996) 9 Free Radical ATHEROGENESIS (Sargowo, 1996) 10 IDENTIFYING THOSE AT RISK OF ATHEROTHROMBOSIS Yusuf S et al. Circulation 2001; 104: 2746–53. 2. Drouet L. Cerebrovasc Dis 2002;13(suppl 1):1–6. Lifestyle Smoking Diet Lack of exercise Genetic Genetic traits Gender Age Generalized disorders Obesity Diabetes Systemic conditions History of vascular events Hypertension Hyperlipidemia Hypercoagulable states Homocystinemia Local factors Elevated prothrombotic factors: fibrinogen, CRP, PAI-1 Blood flow patterns, vessel diameter, arterial wall structure Atherothrombosis manifestations (myocardial infarction, stroke, vascular death) 11 Arici. 2010 Risk Factors for Atherosclerosis Classic Hypertension, Hyper-lipidemia, DM, Smoking Uremia Related Increase ox-LDL, Free radicals, Uremic toxin Infection Bacterial and viral infection Proinflammatory cytokine release Endothelial dysfunction Systemic inflammatory respones Acute phase response Elevated CRP Binding LDL, cemplement activation, tissue factor secretion Accelerated ATHEROSCLEROSIS 12 LDL CD40L=CD40 ligand; TNF-α=tumor necrosis factor-alpha; IL=interleukin; VCAM=vascular cell adhesion molecule; ICAM=intercellular adhesion molecule. Cockerill GW et al. Arterioscler Thromb Vasc Biol. 1995;15:1987-1994; Andre P et al. Circulation. 2002;106:896-899; Libby P. Circulation. 2001;104:365-372; Libby P et al. Circulation. 2002;105:1135-1143; Ross R. N Engl J Med. 1999;340:115-126. Vessel lumen Monocyte Macrophage Adhesionmolecules (VCAM-1, ICAM-1) Inflammatory mediators (CRP, CD40/CD40L, TNF-α, IL-1, IL-6) Intima Foam cell INFLAMMATION PROMOTES PROGRESSION OF ATHEROSCLEROSIS Endothelium LDL Ox-LDL 13 14 Atherosclerosis is a fibroproliferative and inflammatory process occurring ins response to a variety of vascular insults The insults come from classical risk factors ( HT, dyslipidemia, endothelial dysfunction, smoking, menopause, diabetes etc) and novel risk factors (Hcy, LVH, Lp(a), TG, oxidative stress, fibrinogen etc) Endothelial dysfunction is regarded as the first abnormality leading to atherosclerosis This implies that modulation of endothelial function may be used as strategy to intervene the process. 15 Two theories gain more acceptance: (a) the lipid theory (b) inflammation theory Endothelial dysfunction is now regarded as the first abnormality leading to AS. More novel cardiovascular risk factors are known, e.g.: Fibrinogen b. PAI-1 Homocysteins d. AT-1 e. CRP f. Lp(a) g. small-dense LDL h. infectious agents i. and more are emerging 16 Acute Coronary Syndrome (endocrine viewpoints) atherosclerotic lesions vascular funtions b.1. inflammatory reaction b.2. thrombogeneity b.3. vasoreactivity b.4. plaque stability b.5. shoulder of plaque endothelium balance between c.1. vasodilating, antithrombotic, antiproliferative factors (NO, prostacyclin, C-natriuretic peptide, EDHF) c.2. vasoconstricting, prothrombotic, proliferative factors (ET, superoxide, thromoboxan A2) 17 NATURAL HISTORY OF CORONARY ATHEROSCLEROSIS Chatzizisis et all. JACC. 2007. Asymtomatic Stable Angina Acute Coronary Syndrome Early fibroatheroma Compensatory expansive remodeling Quiescent plaque Contrictive remodeling Stenotic plaque Exessive expansive remodeling Thin cap fibroatheroma Erosion Physiologic coronary artery Local factors, e.g. low ESS Systemic factors, e.g. hyperlipidemia Genetic factors Physiologic ESS Limited inflammation Fibroproliferation Microruptures 18 ATHEROSCLEROSIS IS AN INFLAMMATORY DISEASE Libby P. Circulation. 2001;104:365-372; Ross R. N Engl J Med. 1999;340:115-126. Monocyte LDL-C Adhesion molecule Macrophage Foam cell OxidizedLDL-C Plaque rupture Smooth muscle cells CRP Plaque instability and thrombus Oxidation Inflammation Endothelial dysfunction 19 20 Reverse Cholesterol Transport Monocyte CRP TXA2 PGI2 Thrombin LDL Platelets HDL HDL Ox-LDL MCP-1 Macrophage P-selectin CD 40L PDGF Foam cell MMP T cell E-selectins CD 40L VCAM-1 ICAM-1 IL-1 Reilly, et.all. 2005 21 THE ROLE OF Lp-PLA2 IN CHD LUMEN Monocytes Adhesion Molecules Oxidated LDL INTIMA MEDIA Lp-PLA2 Lyso-PC OxFA Cytokines Plaque Formation Foam Cell Macrophage 22 MC T T FC FC LDL Oxidation Lyso-PC Ox-chol Cytokines Cytokines ? C5a C’ MCP-1 F SMC 23 Intracelluler proteolysis and fusion of LDL Figure : Proposed Dual Action of Exocytosed Mast Cell Granules (The Granule Remnants) of Lipoprotein Metabolism in The Arterial Intima 24 HSCRP 25 26 GM-CSF VCAM-1 MPC-1 Transcription Factors : Endothelial Cell Pro-inflammatory Genes Oxidative Stress NF-xB AP-1 Leucocyte infiltration / activation Plaque Rupture Gibbons, 97 LEUCOCYTE ACTIVATION IN ATHEROGENESIS : IMPLICATIONS FOR ACUTE ISCHEMIC SYNDROMES 27 p38 c-Jun activation Caspases Apoptosis NIK ? ? MEKK1?   CKII IKK complex TNFR-1 TNFR-1 IL-1R Shear stress p65 p50 CBP/p300 Gene activation p65 p50 IB pKAc IB Ub Target genes : - IL-1, IL-8, IL-6, IFN  - TNF, MCP-1 - CSFs, c-myc - VCAM-1, ICAM-1, E-selectin - Tissue factor - Survival factor Thurberg and Collins : Curr Opin Lipidol 9:387-396,1998 Ub Ox-LDL ROIs ??? Lipid peroxides ? H2O2 Ubiquitination and proteosome degradation T R A D D R I P F A D D R I P T R A D D T R A F 2 T R A F 6 28 Visual Medica. 2009 29 Stockley. 2006 Cytokines : IL-6, TNF-α MACROPHAGE FOAM CELL Oxidized LDL CRP CRP Chemokines: MCO-1 Atherosclerotic plaque MONOCYTE Inflammatory Mediators: CRP Prothrombotic factors FCR Receptor 30 POTENTIAL MECHANISM OF CRP Stevens, R. 2005 CRP LDL opsonisation Monocyte infiltration Foam cell formation Increased MCP-1 and CAM EC activation Inflammatory cell recruitment Atherosclerosis plaque formation Complement activation EC sensitisation T-cell attack EC damage Atherosclerotic plaque rupture 31 Rheumatoid arthritis Atherosclerosis Multiple sclerosis Asthma Inflammatory bowel disease Helicobacter pylori-associated gastritis Systemic inflammatory response syndrome NF-KB ACTIVATION INFLAMMATORY DISEASE The Journal of Clinical Investigation, 2001 32 PROTEIN REGULATED BY NF-KB Inflammatory Enzyme Adhesion Molecule Inducible nitric oxide synthase Inducide cylooxigenase-2 5-Lipoxigenase Cytosolic phospolipase A2 ICAM-1 VCAM-1 E-selectin Receptor Interlekin-2 receptor (alpha chain) T-cell receptors (beta chain) NEJM, 1997 33 BIOMARKERS OF ACTIVITY STUDIED FOR CAD Cytokines (IL-1β, IL-6, IL-8, IL-10, TNF-α, sCD40 ligand, myeloperoxidase) Adhesion molecules (sICAM-1, sVCAM-1, p-selectin) Acute phase reactans (fibrinogen, AAS, CRP) White blood cells Erythrocyte sedimentation rate Neopterin Heat shock proteins Adiponectin Lipoprotein associated phospholipase A2 Placental growth factos Cystatin C Kaski, JC. 2006. 34 Are you hungry or sleepy ???? Sciences 35 The inflammatory cascade. IL indicates interleukin; ICAM, intercellular adhesion molecule; and HSP, heat shock protein. (Libby, Ridker; 1999) Pro-Inflammatory Risk Factors Primary Pro-Inflammatory Cytokines (eg. IL-1, TNF-) IL-6 “Mesenger” Cytokine CRP SAA Endothelium and other cells LIVER Circulation 36 (Ridker, 2004) MORE THAN A MARKER : DOES CRP PLAY A DIRECT ROLE IN ATHEROTHROMBOSIS ? CRP localizes in atherosclerotic but not normal intima CRP induced Complement activation CRP dependent monocyte recruitment into arterial wall CRP induced production of tissue factor in monocytes CRP based blunting of endothelial vasoreactivity CRP mediated LDL uptake by macrophages CRP triggered oxidation of LDL cholesterol CRP induced PAI-1 expression stabilizes PAI-1 mRNA CRP attenuates NO production and decreases eNOS expression CRP induced production of cell adhesion moleculas MCP-1, ET-1 37 ROLE OF INFLAMATORY MARKERS Interleukin-6 Total cholesterol LDL-cholesterol siCAM-1 Serum amyloid A Apolipoprotein B Total cholesterol: HDL-cholesterol Hs-CRP Hs-CRP + total cholesterol: HDL-cholesterol 0 1.0 2.0 4.0 6.0 Relative Risk (New England Journal of Medicine) 38 39 Weissberg, 1999 Inflammation Repair 40 REDOX REGULATION OF ENDOTHELIAL DYSFUNCTION & ACTIVATION O2– OH H2O2  NO Activity  G-Protein Function  Protein Kinase C Oxidation Endothelial Dysfunction (D. Sargowo) 41 ENDOTHELIAL DYSFUNCTION AND ACUTE CORONARY SYNDROMES Vasoconstriction Platelet Aggregation SMC Proliferation Leukocyte Adhesion LDL Oxidation Activation of MMPs Endothelial Dysfunction Plaque Rupture Thrombosis Matrix Remodeling (D. Sargowo) 42 ENDOTHELIAL DYSFUNCTION AND ACUTE CORONARY SYNDROMES Vasospasm Plaque Rupture Thrombosis Matrix Remodeling ACUTE CORONARY SYNDROMES (D. Sargowo) 43 44 Diabetes Smoking AII Oxidative Stress Endothelial Dysfunction and Smooth Muscle Activation Growth FactorsCytokinesMatrix Proteolysis Inflammation VCAM/1CAMCytokines EndothelinCatecholamines BP LDL  NO • ∆ Local Mediators •  Tissue ACE, AII PAI-1, Platelet Aggregation, Tissue Factor Vasoconstriction Thrombosis Inflammation Plaque Rupture Vascular Lesion and Remodeling Clinical Sequelae Risk Factors Reprinted with permission from Dzau VJ. Hypertension. 2001;37:1047–1052. 45 THERAPEUTICS : WHERE DO WE STAND TODAY ? Lipid lowering drugs ACEI / ARB Peroxisome proliferators-activated receptor (PPAR) Chemokine receptor antagonist TNF Inhibitor MMP Inhibitor 46 BIOCHEMICAL PARAMETER FOR ENDOTHELIAL DYSFUNCTION - vWF - Thrombomodulin - E-Selection - ICAM-1 - VCAM-1 - NO - Microalbuminuria - PAI-1 (D. Sargowo) - Ox LDL – MDA – F2 - Isoprostane - LP – PLA2 - Lyso-PC OxFA BIOCHEMICAL PARAMETER FOR ENDOTHELIAL DYSFUNCTION - vWF - Thrombomodulin - E-Selection - NO - Microalbuminuria - PAI-1 - Ox LDL – MDA – F2 - Isoprostane - LP – PLA2 - Lyso-PC OxFA 47 INFLAMMATORY MARKERS FOR CONSIDERATION AS PREDICTORS OF CARDIOVASCULAR RISK Adhesion molecules Cytokines Acute-phase reactants Fibrinogen SAA CRP WBC count Other (eg, erytrocyte sedimentation rate) (Pearson et al, 2003) 48 SURREGATE BIOMARKERS FOR ACS HS CRP MMP Stromelysin Kalogenase Elastase INFj, TNF, IL1 Gelatinase LDH CPK MBCK Troponin T-I Fibrinogen Albuminuri D. Sargowo 49 Rudolf Virchow Inflammation-based arterial changes as a mechanism of primary importance in atherogenesis mid 19th century Lamond, B. The American Journal of Pathology. 2008 SUMMARY
Slide 50 - 1 Nama : Prof. Dr. H. Djanggan Sargowo, dr., SpPD., SpJP(K), FIHA, FACC, FESC, FCAPC, FASCC Tempat/Tgl lahir : Sragen, 21 September 1947 Alamat : Wilis Indah E-10 Malang, Telp. 0341-552395 Pendidikan : Lulus Dokter dari UGM, tahun 1974 Lulus Cardiologist dari Univ. Indonesia, tahun 1983 Lulus Internist dari Univ. Airlangga, tahun 1986 Lulus Doktor, Univ. Airlangga, tahun 1996 Advanced Cardiology Course, Univ. Hongkong, tahun 1984 Senior Visiting Program, Institut Jantung Negara, Kualalumpur, 1996 Fellow American College of Cardiology (FACC), September 2006. Fellow Collage Asia Pacific Society of Cardiology (FCAPC), Desember 2007 Fellow European Sociaty of Cardiology (FESC), 2008 Fellow Asean Collage of Cardiology (FASCC), 2008 Jabatan : Dosen Pengajar Program Pascasarjana Universitas Brawijaya Ketua MKEK Ikatan Dokter Indonesia Cabang Malang Raya Ketua PERKI Cabang Malang Raya Anggota Kolegium Kardiovaskuler Indonesia Dekan Fak. Kedokteran Univ. Wijaya Kusuma Surabaya Ketua Dewan Pengawas Rumah Sakit Pendidikan Ketua Program Studi Kardiovascular Fak. Kedokteran Univ. Brawijaya Curriculum Vitae 2 Djanggan Sargowo Surabaya, 15 April 2012 INFLAMMATION IN ATHEROSCLEROSIS : FROM BENCH TO BEDSIDE 3 4 RUDOLF VIRCHOW Inflammation-based arterial changes as a mechanism of primary importance in atherogenesis mid 19th century Lamond, B. The American Journal of Pathology. 2008 5 Atherosclerosis Start from very young To Old age ? 6 Atherothrombosis* is aLeading Cause of Death Worldwide1† The World Health Report, 2002, WHO Geneva, 2002 28.7 17.8 12.6 9.1 6 5.1 0 5 10 15 20 25 30 Atherothrombosis* Infectious disease Cancer Injuries Pulmonary disease AIDS Mortality (%) * Ischemic heart disease, cerebrovascular disease, inflammatory heart disease and hypertensive heart disease † Worldwide defined as Member States by WHO Region (Africa, Americas, Eastern Mediterranean, European, South-East Asia and Western Pacific) 7 MAJOR CLINICAL MANIFESTATIONS OF ATHEROTHROMBOSIS Adapted from: Drouet L. Cerebrovasc Dis 2002; 13(suppl 1): 1–6. Transient ischemic attack Angina: Stable Unstable Ischemic stroke Myocardial infarction Peripheral arterial disease: Intermittent claudication Rest Pain Gangrene Necrosis 8  Dyslipidemia  Endothelial dysfunction  Free radicals  Immunologic Atherosclerosis/CAD THEORY AND CONCEPT OF ATHEROSCLEROSIS Inflamation (Sargowo, 1996) 9 Free Radical ATHEROGENESIS (Sargowo, 1996) 10 IDENTIFYING THOSE AT RISK OF ATHEROTHROMBOSIS Yusuf S et al. Circulation 2001; 104: 2746–53. 2. Drouet L. Cerebrovasc Dis 2002;13(suppl 1):1–6. Lifestyle Smoking Diet Lack of exercise Genetic Genetic traits Gender Age Generalized disorders Obesity Diabetes Systemic conditions History of vascular events Hypertension Hyperlipidemia Hypercoagulable states Homocystinemia Local factors Elevated prothrombotic factors: fibrinogen, CRP, PAI-1 Blood flow patterns, vessel diameter, arterial wall structure Atherothrombosis manifestations (myocardial infarction, stroke, vascular death) 11 Arici. 2010 Risk Factors for Atherosclerosis Classic Hypertension, Hyper-lipidemia, DM, Smoking Uremia Related Increase ox-LDL, Free radicals, Uremic toxin Infection Bacterial and viral infection Proinflammatory cytokine release Endothelial dysfunction Systemic inflammatory respones Acute phase response Elevated CRP Binding LDL, cemplement activation, tissue factor secretion Accelerated ATHEROSCLEROSIS 12 LDL CD40L=CD40 ligand; TNF-α=tumor necrosis factor-alpha; IL=interleukin; VCAM=vascular cell adhesion molecule; ICAM=intercellular adhesion molecule. Cockerill GW et al. Arterioscler Thromb Vasc Biol. 1995;15:1987-1994; Andre P et al. Circulation. 2002;106:896-899; Libby P. Circulation. 2001;104:365-372; Libby P et al. Circulation. 2002;105:1135-1143; Ross R. N Engl J Med. 1999;340:115-126. Vessel lumen Monocyte Macrophage Adhesionmolecules (VCAM-1, ICAM-1) Inflammatory mediators (CRP, CD40/CD40L, TNF-α, IL-1, IL-6) Intima Foam cell INFLAMMATION PROMOTES PROGRESSION OF ATHEROSCLEROSIS Endothelium LDL Ox-LDL 13 14 Atherosclerosis is a fibroproliferative and inflammatory process occurring ins response to a variety of vascular insults The insults come from classical risk factors ( HT, dyslipidemia, endothelial dysfunction, smoking, menopause, diabetes etc) and novel risk factors (Hcy, LVH, Lp(a), TG, oxidative stress, fibrinogen etc) Endothelial dysfunction is regarded as the first abnormality leading to atherosclerosis This implies that modulation of endothelial function may be used as strategy to intervene the process. 15 Two theories gain more acceptance: (a) the lipid theory (b) inflammation theory Endothelial dysfunction is now regarded as the first abnormality leading to AS. More novel cardiovascular risk factors are known, e.g.: Fibrinogen b. PAI-1 Homocysteins d. AT-1 e. CRP f. Lp(a) g. small-dense LDL h. infectious agents i. and more are emerging 16 Acute Coronary Syndrome (endocrine viewpoints) atherosclerotic lesions vascular funtions b.1. inflammatory reaction b.2. thrombogeneity b.3. vasoreactivity b.4. plaque stability b.5. shoulder of plaque endothelium balance between c.1. vasodilating, antithrombotic, antiproliferative factors (NO, prostacyclin, C-natriuretic peptide, EDHF) c.2. vasoconstricting, prothrombotic, proliferative factors (ET, superoxide, thromoboxan A2) 17 NATURAL HISTORY OF CORONARY ATHEROSCLEROSIS Chatzizisis et all. JACC. 2007. Asymtomatic Stable Angina Acute Coronary Syndrome Early fibroatheroma Compensatory expansive remodeling Quiescent plaque Contrictive remodeling Stenotic plaque Exessive expansive remodeling Thin cap fibroatheroma Erosion Physiologic coronary artery Local factors, e.g. low ESS Systemic factors, e.g. hyperlipidemia Genetic factors Physiologic ESS Limited inflammation Fibroproliferation Microruptures 18 ATHEROSCLEROSIS IS AN INFLAMMATORY DISEASE Libby P. Circulation. 2001;104:365-372; Ross R. N Engl J Med. 1999;340:115-126. Monocyte LDL-C Adhesion molecule Macrophage Foam cell OxidizedLDL-C Plaque rupture Smooth muscle cells CRP Plaque instability and thrombus Oxidation Inflammation Endothelial dysfunction 19 20 Reverse Cholesterol Transport Monocyte CRP TXA2 PGI2 Thrombin LDL Platelets HDL HDL Ox-LDL MCP-1 Macrophage P-selectin CD 40L PDGF Foam cell MMP T cell E-selectins CD 40L VCAM-1 ICAM-1 IL-1 Reilly, et.all. 2005 21 THE ROLE OF Lp-PLA2 IN CHD LUMEN Monocytes Adhesion Molecules Oxidated LDL INTIMA MEDIA Lp-PLA2 Lyso-PC OxFA Cytokines Plaque Formation Foam Cell Macrophage 22 MC T T FC FC LDL Oxidation Lyso-PC Ox-chol Cytokines Cytokines ? C5a C’ MCP-1 F SMC 23 Intracelluler proteolysis and fusion of LDL Figure : Proposed Dual Action of Exocytosed Mast Cell Granules (The Granule Remnants) of Lipoprotein Metabolism in The Arterial Intima 24 HSCRP 25 26 GM-CSF VCAM-1 MPC-1 Transcription Factors : Endothelial Cell Pro-inflammatory Genes Oxidative Stress NF-xB AP-1 Leucocyte infiltration / activation Plaque Rupture Gibbons, 97 LEUCOCYTE ACTIVATION IN ATHEROGENESIS : IMPLICATIONS FOR ACUTE ISCHEMIC SYNDROMES 27 p38 c-Jun activation Caspases Apoptosis NIK ? ? MEKK1?   CKII IKK complex TNFR-1 TNFR-1 IL-1R Shear stress p65 p50 CBP/p300 Gene activation p65 p50 IB pKAc IB Ub Target genes : - IL-1, IL-8, IL-6, IFN  - TNF, MCP-1 - CSFs, c-myc - VCAM-1, ICAM-1, E-selectin - Tissue factor - Survival factor Thurberg and Collins : Curr Opin Lipidol 9:387-396,1998 Ub Ox-LDL ROIs ??? Lipid peroxides ? H2O2 Ubiquitination and proteosome degradation T R A D D R I P F A D D R I P T R A D D T R A F 2 T R A F 6 28 Visual Medica. 2009 29 Stockley. 2006 Cytokines : IL-6, TNF-α MACROPHAGE FOAM CELL Oxidized LDL CRP CRP Chemokines: MCO-1 Atherosclerotic plaque MONOCYTE Inflammatory Mediators: CRP Prothrombotic factors FCR Receptor 30 POTENTIAL MECHANISM OF CRP Stevens, R. 2005 CRP LDL opsonisation Monocyte infiltration Foam cell formation Increased MCP-1 and CAM EC activation Inflammatory cell recruitment Atherosclerosis plaque formation Complement activation EC sensitisation T-cell attack EC damage Atherosclerotic plaque rupture 31 Rheumatoid arthritis Atherosclerosis Multiple sclerosis Asthma Inflammatory bowel disease Helicobacter pylori-associated gastritis Systemic inflammatory response syndrome NF-KB ACTIVATION INFLAMMATORY DISEASE The Journal of Clinical Investigation, 2001 32 PROTEIN REGULATED BY NF-KB Inflammatory Enzyme Adhesion Molecule Inducible nitric oxide synthase Inducide cylooxigenase-2 5-Lipoxigenase Cytosolic phospolipase A2 ICAM-1 VCAM-1 E-selectin Receptor Interlekin-2 receptor (alpha chain) T-cell receptors (beta chain) NEJM, 1997 33 BIOMARKERS OF ACTIVITY STUDIED FOR CAD Cytokines (IL-1β, IL-6, IL-8, IL-10, TNF-α, sCD40 ligand, myeloperoxidase) Adhesion molecules (sICAM-1, sVCAM-1, p-selectin) Acute phase reactans (fibrinogen, AAS, CRP) White blood cells Erythrocyte sedimentation rate Neopterin Heat shock proteins Adiponectin Lipoprotein associated phospholipase A2 Placental growth factos Cystatin C Kaski, JC. 2006. 34 Are you hungry or sleepy ???? Sciences 35 The inflammatory cascade. IL indicates interleukin; ICAM, intercellular adhesion molecule; and HSP, heat shock protein. (Libby, Ridker; 1999) Pro-Inflammatory Risk Factors Primary Pro-Inflammatory Cytokines (eg. IL-1, TNF-) IL-6 “Mesenger” Cytokine CRP SAA Endothelium and other cells LIVER Circulation 36 (Ridker, 2004) MORE THAN A MARKER : DOES CRP PLAY A DIRECT ROLE IN ATHEROTHROMBOSIS ? CRP localizes in atherosclerotic but not normal intima CRP induced Complement activation CRP dependent monocyte recruitment into arterial wall CRP induced production of tissue factor in monocytes CRP based blunting of endothelial vasoreactivity CRP mediated LDL uptake by macrophages CRP triggered oxidation of LDL cholesterol CRP induced PAI-1 expression stabilizes PAI-1 mRNA CRP attenuates NO production and decreases eNOS expression CRP induced production of cell adhesion moleculas MCP-1, ET-1 37 ROLE OF INFLAMATORY MARKERS Interleukin-6 Total cholesterol LDL-cholesterol siCAM-1 Serum amyloid A Apolipoprotein B Total cholesterol: HDL-cholesterol Hs-CRP Hs-CRP + total cholesterol: HDL-cholesterol 0 1.0 2.0 4.0 6.0 Relative Risk (New England Journal of Medicine) 38 39 Weissberg, 1999 Inflammation Repair 40 REDOX REGULATION OF ENDOTHELIAL DYSFUNCTION & ACTIVATION O2– OH H2O2  NO Activity  G-Protein Function  Protein Kinase C Oxidation Endothelial Dysfunction (D. Sargowo) 41 ENDOTHELIAL DYSFUNCTION AND ACUTE CORONARY SYNDROMES Vasoconstriction Platelet Aggregation SMC Proliferation Leukocyte Adhesion LDL Oxidation Activation of MMPs Endothelial Dysfunction Plaque Rupture Thrombosis Matrix Remodeling (D. Sargowo) 42 ENDOTHELIAL DYSFUNCTION AND ACUTE CORONARY SYNDROMES Vasospasm Plaque Rupture Thrombosis Matrix Remodeling ACUTE CORONARY SYNDROMES (D. Sargowo) 43 44 Diabetes Smoking AII Oxidative Stress Endothelial Dysfunction and Smooth Muscle Activation Growth FactorsCytokinesMatrix Proteolysis Inflammation VCAM/1CAMCytokines EndothelinCatecholamines BP LDL  NO • ∆ Local Mediators •  Tissue ACE, AII PAI-1, Platelet Aggregation, Tissue Factor Vasoconstriction Thrombosis Inflammation Plaque Rupture Vascular Lesion and Remodeling Clinical Sequelae Risk Factors Reprinted with permission from Dzau VJ. Hypertension. 2001;37:1047–1052. 45 THERAPEUTICS : WHERE DO WE STAND TODAY ? Lipid lowering drugs ACEI / ARB Peroxisome proliferators-activated receptor (PPAR) Chemokine receptor antagonist TNF Inhibitor MMP Inhibitor 46 BIOCHEMICAL PARAMETER FOR ENDOTHELIAL DYSFUNCTION - vWF - Thrombomodulin - E-Selection - ICAM-1 - VCAM-1 - NO - Microalbuminuria - PAI-1 (D. Sargowo) - Ox LDL – MDA – F2 - Isoprostane - LP – PLA2 - Lyso-PC OxFA BIOCHEMICAL PARAMETER FOR ENDOTHELIAL DYSFUNCTION - vWF - Thrombomodulin - E-Selection - NO - Microalbuminuria - PAI-1 - Ox LDL – MDA – F2 - Isoprostane - LP – PLA2 - Lyso-PC OxFA 47 INFLAMMATORY MARKERS FOR CONSIDERATION AS PREDICTORS OF CARDIOVASCULAR RISK Adhesion molecules Cytokines Acute-phase reactants Fibrinogen SAA CRP WBC count Other (eg, erytrocyte sedimentation rate) (Pearson et al, 2003) 48 SURREGATE BIOMARKERS FOR ACS HS CRP MMP Stromelysin Kalogenase Elastase INFj, TNF, IL1 Gelatinase LDH CPK MBCK Troponin T-I Fibrinogen Albuminuri D. Sargowo 49 Rudolf Virchow Inflammation-based arterial changes as a mechanism of primary importance in atherogenesis mid 19th century Lamond, B. The American Journal of Pathology. 2008 SUMMARY 50
Slide 51 - 1 Nama : Prof. Dr. H. Djanggan Sargowo, dr., SpPD., SpJP(K), FIHA, FACC, FESC, FCAPC, FASCC Tempat/Tgl lahir : Sragen, 21 September 1947 Alamat : Wilis Indah E-10 Malang, Telp. 0341-552395 Pendidikan : Lulus Dokter dari UGM, tahun 1974 Lulus Cardiologist dari Univ. Indonesia, tahun 1983 Lulus Internist dari Univ. Airlangga, tahun 1986 Lulus Doktor, Univ. Airlangga, tahun 1996 Advanced Cardiology Course, Univ. Hongkong, tahun 1984 Senior Visiting Program, Institut Jantung Negara, Kualalumpur, 1996 Fellow American College of Cardiology (FACC), September 2006. Fellow Collage Asia Pacific Society of Cardiology (FCAPC), Desember 2007 Fellow European Sociaty of Cardiology (FESC), 2008 Fellow Asean Collage of Cardiology (FASCC), 2008 Jabatan : Dosen Pengajar Program Pascasarjana Universitas Brawijaya Ketua MKEK Ikatan Dokter Indonesia Cabang Malang Raya Ketua PERKI Cabang Malang Raya Anggota Kolegium Kardiovaskuler Indonesia Dekan Fak. Kedokteran Univ. Wijaya Kusuma Surabaya Ketua Dewan Pengawas Rumah Sakit Pendidikan Ketua Program Studi Kardiovascular Fak. Kedokteran Univ. Brawijaya Curriculum Vitae 2 Djanggan Sargowo Surabaya, 15 April 2012 INFLAMMATION IN ATHEROSCLEROSIS : FROM BENCH TO BEDSIDE 3 4 RUDOLF VIRCHOW Inflammation-based arterial changes as a mechanism of primary importance in atherogenesis mid 19th century Lamond, B. The American Journal of Pathology. 2008 5 Atherosclerosis Start from very young To Old age ? 6 Atherothrombosis* is aLeading Cause of Death Worldwide1† The World Health Report, 2002, WHO Geneva, 2002 28.7 17.8 12.6 9.1 6 5.1 0 5 10 15 20 25 30 Atherothrombosis* Infectious disease Cancer Injuries Pulmonary disease AIDS Mortality (%) * Ischemic heart disease, cerebrovascular disease, inflammatory heart disease and hypertensive heart disease † Worldwide defined as Member States by WHO Region (Africa, Americas, Eastern Mediterranean, European, South-East Asia and Western Pacific) 7 MAJOR CLINICAL MANIFESTATIONS OF ATHEROTHROMBOSIS Adapted from: Drouet L. Cerebrovasc Dis 2002; 13(suppl 1): 1–6. Transient ischemic attack Angina: Stable Unstable Ischemic stroke Myocardial infarction Peripheral arterial disease: Intermittent claudication Rest Pain Gangrene Necrosis 8  Dyslipidemia  Endothelial dysfunction  Free radicals  Immunologic Atherosclerosis/CAD THEORY AND CONCEPT OF ATHEROSCLEROSIS Inflamation (Sargowo, 1996) 9 Free Radical ATHEROGENESIS (Sargowo, 1996) 10 IDENTIFYING THOSE AT RISK OF ATHEROTHROMBOSIS Yusuf S et al. Circulation 2001; 104: 2746–53. 2. Drouet L. Cerebrovasc Dis 2002;13(suppl 1):1–6. Lifestyle Smoking Diet Lack of exercise Genetic Genetic traits Gender Age Generalized disorders Obesity Diabetes Systemic conditions History of vascular events Hypertension Hyperlipidemia Hypercoagulable states Homocystinemia Local factors Elevated prothrombotic factors: fibrinogen, CRP, PAI-1 Blood flow patterns, vessel diameter, arterial wall structure Atherothrombosis manifestations (myocardial infarction, stroke, vascular death) 11 Arici. 2010 Risk Factors for Atherosclerosis Classic Hypertension, Hyper-lipidemia, DM, Smoking Uremia Related Increase ox-LDL, Free radicals, Uremic toxin Infection Bacterial and viral infection Proinflammatory cytokine release Endothelial dysfunction Systemic inflammatory respones Acute phase response Elevated CRP Binding LDL, cemplement activation, tissue factor secretion Accelerated ATHEROSCLEROSIS 12 LDL CD40L=CD40 ligand; TNF-α=tumor necrosis factor-alpha; IL=interleukin; VCAM=vascular cell adhesion molecule; ICAM=intercellular adhesion molecule. Cockerill GW et al. Arterioscler Thromb Vasc Biol. 1995;15:1987-1994; Andre P et al. Circulation. 2002;106:896-899; Libby P. Circulation. 2001;104:365-372; Libby P et al. Circulation. 2002;105:1135-1143; Ross R. N Engl J Med. 1999;340:115-126. Vessel lumen Monocyte Macrophage Adhesionmolecules (VCAM-1, ICAM-1) Inflammatory mediators (CRP, CD40/CD40L, TNF-α, IL-1, IL-6) Intima Foam cell INFLAMMATION PROMOTES PROGRESSION OF ATHEROSCLEROSIS Endothelium LDL Ox-LDL 13 14 Atherosclerosis is a fibroproliferative and inflammatory process occurring ins response to a variety of vascular insults The insults come from classical risk factors ( HT, dyslipidemia, endothelial dysfunction, smoking, menopause, diabetes etc) and novel risk factors (Hcy, LVH, Lp(a), TG, oxidative stress, fibrinogen etc) Endothelial dysfunction is regarded as the first abnormality leading to atherosclerosis This implies that modulation of endothelial function may be used as strategy to intervene the process. 15 Two theories gain more acceptance: (a) the lipid theory (b) inflammation theory Endothelial dysfunction is now regarded as the first abnormality leading to AS. More novel cardiovascular risk factors are known, e.g.: Fibrinogen b. PAI-1 Homocysteins d. AT-1 e. CRP f. Lp(a) g. small-dense LDL h. infectious agents i. and more are emerging 16 Acute Coronary Syndrome (endocrine viewpoints) atherosclerotic lesions vascular funtions b.1. inflammatory reaction b.2. thrombogeneity b.3. vasoreactivity b.4. plaque stability b.5. shoulder of plaque endothelium balance between c.1. vasodilating, antithrombotic, antiproliferative factors (NO, prostacyclin, C-natriuretic peptide, EDHF) c.2. vasoconstricting, prothrombotic, proliferative factors (ET, superoxide, thromoboxan A2) 17 NATURAL HISTORY OF CORONARY ATHEROSCLEROSIS Chatzizisis et all. JACC. 2007. Asymtomatic Stable Angina Acute Coronary Syndrome Early fibroatheroma Compensatory expansive remodeling Quiescent plaque Contrictive remodeling Stenotic plaque Exessive expansive remodeling Thin cap fibroatheroma Erosion Physiologic coronary artery Local factors, e.g. low ESS Systemic factors, e.g. hyperlipidemia Genetic factors Physiologic ESS Limited inflammation Fibroproliferation Microruptures 18 ATHEROSCLEROSIS IS AN INFLAMMATORY DISEASE Libby P. Circulation. 2001;104:365-372; Ross R. N Engl J Med. 1999;340:115-126. Monocyte LDL-C Adhesion molecule Macrophage Foam cell OxidizedLDL-C Plaque rupture Smooth muscle cells CRP Plaque instability and thrombus Oxidation Inflammation Endothelial dysfunction 19 20 Reverse Cholesterol Transport Monocyte CRP TXA2 PGI2 Thrombin LDL Platelets HDL HDL Ox-LDL MCP-1 Macrophage P-selectin CD 40L PDGF Foam cell MMP T cell E-selectins CD 40L VCAM-1 ICAM-1 IL-1 Reilly, et.all. 2005 21 THE ROLE OF Lp-PLA2 IN CHD LUMEN Monocytes Adhesion Molecules Oxidated LDL INTIMA MEDIA Lp-PLA2 Lyso-PC OxFA Cytokines Plaque Formation Foam Cell Macrophage 22 MC T T FC FC LDL Oxidation Lyso-PC Ox-chol Cytokines Cytokines ? C5a C’ MCP-1 F SMC 23 Intracelluler proteolysis and fusion of LDL Figure : Proposed Dual Action of Exocytosed Mast Cell Granules (The Granule Remnants) of Lipoprotein Metabolism in The Arterial Intima 24 HSCRP 25 26 GM-CSF VCAM-1 MPC-1 Transcription Factors : Endothelial Cell Pro-inflammatory Genes Oxidative Stress NF-xB AP-1 Leucocyte infiltration / activation Plaque Rupture Gibbons, 97 LEUCOCYTE ACTIVATION IN ATHEROGENESIS : IMPLICATIONS FOR ACUTE ISCHEMIC SYNDROMES 27 p38 c-Jun activation Caspases Apoptosis NIK ? ? MEKK1?   CKII IKK complex TNFR-1 TNFR-1 IL-1R Shear stress p65 p50 CBP/p300 Gene activation p65 p50 IB pKAc IB Ub Target genes : - IL-1, IL-8, IL-6, IFN  - TNF, MCP-1 - CSFs, c-myc - VCAM-1, ICAM-1, E-selectin - Tissue factor - Survival factor Thurberg and Collins : Curr Opin Lipidol 9:387-396,1998 Ub Ox-LDL ROIs ??? Lipid peroxides ? H2O2 Ubiquitination and proteosome degradation T R A D D R I P F A D D R I P T R A D D T R A F 2 T R A F 6 28 Visual Medica. 2009 29 Stockley. 2006 Cytokines : IL-6, TNF-α MACROPHAGE FOAM CELL Oxidized LDL CRP CRP Chemokines: MCO-1 Atherosclerotic plaque MONOCYTE Inflammatory Mediators: CRP Prothrombotic factors FCR Receptor 30 POTENTIAL MECHANISM OF CRP Stevens, R. 2005 CRP LDL opsonisation Monocyte infiltration Foam cell formation Increased MCP-1 and CAM EC activation Inflammatory cell recruitment Atherosclerosis plaque formation Complement activation EC sensitisation T-cell attack EC damage Atherosclerotic plaque rupture 31 Rheumatoid arthritis Atherosclerosis Multiple sclerosis Asthma Inflammatory bowel disease Helicobacter pylori-associated gastritis Systemic inflammatory response syndrome NF-KB ACTIVATION INFLAMMATORY DISEASE The Journal of Clinical Investigation, 2001 32 PROTEIN REGULATED BY NF-KB Inflammatory Enzyme Adhesion Molecule Inducible nitric oxide synthase Inducide cylooxigenase-2 5-Lipoxigenase Cytosolic phospolipase A2 ICAM-1 VCAM-1 E-selectin Receptor Interlekin-2 receptor (alpha chain) T-cell receptors (beta chain) NEJM, 1997 33 BIOMARKERS OF ACTIVITY STUDIED FOR CAD Cytokines (IL-1β, IL-6, IL-8, IL-10, TNF-α, sCD40 ligand, myeloperoxidase) Adhesion molecules (sICAM-1, sVCAM-1, p-selectin) Acute phase reactans (fibrinogen, AAS, CRP) White blood cells Erythrocyte sedimentation rate Neopterin Heat shock proteins Adiponectin Lipoprotein associated phospholipase A2 Placental growth factos Cystatin C Kaski, JC. 2006. 34 Are you hungry or sleepy ???? Sciences 35 The inflammatory cascade. IL indicates interleukin; ICAM, intercellular adhesion molecule; and HSP, heat shock protein. (Libby, Ridker; 1999) Pro-Inflammatory Risk Factors Primary Pro-Inflammatory Cytokines (eg. IL-1, TNF-) IL-6 “Mesenger” Cytokine CRP SAA Endothelium and other cells LIVER Circulation 36 (Ridker, 2004) MORE THAN A MARKER : DOES CRP PLAY A DIRECT ROLE IN ATHEROTHROMBOSIS ? CRP localizes in atherosclerotic but not normal intima CRP induced Complement activation CRP dependent monocyte recruitment into arterial wall CRP induced production of tissue factor in monocytes CRP based blunting of endothelial vasoreactivity CRP mediated LDL uptake by macrophages CRP triggered oxidation of LDL cholesterol CRP induced PAI-1 expression stabilizes PAI-1 mRNA CRP attenuates NO production and decreases eNOS expression CRP induced production of cell adhesion moleculas MCP-1, ET-1 37 ROLE OF INFLAMATORY MARKERS Interleukin-6 Total cholesterol LDL-cholesterol siCAM-1 Serum amyloid A Apolipoprotein B Total cholesterol: HDL-cholesterol Hs-CRP Hs-CRP + total cholesterol: HDL-cholesterol 0 1.0 2.0 4.0 6.0 Relative Risk (New England Journal of Medicine) 38 39 Weissberg, 1999 Inflammation Repair 40 REDOX REGULATION OF ENDOTHELIAL DYSFUNCTION & ACTIVATION O2– OH H2O2  NO Activity  G-Protein Function  Protein Kinase C Oxidation Endothelial Dysfunction (D. Sargowo) 41 ENDOTHELIAL DYSFUNCTION AND ACUTE CORONARY SYNDROMES Vasoconstriction Platelet Aggregation SMC Proliferation Leukocyte Adhesion LDL Oxidation Activation of MMPs Endothelial Dysfunction Plaque Rupture Thrombosis Matrix Remodeling (D. Sargowo) 42 ENDOTHELIAL DYSFUNCTION AND ACUTE CORONARY SYNDROMES Vasospasm Plaque Rupture Thrombosis Matrix Remodeling ACUTE CORONARY SYNDROMES (D. Sargowo) 43 44 Diabetes Smoking AII Oxidative Stress Endothelial Dysfunction and Smooth Muscle Activation Growth FactorsCytokinesMatrix Proteolysis Inflammation VCAM/1CAMCytokines EndothelinCatecholamines BP LDL  NO • ∆ Local Mediators •  Tissue ACE, AII PAI-1, Platelet Aggregation, Tissue Factor Vasoconstriction Thrombosis Inflammation Plaque Rupture Vascular Lesion and Remodeling Clinical Sequelae Risk Factors Reprinted with permission from Dzau VJ. Hypertension. 2001;37:1047–1052. 45 THERAPEUTICS : WHERE DO WE STAND TODAY ? Lipid lowering drugs ACEI / ARB Peroxisome proliferators-activated receptor (PPAR) Chemokine receptor antagonist TNF Inhibitor MMP Inhibitor 46 BIOCHEMICAL PARAMETER FOR ENDOTHELIAL DYSFUNCTION - vWF - Thrombomodulin - E-Selection - ICAM-1 - VCAM-1 - NO - Microalbuminuria - PAI-1 (D. Sargowo) - Ox LDL – MDA – F2 - Isoprostane - LP – PLA2 - Lyso-PC OxFA BIOCHEMICAL PARAMETER FOR ENDOTHELIAL DYSFUNCTION - vWF - Thrombomodulin - E-Selection - NO - Microalbuminuria - PAI-1 - Ox LDL – MDA – F2 - Isoprostane - LP – PLA2 - Lyso-PC OxFA 47 INFLAMMATORY MARKERS FOR CONSIDERATION AS PREDICTORS OF CARDIOVASCULAR RISK Adhesion molecules Cytokines Acute-phase reactants Fibrinogen SAA CRP WBC count Other (eg, erytrocyte sedimentation rate) (Pearson et al, 2003) 48 SURREGATE BIOMARKERS FOR ACS HS CRP MMP Stromelysin Kalogenase Elastase INFj, TNF, IL1 Gelatinase LDH CPK MBCK Troponin T-I Fibrinogen Albuminuri D. Sargowo 49 Rudolf Virchow Inflammation-based arterial changes as a mechanism of primary importance in atherogenesis mid 19th century Lamond, B. The American Journal of Pathology. 2008 SUMMARY 50 51 Thank You
Slide 52 - 1 Nama : Prof. Dr. H. Djanggan Sargowo, dr., SpPD., SpJP(K), FIHA, FACC, FESC, FCAPC, FASCC Tempat/Tgl lahir : Sragen, 21 September 1947 Alamat : Wilis Indah E-10 Malang, Telp. 0341-552395 Pendidikan : Lulus Dokter dari UGM, tahun 1974 Lulus Cardiologist dari Univ. Indonesia, tahun 1983 Lulus Internist dari Univ. Airlangga, tahun 1986 Lulus Doktor, Univ. Airlangga, tahun 1996 Advanced Cardiology Course, Univ. Hongkong, tahun 1984 Senior Visiting Program, Institut Jantung Negara, Kualalumpur, 1996 Fellow American College of Cardiology (FACC), September 2006. Fellow Collage Asia Pacific Society of Cardiology (FCAPC), Desember 2007 Fellow European Sociaty of Cardiology (FESC), 2008 Fellow Asean Collage of Cardiology (FASCC), 2008 Jabatan : Dosen Pengajar Program Pascasarjana Universitas Brawijaya Ketua MKEK Ikatan Dokter Indonesia Cabang Malang Raya Ketua PERKI Cabang Malang Raya Anggota Kolegium Kardiovaskuler Indonesia Dekan Fak. Kedokteran Univ. Wijaya Kusuma Surabaya Ketua Dewan Pengawas Rumah Sakit Pendidikan Ketua Program Studi Kardiovascular Fak. Kedokteran Univ. Brawijaya Curriculum Vitae 2 Djanggan Sargowo Surabaya, 15 April 2012 INFLAMMATION IN ATHEROSCLEROSIS : FROM BENCH TO BEDSIDE 3 4 RUDOLF VIRCHOW Inflammation-based arterial changes as a mechanism of primary importance in atherogenesis mid 19th century Lamond, B. The American Journal of Pathology. 2008 5 Atherosclerosis Start from very young To Old age ? 6 Atherothrombosis* is aLeading Cause of Death Worldwide1† The World Health Report, 2002, WHO Geneva, 2002 28.7 17.8 12.6 9.1 6 5.1 0 5 10 15 20 25 30 Atherothrombosis* Infectious disease Cancer Injuries Pulmonary disease AIDS Mortality (%) * Ischemic heart disease, cerebrovascular disease, inflammatory heart disease and hypertensive heart disease † Worldwide defined as Member States by WHO Region (Africa, Americas, Eastern Mediterranean, European, South-East Asia and Western Pacific) 7 MAJOR CLINICAL MANIFESTATIONS OF ATHEROTHROMBOSIS Adapted from: Drouet L. Cerebrovasc Dis 2002; 13(suppl 1): 1–6. Transient ischemic attack Angina: Stable Unstable Ischemic stroke Myocardial infarction Peripheral arterial disease: Intermittent claudication Rest Pain Gangrene Necrosis 8  Dyslipidemia  Endothelial dysfunction  Free radicals  Immunologic Atherosclerosis/CAD THEORY AND CONCEPT OF ATHEROSCLEROSIS Inflamation (Sargowo, 1996) 9 Free Radical ATHEROGENESIS (Sargowo, 1996) 10 IDENTIFYING THOSE AT RISK OF ATHEROTHROMBOSIS Yusuf S et al. Circulation 2001; 104: 2746–53. 2. Drouet L. Cerebrovasc Dis 2002;13(suppl 1):1–6. Lifestyle Smoking Diet Lack of exercise Genetic Genetic traits Gender Age Generalized disorders Obesity Diabetes Systemic conditions History of vascular events Hypertension Hyperlipidemia Hypercoagulable states Homocystinemia Local factors Elevated prothrombotic factors: fibrinogen, CRP, PAI-1 Blood flow patterns, vessel diameter, arterial wall structure Atherothrombosis manifestations (myocardial infarction, stroke, vascular death) 11 Arici. 2010 Risk Factors for Atherosclerosis Classic Hypertension, Hyper-lipidemia, DM, Smoking Uremia Related Increase ox-LDL, Free radicals, Uremic toxin Infection Bacterial and viral infection Proinflammatory cytokine release Endothelial dysfunction Systemic inflammatory respones Acute phase response Elevated CRP Binding LDL, cemplement activation, tissue factor secretion Accelerated ATHEROSCLEROSIS 12 LDL CD40L=CD40 ligand; TNF-α=tumor necrosis factor-alpha; IL=interleukin; VCAM=vascular cell adhesion molecule; ICAM=intercellular adhesion molecule. Cockerill GW et al. Arterioscler Thromb Vasc Biol. 1995;15:1987-1994; Andre P et al. Circulation. 2002;106:896-899; Libby P. Circulation. 2001;104:365-372; Libby P et al. Circulation. 2002;105:1135-1143; Ross R. N Engl J Med. 1999;340:115-126. Vessel lumen Monocyte Macrophage Adhesionmolecules (VCAM-1, ICAM-1) Inflammatory mediators (CRP, CD40/CD40L, TNF-α, IL-1, IL-6) Intima Foam cell INFLAMMATION PROMOTES PROGRESSION OF ATHEROSCLEROSIS Endothelium LDL Ox-LDL 13 14 Atherosclerosis is a fibroproliferative and inflammatory process occurring ins response to a variety of vascular insults The insults come from classical risk factors ( HT, dyslipidemia, endothelial dysfunction, smoking, menopause, diabetes etc) and novel risk factors (Hcy, LVH, Lp(a), TG, oxidative stress, fibrinogen etc) Endothelial dysfunction is regarded as the first abnormality leading to atherosclerosis This implies that modulation of endothelial function may be used as strategy to intervene the process. 15 Two theories gain more acceptance: (a) the lipid theory (b) inflammation theory Endothelial dysfunction is now regarded as the first abnormality leading to AS. More novel cardiovascular risk factors are known, e.g.: Fibrinogen b. PAI-1 Homocysteins d. AT-1 e. CRP f. Lp(a) g. small-dense LDL h. infectious agents i. and more are emerging 16 Acute Coronary Syndrome (endocrine viewpoints) atherosclerotic lesions vascular funtions b.1. inflammatory reaction b.2. thrombogeneity b.3. vasoreactivity b.4. plaque stability b.5. shoulder of plaque endothelium balance between c.1. vasodilating, antithrombotic, antiproliferative factors (NO, prostacyclin, C-natriuretic peptide, EDHF) c.2. vasoconstricting, prothrombotic, proliferative factors (ET, superoxide, thromoboxan A2) 17 NATURAL HISTORY OF CORONARY ATHEROSCLEROSIS Chatzizisis et all. JACC. 2007. Asymtomatic Stable Angina Acute Coronary Syndrome Early fibroatheroma Compensatory expansive remodeling Quiescent plaque Contrictive remodeling Stenotic plaque Exessive expansive remodeling Thin cap fibroatheroma Erosion Physiologic coronary artery Local factors, e.g. low ESS Systemic factors, e.g. hyperlipidemia Genetic factors Physiologic ESS Limited inflammation Fibroproliferation Microruptures 18 ATHEROSCLEROSIS IS AN INFLAMMATORY DISEASE Libby P. Circulation. 2001;104:365-372; Ross R. N Engl J Med. 1999;340:115-126. Monocyte LDL-C Adhesion molecule Macrophage Foam cell OxidizedLDL-C Plaque rupture Smooth muscle cells CRP Plaque instability and thrombus Oxidation Inflammation Endothelial dysfunction 19 20 Reverse Cholesterol Transport Monocyte CRP TXA2 PGI2 Thrombin LDL Platelets HDL HDL Ox-LDL MCP-1 Macrophage P-selectin CD 40L PDGF Foam cell MMP T cell E-selectins CD 40L VCAM-1 ICAM-1 IL-1 Reilly, et.all. 2005 21 THE ROLE OF Lp-PLA2 IN CHD LUMEN Monocytes Adhesion Molecules Oxidated LDL INTIMA MEDIA Lp-PLA2 Lyso-PC OxFA Cytokines Plaque Formation Foam Cell Macrophage 22 MC T T FC FC LDL Oxidation Lyso-PC Ox-chol Cytokines Cytokines ? C5a C’ MCP-1 F SMC 23 Intracelluler proteolysis and fusion of LDL Figure : Proposed Dual Action of Exocytosed Mast Cell Granules (The Granule Remnants) of Lipoprotein Metabolism in The Arterial Intima 24 HSCRP 25 26 GM-CSF VCAM-1 MPC-1 Transcription Factors : Endothelial Cell Pro-inflammatory Genes Oxidative Stress NF-xB AP-1 Leucocyte infiltration / activation Plaque Rupture Gibbons, 97 LEUCOCYTE ACTIVATION IN ATHEROGENESIS : IMPLICATIONS FOR ACUTE ISCHEMIC SYNDROMES 27 p38 c-Jun activation Caspases Apoptosis NIK ? ? MEKK1?   CKII IKK complex TNFR-1 TNFR-1 IL-1R Shear stress p65 p50 CBP/p300 Gene activation p65 p50 IB pKAc IB Ub Target genes : - IL-1, IL-8, IL-6, IFN  - TNF, MCP-1 - CSFs, c-myc - VCAM-1, ICAM-1, E-selectin - Tissue factor - Survival factor Thurberg and Collins : Curr Opin Lipidol 9:387-396,1998 Ub Ox-LDL ROIs ??? Lipid peroxides ? H2O2 Ubiquitination and proteosome degradation T R A D D R I P F A D D R I P T R A D D T R A F 2 T R A F 6 28 Visual Medica. 2009 29 Stockley. 2006 Cytokines : IL-6, TNF-α MACROPHAGE FOAM CELL Oxidized LDL CRP CRP Chemokines: MCO-1 Atherosclerotic plaque MONOCYTE Inflammatory Mediators: CRP Prothrombotic factors FCR Receptor 30 POTENTIAL MECHANISM OF CRP Stevens, R. 2005 CRP LDL opsonisation Monocyte infiltration Foam cell formation Increased MCP-1 and CAM EC activation Inflammatory cell recruitment Atherosclerosis plaque formation Complement activation EC sensitisation T-cell attack EC damage Atherosclerotic plaque rupture 31 Rheumatoid arthritis Atherosclerosis Multiple sclerosis Asthma Inflammatory bowel disease Helicobacter pylori-associated gastritis Systemic inflammatory response syndrome NF-KB ACTIVATION INFLAMMATORY DISEASE The Journal of Clinical Investigation, 2001 32 PROTEIN REGULATED BY NF-KB Inflammatory Enzyme Adhesion Molecule Inducible nitric oxide synthase Inducide cylooxigenase-2 5-Lipoxigenase Cytosolic phospolipase A2 ICAM-1 VCAM-1 E-selectin Receptor Interlekin-2 receptor (alpha chain) T-cell receptors (beta chain) NEJM, 1997 33 BIOMARKERS OF ACTIVITY STUDIED FOR CAD Cytokines (IL-1β, IL-6, IL-8, IL-10, TNF-α, sCD40 ligand, myeloperoxidase) Adhesion molecules (sICAM-1, sVCAM-1, p-selectin) Acute phase reactans (fibrinogen, AAS, CRP) White blood cells Erythrocyte sedimentation rate Neopterin Heat shock proteins Adiponectin Lipoprotein associated phospholipase A2 Placental growth factos Cystatin C Kaski, JC. 2006. 34 Are you hungry or sleepy ???? Sciences 35 The inflammatory cascade. IL indicates interleukin; ICAM, intercellular adhesion molecule; and HSP, heat shock protein. (Libby, Ridker; 1999) Pro-Inflammatory Risk Factors Primary Pro-Inflammatory Cytokines (eg. IL-1, TNF-) IL-6 “Mesenger” Cytokine CRP SAA Endothelium and other cells LIVER Circulation 36 (Ridker, 2004) MORE THAN A MARKER : DOES CRP PLAY A DIRECT ROLE IN ATHEROTHROMBOSIS ? CRP localizes in atherosclerotic but not normal intima CRP induced Complement activation CRP dependent monocyte recruitment into arterial wall CRP induced production of tissue factor in monocytes CRP based blunting of endothelial vasoreactivity CRP mediated LDL uptake by macrophages CRP triggered oxidation of LDL cholesterol CRP induced PAI-1 expression stabilizes PAI-1 mRNA CRP attenuates NO production and decreases eNOS expression CRP induced production of cell adhesion moleculas MCP-1, ET-1 37 ROLE OF INFLAMATORY MARKERS Interleukin-6 Total cholesterol LDL-cholesterol siCAM-1 Serum amyloid A Apolipoprotein B Total cholesterol: HDL-cholesterol Hs-CRP Hs-CRP + total cholesterol: HDL-cholesterol 0 1.0 2.0 4.0 6.0 Relative Risk (New England Journal of Medicine) 38 39 Weissberg, 1999 Inflammation Repair 40 REDOX REGULATION OF ENDOTHELIAL DYSFUNCTION & ACTIVATION O2– OH H2O2  NO Activity  G-Protein Function  Protein Kinase C Oxidation Endothelial Dysfunction (D. Sargowo) 41 ENDOTHELIAL DYSFUNCTION AND ACUTE CORONARY SYNDROMES Vasoconstriction Platelet Aggregation SMC Proliferation Leukocyte Adhesion LDL Oxidation Activation of MMPs Endothelial Dysfunction Plaque Rupture Thrombosis Matrix Remodeling (D. Sargowo) 42 ENDOTHELIAL DYSFUNCTION AND ACUTE CORONARY SYNDROMES Vasospasm Plaque Rupture Thrombosis Matrix Remodeling ACUTE CORONARY SYNDROMES (D. Sargowo) 43 44 Diabetes Smoking AII Oxidative Stress Endothelial Dysfunction and Smooth Muscle Activation Growth FactorsCytokinesMatrix Proteolysis Inflammation VCAM/1CAMCytokines EndothelinCatecholamines BP LDL  NO • ∆ Local Mediators •  Tissue ACE, AII PAI-1, Platelet Aggregation, Tissue Factor Vasoconstriction Thrombosis Inflammation Plaque Rupture Vascular Lesion and Remodeling Clinical Sequelae Risk Factors Reprinted with permission from Dzau VJ. Hypertension. 2001;37:1047–1052. 45 THERAPEUTICS : WHERE DO WE STAND TODAY ? Lipid lowering drugs ACEI / ARB Peroxisome proliferators-activated receptor (PPAR) Chemokine receptor antagonist TNF Inhibitor MMP Inhibitor 46 BIOCHEMICAL PARAMETER FOR ENDOTHELIAL DYSFUNCTION - vWF - Thrombomodulin - E-Selection - ICAM-1 - VCAM-1 - NO - Microalbuminuria - PAI-1 (D. Sargowo) - Ox LDL – MDA – F2 - Isoprostane - LP – PLA2 - Lyso-PC OxFA BIOCHEMICAL PARAMETER FOR ENDOTHELIAL DYSFUNCTION - vWF - Thrombomodulin - E-Selection - NO - Microalbuminuria - PAI-1 - Ox LDL – MDA – F2 - Isoprostane - LP – PLA2 - Lyso-PC OxFA 47 INFLAMMATORY MARKERS FOR CONSIDERATION AS PREDICTORS OF CARDIOVASCULAR RISK Adhesion molecules Cytokines Acute-phase reactants Fibrinogen SAA CRP WBC count Other (eg, erytrocyte sedimentation rate) (Pearson et al, 2003) 48 SURREGATE BIOMARKERS FOR ACS HS CRP MMP Stromelysin Kalogenase Elastase INFj, TNF, IL1 Gelatinase LDH CPK MBCK Troponin T-I Fibrinogen Albuminuri D. Sargowo 49 Rudolf Virchow Inflammation-based arterial changes as a mechanism of primary importance in atherogenesis mid 19th century Lamond, B. The American Journal of Pathology. 2008 SUMMARY 50 51 Thank You 52 The Role of Lp-PLA2 in CHD LUMEN Monocytes Adhesion Molecules Oxidated LDL INTIMA MEDIA Lp-PLA2 Lyso-PC OxFA Cytokines Plaque Formation Foam Cell Macrophage
Slide 53 - 1 Nama : Prof. Dr. H. Djanggan Sargowo, dr., SpPD., SpJP(K), FIHA, FACC, FESC, FCAPC, FASCC Tempat/Tgl lahir : Sragen, 21 September 1947 Alamat : Wilis Indah E-10 Malang, Telp. 0341-552395 Pendidikan : Lulus Dokter dari UGM, tahun 1974 Lulus Cardiologist dari Univ. Indonesia, tahun 1983 Lulus Internist dari Univ. Airlangga, tahun 1986 Lulus Doktor, Univ. Airlangga, tahun 1996 Advanced Cardiology Course, Univ. Hongkong, tahun 1984 Senior Visiting Program, Institut Jantung Negara, Kualalumpur, 1996 Fellow American College of Cardiology (FACC), September 2006. Fellow Collage Asia Pacific Society of Cardiology (FCAPC), Desember 2007 Fellow European Sociaty of Cardiology (FESC), 2008 Fellow Asean Collage of Cardiology (FASCC), 2008 Jabatan : Dosen Pengajar Program Pascasarjana Universitas Brawijaya Ketua MKEK Ikatan Dokter Indonesia Cabang Malang Raya Ketua PERKI Cabang Malang Raya Anggota Kolegium Kardiovaskuler Indonesia Dekan Fak. Kedokteran Univ. Wijaya Kusuma Surabaya Ketua Dewan Pengawas Rumah Sakit Pendidikan Ketua Program Studi Kardiovascular Fak. Kedokteran Univ. Brawijaya Curriculum Vitae 2 Djanggan Sargowo Surabaya, 15 April 2012 INFLAMMATION IN ATHEROSCLEROSIS : FROM BENCH TO BEDSIDE 3 4 RUDOLF VIRCHOW Inflammation-based arterial changes as a mechanism of primary importance in atherogenesis mid 19th century Lamond, B. The American Journal of Pathology. 2008 5 Atherosclerosis Start from very young To Old age ? 6 Atherothrombosis* is aLeading Cause of Death Worldwide1† The World Health Report, 2002, WHO Geneva, 2002 28.7 17.8 12.6 9.1 6 5.1 0 5 10 15 20 25 30 Atherothrombosis* Infectious disease Cancer Injuries Pulmonary disease AIDS Mortality (%) * Ischemic heart disease, cerebrovascular disease, inflammatory heart disease and hypertensive heart disease † Worldwide defined as Member States by WHO Region (Africa, Americas, Eastern Mediterranean, European, South-East Asia and Western Pacific) 7 MAJOR CLINICAL MANIFESTATIONS OF ATHEROTHROMBOSIS Adapted from: Drouet L. Cerebrovasc Dis 2002; 13(suppl 1): 1–6. Transient ischemic attack Angina: Stable Unstable Ischemic stroke Myocardial infarction Peripheral arterial disease: Intermittent claudication Rest Pain Gangrene Necrosis 8  Dyslipidemia  Endothelial dysfunction  Free radicals  Immunologic Atherosclerosis/CAD THEORY AND CONCEPT OF ATHEROSCLEROSIS Inflamation (Sargowo, 1996) 9 Free Radical ATHEROGENESIS (Sargowo, 1996) 10 IDENTIFYING THOSE AT RISK OF ATHEROTHROMBOSIS Yusuf S et al. Circulation 2001; 104: 2746–53. 2. Drouet L. Cerebrovasc Dis 2002;13(suppl 1):1–6. Lifestyle Smoking Diet Lack of exercise Genetic Genetic traits Gender Age Generalized disorders Obesity Diabetes Systemic conditions History of vascular events Hypertension Hyperlipidemia Hypercoagulable states Homocystinemia Local factors Elevated prothrombotic factors: fibrinogen, CRP, PAI-1 Blood flow patterns, vessel diameter, arterial wall structure Atherothrombosis manifestations (myocardial infarction, stroke, vascular death) 11 Arici. 2010 Risk Factors for Atherosclerosis Classic Hypertension, Hyper-lipidemia, DM, Smoking Uremia Related Increase ox-LDL, Free radicals, Uremic toxin Infection Bacterial and viral infection Proinflammatory cytokine release Endothelial dysfunction Systemic inflammatory respones Acute phase response Elevated CRP Binding LDL, cemplement activation, tissue factor secretion Accelerated ATHEROSCLEROSIS 12 LDL CD40L=CD40 ligand; TNF-α=tumor necrosis factor-alpha; IL=interleukin; VCAM=vascular cell adhesion molecule; ICAM=intercellular adhesion molecule. Cockerill GW et al. Arterioscler Thromb Vasc Biol. 1995;15:1987-1994; Andre P et al. Circulation. 2002;106:896-899; Libby P. Circulation. 2001;104:365-372; Libby P et al. Circulation. 2002;105:1135-1143; Ross R. N Engl J Med. 1999;340:115-126. Vessel lumen Monocyte Macrophage Adhesionmolecules (VCAM-1, ICAM-1) Inflammatory mediators (CRP, CD40/CD40L, TNF-α, IL-1, IL-6) Intima Foam cell INFLAMMATION PROMOTES PROGRESSION OF ATHEROSCLEROSIS Endothelium LDL Ox-LDL 13 14 Atherosclerosis is a fibroproliferative and inflammatory process occurring ins response to a variety of vascular insults The insults come from classical risk factors ( HT, dyslipidemia, endothelial dysfunction, smoking, menopause, diabetes etc) and novel risk factors (Hcy, LVH, Lp(a), TG, oxidative stress, fibrinogen etc) Endothelial dysfunction is regarded as the first abnormality leading to atherosclerosis This implies that modulation of endothelial function may be used as strategy to intervene the process. 15 Two theories gain more acceptance: (a) the lipid theory (b) inflammation theory Endothelial dysfunction is now regarded as the first abnormality leading to AS. More novel cardiovascular risk factors are known, e.g.: Fibrinogen b. PAI-1 Homocysteins d. AT-1 e. CRP f. Lp(a) g. small-dense LDL h. infectious agents i. and more are emerging 16 Acute Coronary Syndrome (endocrine viewpoints) atherosclerotic lesions vascular funtions b.1. inflammatory reaction b.2. thrombogeneity b.3. vasoreactivity b.4. plaque stability b.5. shoulder of plaque endothelium balance between c.1. vasodilating, antithrombotic, antiproliferative factors (NO, prostacyclin, C-natriuretic peptide, EDHF) c.2. vasoconstricting, prothrombotic, proliferative factors (ET, superoxide, thromoboxan A2) 17 NATURAL HISTORY OF CORONARY ATHEROSCLEROSIS Chatzizisis et all. JACC. 2007. Asymtomatic Stable Angina Acute Coronary Syndrome Early fibroatheroma Compensatory expansive remodeling Quiescent plaque Contrictive remodeling Stenotic plaque Exessive expansive remodeling Thin cap fibroatheroma Erosion Physiologic coronary artery Local factors, e.g. low ESS Systemic factors, e.g. hyperlipidemia Genetic factors Physiologic ESS Limited inflammation Fibroproliferation Microruptures 18 ATHEROSCLEROSIS IS AN INFLAMMATORY DISEASE Libby P. Circulation. 2001;104:365-372; Ross R. N Engl J Med. 1999;340:115-126. Monocyte LDL-C Adhesion molecule Macrophage Foam cell OxidizedLDL-C Plaque rupture Smooth muscle cells CRP Plaque instability and thrombus Oxidation Inflammation Endothelial dysfunction 19 20 Reverse Cholesterol Transport Monocyte CRP TXA2 PGI2 Thrombin LDL Platelets HDL HDL Ox-LDL MCP-1 Macrophage P-selectin CD 40L PDGF Foam cell MMP T cell E-selectins CD 40L VCAM-1 ICAM-1 IL-1 Reilly, et.all. 2005 21 THE ROLE OF Lp-PLA2 IN CHD LUMEN Monocytes Adhesion Molecules Oxidated LDL INTIMA MEDIA Lp-PLA2 Lyso-PC OxFA Cytokines Plaque Formation Foam Cell Macrophage 22 MC T T FC FC LDL Oxidation Lyso-PC Ox-chol Cytokines Cytokines ? C5a C’ MCP-1 F SMC 23 Intracelluler proteolysis and fusion of LDL Figure : Proposed Dual Action of Exocytosed Mast Cell Granules (The Granule Remnants) of Lipoprotein Metabolism in The Arterial Intima 24 HSCRP 25 26 GM-CSF VCAM-1 MPC-1 Transcription Factors : Endothelial Cell Pro-inflammatory Genes Oxidative Stress NF-xB AP-1 Leucocyte infiltration / activation Plaque Rupture Gibbons, 97 LEUCOCYTE ACTIVATION IN ATHEROGENESIS : IMPLICATIONS FOR ACUTE ISCHEMIC SYNDROMES 27 p38 c-Jun activation Caspases Apoptosis NIK ? ? MEKK1?   CKII IKK complex TNFR-1 TNFR-1 IL-1R Shear stress p65 p50 CBP/p300 Gene activation p65 p50 IB pKAc IB Ub Target genes : - IL-1, IL-8, IL-6, IFN  - TNF, MCP-1 - CSFs, c-myc - VCAM-1, ICAM-1, E-selectin - Tissue factor - Survival factor Thurberg and Collins : Curr Opin Lipidol 9:387-396,1998 Ub Ox-LDL ROIs ??? Lipid peroxides ? H2O2 Ubiquitination and proteosome degradation T R A D D R I P F A D D R I P T R A D D T R A F 2 T R A F 6 28 Visual Medica. 2009 29 Stockley. 2006 Cytokines : IL-6, TNF-α MACROPHAGE FOAM CELL Oxidized LDL CRP CRP Chemokines: MCO-1 Atherosclerotic plaque MONOCYTE Inflammatory Mediators: CRP Prothrombotic factors FCR Receptor 30 POTENTIAL MECHANISM OF CRP Stevens, R. 2005 CRP LDL opsonisation Monocyte infiltration Foam cell formation Increased MCP-1 and CAM EC activation Inflammatory cell recruitment Atherosclerosis plaque formation Complement activation EC sensitisation T-cell attack EC damage Atherosclerotic plaque rupture 31 Rheumatoid arthritis Atherosclerosis Multiple sclerosis Asthma Inflammatory bowel disease Helicobacter pylori-associated gastritis Systemic inflammatory response syndrome NF-KB ACTIVATION INFLAMMATORY DISEASE The Journal of Clinical Investigation, 2001 32 PROTEIN REGULATED BY NF-KB Inflammatory Enzyme Adhesion Molecule Inducible nitric oxide synthase Inducide cylooxigenase-2 5-Lipoxigenase Cytosolic phospolipase A2 ICAM-1 VCAM-1 E-selectin Receptor Interlekin-2 receptor (alpha chain) T-cell receptors (beta chain) NEJM, 1997 33 BIOMARKERS OF ACTIVITY STUDIED FOR CAD Cytokines (IL-1β, IL-6, IL-8, IL-10, TNF-α, sCD40 ligand, myeloperoxidase) Adhesion molecules (sICAM-1, sVCAM-1, p-selectin) Acute phase reactans (fibrinogen, AAS, CRP) White blood cells Erythrocyte sedimentation rate Neopterin Heat shock proteins Adiponectin Lipoprotein associated phospholipase A2 Placental growth factos Cystatin C Kaski, JC. 2006. 34 Are you hungry or sleepy ???? Sciences 35 The inflammatory cascade. IL indicates interleukin; ICAM, intercellular adhesion molecule; and HSP, heat shock protein. (Libby, Ridker; 1999) Pro-Inflammatory Risk Factors Primary Pro-Inflammatory Cytokines (eg. IL-1, TNF-) IL-6 “Mesenger” Cytokine CRP SAA Endothelium and other cells LIVER Circulation 36 (Ridker, 2004) MORE THAN A MARKER : DOES CRP PLAY A DIRECT ROLE IN ATHEROTHROMBOSIS ? CRP localizes in atherosclerotic but not normal intima CRP induced Complement activation CRP dependent monocyte recruitment into arterial wall CRP induced production of tissue factor in monocytes CRP based blunting of endothelial vasoreactivity CRP mediated LDL uptake by macrophages CRP triggered oxidation of LDL cholesterol CRP induced PAI-1 expression stabilizes PAI-1 mRNA CRP attenuates NO production and decreases eNOS expression CRP induced production of cell adhesion moleculas MCP-1, ET-1 37 ROLE OF INFLAMATORY MARKERS Interleukin-6 Total cholesterol LDL-cholesterol siCAM-1 Serum amyloid A Apolipoprotein B Total cholesterol: HDL-cholesterol Hs-CRP Hs-CRP + total cholesterol: HDL-cholesterol 0 1.0 2.0 4.0 6.0 Relative Risk (New England Journal of Medicine) 38 39 Weissberg, 1999 Inflammation Repair 40 REDOX REGULATION OF ENDOTHELIAL DYSFUNCTION & ACTIVATION O2– OH H2O2  NO Activity  G-Protein Function  Protein Kinase C Oxidation Endothelial Dysfunction (D. Sargowo) 41 ENDOTHELIAL DYSFUNCTION AND ACUTE CORONARY SYNDROMES Vasoconstriction Platelet Aggregation SMC Proliferation Leukocyte Adhesion LDL Oxidation Activation of MMPs Endothelial Dysfunction Plaque Rupture Thrombosis Matrix Remodeling (D. Sargowo) 42 ENDOTHELIAL DYSFUNCTION AND ACUTE CORONARY SYNDROMES Vasospasm Plaque Rupture Thrombosis Matrix Remodeling ACUTE CORONARY SYNDROMES (D. Sargowo) 43 44 Diabetes Smoking AII Oxidative Stress Endothelial Dysfunction and Smooth Muscle Activation Growth FactorsCytokinesMatrix Proteolysis Inflammation VCAM/1CAMCytokines EndothelinCatecholamines BP LDL  NO • ∆ Local Mediators •  Tissue ACE, AII PAI-1, Platelet Aggregation, Tissue Factor Vasoconstriction Thrombosis Inflammation Plaque Rupture Vascular Lesion and Remodeling Clinical Sequelae Risk Factors Reprinted with permission from Dzau VJ. Hypertension. 2001;37:1047–1052. 45 THERAPEUTICS : WHERE DO WE STAND TODAY ? Lipid lowering drugs ACEI / ARB Peroxisome proliferators-activated receptor (PPAR) Chemokine receptor antagonist TNF Inhibitor MMP Inhibitor 46 BIOCHEMICAL PARAMETER FOR ENDOTHELIAL DYSFUNCTION - vWF - Thrombomodulin - E-Selection - ICAM-1 - VCAM-1 - NO - Microalbuminuria - PAI-1 (D. Sargowo) - Ox LDL – MDA – F2 - Isoprostane - LP – PLA2 - Lyso-PC OxFA BIOCHEMICAL PARAMETER FOR ENDOTHELIAL DYSFUNCTION - vWF - Thrombomodulin - E-Selection - NO - Microalbuminuria - PAI-1 - Ox LDL – MDA – F2 - Isoprostane - LP – PLA2 - Lyso-PC OxFA 47 INFLAMMATORY MARKERS FOR CONSIDERATION AS PREDICTORS OF CARDIOVASCULAR RISK Adhesion molecules Cytokines Acute-phase reactants Fibrinogen SAA CRP WBC count Other (eg, erytrocyte sedimentation rate) (Pearson et al, 2003) 48 SURREGATE BIOMARKERS FOR ACS HS CRP MMP Stromelysin Kalogenase Elastase INFj, TNF, IL1 Gelatinase LDH CPK MBCK Troponin T-I Fibrinogen Albuminuri D. Sargowo 49 Rudolf Virchow Inflammation-based arterial changes as a mechanism of primary importance in atherogenesis mid 19th century Lamond, B. The American Journal of Pathology. 2008 SUMMARY 50 51 Thank You 52 The Role of Lp-PLA2 in CHD LUMEN Monocytes Adhesion Molecules Oxidated LDL INTIMA MEDIA Lp-PLA2 Lyso-PC OxFA Cytokines Plaque Formation Foam Cell Macrophage 53 Intracelluler proteolysis and fusion of LDL Figure : Proposed Dual Action of Exocytosed Mast Cell Granules (The Granule Remnants) of Lipoprotein Metabolism in The Arterial Intima
Slide 54 - 1 Nama : Prof. Dr. H. Djanggan Sargowo, dr., SpPD., SpJP(K), FIHA, FACC, FESC, FCAPC, FASCC Tempat/Tgl lahir : Sragen, 21 September 1947 Alamat : Wilis Indah E-10 Malang, Telp. 0341-552395 Pendidikan : Lulus Dokter dari UGM, tahun 1974 Lulus Cardiologist dari Univ. Indonesia, tahun 1983 Lulus Internist dari Univ. Airlangga, tahun 1986 Lulus Doktor, Univ. Airlangga, tahun 1996 Advanced Cardiology Course, Univ. Hongkong, tahun 1984 Senior Visiting Program, Institut Jantung Negara, Kualalumpur, 1996 Fellow American College of Cardiology (FACC), September 2006. Fellow Collage Asia Pacific Society of Cardiology (FCAPC), Desember 2007 Fellow European Sociaty of Cardiology (FESC), 2008 Fellow Asean Collage of Cardiology (FASCC), 2008 Jabatan : Dosen Pengajar Program Pascasarjana Universitas Brawijaya Ketua MKEK Ikatan Dokter Indonesia Cabang Malang Raya Ketua PERKI Cabang Malang Raya Anggota Kolegium Kardiovaskuler Indonesia Dekan Fak. Kedokteran Univ. Wijaya Kusuma Surabaya Ketua Dewan Pengawas Rumah Sakit Pendidikan Ketua Program Studi Kardiovascular Fak. Kedokteran Univ. Brawijaya Curriculum Vitae 2 Djanggan Sargowo Surabaya, 15 April 2012 INFLAMMATION IN ATHEROSCLEROSIS : FROM BENCH TO BEDSIDE 3 4 RUDOLF VIRCHOW Inflammation-based arterial changes as a mechanism of primary importance in atherogenesis mid 19th century Lamond, B. The American Journal of Pathology. 2008 5 Atherosclerosis Start from very young To Old age ? 6 Atherothrombosis* is aLeading Cause of Death Worldwide1† The World Health Report, 2002, WHO Geneva, 2002 28.7 17.8 12.6 9.1 6 5.1 0 5 10 15 20 25 30 Atherothrombosis* Infectious disease Cancer Injuries Pulmonary disease AIDS Mortality (%) * Ischemic heart disease, cerebrovascular disease, inflammatory heart disease and hypertensive heart disease † Worldwide defined as Member States by WHO Region (Africa, Americas, Eastern Mediterranean, European, South-East Asia and Western Pacific) 7 MAJOR CLINICAL MANIFESTATIONS OF ATHEROTHROMBOSIS Adapted from: Drouet L. Cerebrovasc Dis 2002; 13(suppl 1): 1–6. Transient ischemic attack Angina: Stable Unstable Ischemic stroke Myocardial infarction Peripheral arterial disease: Intermittent claudication Rest Pain Gangrene Necrosis 8  Dyslipidemia  Endothelial dysfunction  Free radicals  Immunologic Atherosclerosis/CAD THEORY AND CONCEPT OF ATHEROSCLEROSIS Inflamation (Sargowo, 1996) 9 Free Radical ATHEROGENESIS (Sargowo, 1996) 10 IDENTIFYING THOSE AT RISK OF ATHEROTHROMBOSIS Yusuf S et al. Circulation 2001; 104: 2746–53. 2. Drouet L. Cerebrovasc Dis 2002;13(suppl 1):1–6. Lifestyle Smoking Diet Lack of exercise Genetic Genetic traits Gender Age Generalized disorders Obesity Diabetes Systemic conditions History of vascular events Hypertension Hyperlipidemia Hypercoagulable states Homocystinemia Local factors Elevated prothrombotic factors: fibrinogen, CRP, PAI-1 Blood flow patterns, vessel diameter, arterial wall structure Atherothrombosis manifestations (myocardial infarction, stroke, vascular death) 11 Arici. 2010 Risk Factors for Atherosclerosis Classic Hypertension, Hyper-lipidemia, DM, Smoking Uremia Related Increase ox-LDL, Free radicals, Uremic toxin Infection Bacterial and viral infection Proinflammatory cytokine release Endothelial dysfunction Systemic inflammatory respones Acute phase response Elevated CRP Binding LDL, cemplement activation, tissue factor secretion Accelerated ATHEROSCLEROSIS 12 LDL CD40L=CD40 ligand; TNF-α=tumor necrosis factor-alpha; IL=interleukin; VCAM=vascular cell adhesion molecule; ICAM=intercellular adhesion molecule. Cockerill GW et al. Arterioscler Thromb Vasc Biol. 1995;15:1987-1994; Andre P et al. Circulation. 2002;106:896-899; Libby P. Circulation. 2001;104:365-372; Libby P et al. Circulation. 2002;105:1135-1143; Ross R. N Engl J Med. 1999;340:115-126. Vessel lumen Monocyte Macrophage Adhesionmolecules (VCAM-1, ICAM-1) Inflammatory mediators (CRP, CD40/CD40L, TNF-α, IL-1, IL-6) Intima Foam cell INFLAMMATION PROMOTES PROGRESSION OF ATHEROSCLEROSIS Endothelium LDL Ox-LDL 13 14 Atherosclerosis is a fibroproliferative and inflammatory process occurring ins response to a variety of vascular insults The insults come from classical risk factors ( HT, dyslipidemia, endothelial dysfunction, smoking, menopause, diabetes etc) and novel risk factors (Hcy, LVH, Lp(a), TG, oxidative stress, fibrinogen etc) Endothelial dysfunction is regarded as the first abnormality leading to atherosclerosis This implies that modulation of endothelial function may be used as strategy to intervene the process. 15 Two theories gain more acceptance: (a) the lipid theory (b) inflammation theory Endothelial dysfunction is now regarded as the first abnormality leading to AS. More novel cardiovascular risk factors are known, e.g.: Fibrinogen b. PAI-1 Homocysteins d. AT-1 e. CRP f. Lp(a) g. small-dense LDL h. infectious agents i. and more are emerging 16 Acute Coronary Syndrome (endocrine viewpoints) atherosclerotic lesions vascular funtions b.1. inflammatory reaction b.2. thrombogeneity b.3. vasoreactivity b.4. plaque stability b.5. shoulder of plaque endothelium balance between c.1. vasodilating, antithrombotic, antiproliferative factors (NO, prostacyclin, C-natriuretic peptide, EDHF) c.2. vasoconstricting, prothrombotic, proliferative factors (ET, superoxide, thromoboxan A2) 17 NATURAL HISTORY OF CORONARY ATHEROSCLEROSIS Chatzizisis et all. JACC. 2007. Asymtomatic Stable Angina Acute Coronary Syndrome Early fibroatheroma Compensatory expansive remodeling Quiescent plaque Contrictive remodeling Stenotic plaque Exessive expansive remodeling Thin cap fibroatheroma Erosion Physiologic coronary artery Local factors, e.g. low ESS Systemic factors, e.g. hyperlipidemia Genetic factors Physiologic ESS Limited inflammation Fibroproliferation Microruptures 18 ATHEROSCLEROSIS IS AN INFLAMMATORY DISEASE Libby P. Circulation. 2001;104:365-372; Ross R. N Engl J Med. 1999;340:115-126. Monocyte LDL-C Adhesion molecule Macrophage Foam cell OxidizedLDL-C Plaque rupture Smooth muscle cells CRP Plaque instability and thrombus Oxidation Inflammation Endothelial dysfunction 19 20 Reverse Cholesterol Transport Monocyte CRP TXA2 PGI2 Thrombin LDL Platelets HDL HDL Ox-LDL MCP-1 Macrophage P-selectin CD 40L PDGF Foam cell MMP T cell E-selectins CD 40L VCAM-1 ICAM-1 IL-1 Reilly, et.all. 2005 21 THE ROLE OF Lp-PLA2 IN CHD LUMEN Monocytes Adhesion Molecules Oxidated LDL INTIMA MEDIA Lp-PLA2 Lyso-PC OxFA Cytokines Plaque Formation Foam Cell Macrophage 22 MC T T FC FC LDL Oxidation Lyso-PC Ox-chol Cytokines Cytokines ? C5a C’ MCP-1 F SMC 23 Intracelluler proteolysis and fusion of LDL Figure : Proposed Dual Action of Exocytosed Mast Cell Granules (The Granule Remnants) of Lipoprotein Metabolism in The Arterial Intima 24 HSCRP 25 26 GM-CSF VCAM-1 MPC-1 Transcription Factors : Endothelial Cell Pro-inflammatory Genes Oxidative Stress NF-xB AP-1 Leucocyte infiltration / activation Plaque Rupture Gibbons, 97 LEUCOCYTE ACTIVATION IN ATHEROGENESIS : IMPLICATIONS FOR ACUTE ISCHEMIC SYNDROMES 27 p38 c-Jun activation Caspases Apoptosis NIK ? ? MEKK1?   CKII IKK complex TNFR-1 TNFR-1 IL-1R Shear stress p65 p50 CBP/p300 Gene activation p65 p50 IB pKAc IB Ub Target genes : - IL-1, IL-8, IL-6, IFN  - TNF, MCP-1 - CSFs, c-myc - VCAM-1, ICAM-1, E-selectin - Tissue factor - Survival factor Thurberg and Collins : Curr Opin Lipidol 9:387-396,1998 Ub Ox-LDL ROIs ??? Lipid peroxides ? H2O2 Ubiquitination and proteosome degradation T R A D D R I P F A D D R I P T R A D D T R A F 2 T R A F 6 28 Visual Medica. 2009 29 Stockley. 2006 Cytokines : IL-6, TNF-α MACROPHAGE FOAM CELL Oxidized LDL CRP CRP Chemokines: MCO-1 Atherosclerotic plaque MONOCYTE Inflammatory Mediators: CRP Prothrombotic factors FCR Receptor 30 POTENTIAL MECHANISM OF CRP Stevens, R. 2005 CRP LDL opsonisation Monocyte infiltration Foam cell formation Increased MCP-1 and CAM EC activation Inflammatory cell recruitment Atherosclerosis plaque formation Complement activation EC sensitisation T-cell attack EC damage Atherosclerotic plaque rupture 31 Rheumatoid arthritis Atherosclerosis Multiple sclerosis Asthma Inflammatory bowel disease Helicobacter pylori-associated gastritis Systemic inflammatory response syndrome NF-KB ACTIVATION INFLAMMATORY DISEASE The Journal of Clinical Investigation, 2001 32 PROTEIN REGULATED BY NF-KB Inflammatory Enzyme Adhesion Molecule Inducible nitric oxide synthase Inducide cylooxigenase-2 5-Lipoxigenase Cytosolic phospolipase A2 ICAM-1 VCAM-1 E-selectin Receptor Interlekin-2 receptor (alpha chain) T-cell receptors (beta chain) NEJM, 1997 33 BIOMARKERS OF ACTIVITY STUDIED FOR CAD Cytokines (IL-1β, IL-6, IL-8, IL-10, TNF-α, sCD40 ligand, myeloperoxidase) Adhesion molecules (sICAM-1, sVCAM-1, p-selectin) Acute phase reactans (fibrinogen, AAS, CRP) White blood cells Erythrocyte sedimentation rate Neopterin Heat shock proteins Adiponectin Lipoprotein associated phospholipase A2 Placental growth factos Cystatin C Kaski, JC. 2006. 34 Are you hungry or sleepy ???? Sciences 35 The inflammatory cascade. IL indicates interleukin; ICAM, intercellular adhesion molecule; and HSP, heat shock protein. (Libby, Ridker; 1999) Pro-Inflammatory Risk Factors Primary Pro-Inflammatory Cytokines (eg. IL-1, TNF-) IL-6 “Mesenger” Cytokine CRP SAA Endothelium and other cells LIVER Circulation 36 (Ridker, 2004) MORE THAN A MARKER : DOES CRP PLAY A DIRECT ROLE IN ATHEROTHROMBOSIS ? CRP localizes in atherosclerotic but not normal intima CRP induced Complement activation CRP dependent monocyte recruitment into arterial wall CRP induced production of tissue factor in monocytes CRP based blunting of endothelial vasoreactivity CRP mediated LDL uptake by macrophages CRP triggered oxidation of LDL cholesterol CRP induced PAI-1 expression stabilizes PAI-1 mRNA CRP attenuates NO production and decreases eNOS expression CRP induced production of cell adhesion moleculas MCP-1, ET-1 37 ROLE OF INFLAMATORY MARKERS Interleukin-6 Total cholesterol LDL-cholesterol siCAM-1 Serum amyloid A Apolipoprotein B Total cholesterol: HDL-cholesterol Hs-CRP Hs-CRP + total cholesterol: HDL-cholesterol 0 1.0 2.0 4.0 6.0 Relative Risk (New England Journal of Medicine) 38 39 Weissberg, 1999 Inflammation Repair 40 REDOX REGULATION OF ENDOTHELIAL DYSFUNCTION & ACTIVATION O2– OH H2O2  NO Activity  G-Protein Function  Protein Kinase C Oxidation Endothelial Dysfunction (D. Sargowo) 41 ENDOTHELIAL DYSFUNCTION AND ACUTE CORONARY SYNDROMES Vasoconstriction Platelet Aggregation SMC Proliferation Leukocyte Adhesion LDL Oxidation Activation of MMPs Endothelial Dysfunction Plaque Rupture Thrombosis Matrix Remodeling (D. Sargowo) 42 ENDOTHELIAL DYSFUNCTION AND ACUTE CORONARY SYNDROMES Vasospasm Plaque Rupture Thrombosis Matrix Remodeling ACUTE CORONARY SYNDROMES (D. Sargowo) 43 44 Diabetes Smoking AII Oxidative Stress Endothelial Dysfunction and Smooth Muscle Activation Growth FactorsCytokinesMatrix Proteolysis Inflammation VCAM/1CAMCytokines EndothelinCatecholamines BP LDL  NO • ∆ Local Mediators •  Tissue ACE, AII PAI-1, Platelet Aggregation, Tissue Factor Vasoconstriction Thrombosis Inflammation Plaque Rupture Vascular Lesion and Remodeling Clinical Sequelae Risk Factors Reprinted with permission from Dzau VJ. Hypertension. 2001;37:1047–1052. 45 THERAPEUTICS : WHERE DO WE STAND TODAY ? Lipid lowering drugs ACEI / ARB Peroxisome proliferators-activated receptor (PPAR) Chemokine receptor antagonist TNF Inhibitor MMP Inhibitor 46 BIOCHEMICAL PARAMETER FOR ENDOTHELIAL DYSFUNCTION - vWF - Thrombomodulin - E-Selection - ICAM-1 - VCAM-1 - NO - Microalbuminuria - PAI-1 (D. Sargowo) - Ox LDL – MDA – F2 - Isoprostane - LP – PLA2 - Lyso-PC OxFA BIOCHEMICAL PARAMETER FOR ENDOTHELIAL DYSFUNCTION - vWF - Thrombomodulin - E-Selection - NO - Microalbuminuria - PAI-1 - Ox LDL – MDA – F2 - Isoprostane - LP – PLA2 - Lyso-PC OxFA 47 INFLAMMATORY MARKERS FOR CONSIDERATION AS PREDICTORS OF CARDIOVASCULAR RISK Adhesion molecules Cytokines Acute-phase reactants Fibrinogen SAA CRP WBC count Other (eg, erytrocyte sedimentation rate) (Pearson et al, 2003) 48 SURREGATE BIOMARKERS FOR ACS HS CRP MMP Stromelysin Kalogenase Elastase INFj, TNF, IL1 Gelatinase LDH CPK MBCK Troponin T-I Fibrinogen Albuminuri D. Sargowo 49 Rudolf Virchow Inflammation-based arterial changes as a mechanism of primary importance in atherogenesis mid 19th century Lamond, B. The American Journal of Pathology. 2008 SUMMARY 50 51 Thank You 52 The Role of Lp-PLA2 in CHD LUMEN Monocytes Adhesion Molecules Oxidated LDL INTIMA MEDIA Lp-PLA2 Lyso-PC OxFA Cytokines Plaque Formation Foam Cell Macrophage 53 Intracelluler proteolysis and fusion of LDL Figure : Proposed Dual Action of Exocytosed Mast Cell Granules (The Granule Remnants) of Lipoprotein Metabolism in The Arterial Intima 54
Slide 55 - 1 Nama : Prof. Dr. H. Djanggan Sargowo, dr., SpPD., SpJP(K), FIHA, FACC, FESC, FCAPC, FASCC Tempat/Tgl lahir : Sragen, 21 September 1947 Alamat : Wilis Indah E-10 Malang, Telp. 0341-552395 Pendidikan : Lulus Dokter dari UGM, tahun 1974 Lulus Cardiologist dari Univ. Indonesia, tahun 1983 Lulus Internist dari Univ. Airlangga, tahun 1986 Lulus Doktor, Univ. Airlangga, tahun 1996 Advanced Cardiology Course, Univ. Hongkong, tahun 1984 Senior Visiting Program, Institut Jantung Negara, Kualalumpur, 1996 Fellow American College of Cardiology (FACC), September 2006. Fellow Collage Asia Pacific Society of Cardiology (FCAPC), Desember 2007 Fellow European Sociaty of Cardiology (FESC), 2008 Fellow Asean Collage of Cardiology (FASCC), 2008 Jabatan : Dosen Pengajar Program Pascasarjana Universitas Brawijaya Ketua MKEK Ikatan Dokter Indonesia Cabang Malang Raya Ketua PERKI Cabang Malang Raya Anggota Kolegium Kardiovaskuler Indonesia Dekan Fak. Kedokteran Univ. Wijaya Kusuma Surabaya Ketua Dewan Pengawas Rumah Sakit Pendidikan Ketua Program Studi Kardiovascular Fak. Kedokteran Univ. Brawijaya Curriculum Vitae 2 Djanggan Sargowo Surabaya, 15 April 2012 INFLAMMATION IN ATHEROSCLEROSIS : FROM BENCH TO BEDSIDE 3 4 RUDOLF VIRCHOW Inflammation-based arterial changes as a mechanism of primary importance in atherogenesis mid 19th century Lamond, B. The American Journal of Pathology. 2008 5 Atherosclerosis Start from very young To Old age ? 6 Atherothrombosis* is aLeading Cause of Death Worldwide1† The World Health Report, 2002, WHO Geneva, 2002 28.7 17.8 12.6 9.1 6 5.1 0 5 10 15 20 25 30 Atherothrombosis* Infectious disease Cancer Injuries Pulmonary disease AIDS Mortality (%) * Ischemic heart disease, cerebrovascular disease, inflammatory heart disease and hypertensive heart disease † Worldwide defined as Member States by WHO Region (Africa, Americas, Eastern Mediterranean, European, South-East Asia and Western Pacific) 7 MAJOR CLINICAL MANIFESTATIONS OF ATHEROTHROMBOSIS Adapted from: Drouet L. Cerebrovasc Dis 2002; 13(suppl 1): 1–6. Transient ischemic attack Angina: Stable Unstable Ischemic stroke Myocardial infarction Peripheral arterial disease: Intermittent claudication Rest Pain Gangrene Necrosis 8  Dyslipidemia  Endothelial dysfunction  Free radicals  Immunologic Atherosclerosis/CAD THEORY AND CONCEPT OF ATHEROSCLEROSIS Inflamation (Sargowo, 1996) 9 Free Radical ATHEROGENESIS (Sargowo, 1996) 10 IDENTIFYING THOSE AT RISK OF ATHEROTHROMBOSIS Yusuf S et al. Circulation 2001; 104: 2746–53. 2. Drouet L. Cerebrovasc Dis 2002;13(suppl 1):1–6. Lifestyle Smoking Diet Lack of exercise Genetic Genetic traits Gender Age Generalized disorders Obesity Diabetes Systemic conditions History of vascular events Hypertension Hyperlipidemia Hypercoagulable states Homocystinemia Local factors Elevated prothrombotic factors: fibrinogen, CRP, PAI-1 Blood flow patterns, vessel diameter, arterial wall structure Atherothrombosis manifestations (myocardial infarction, stroke, vascular death) 11 Arici. 2010 Risk Factors for Atherosclerosis Classic Hypertension, Hyper-lipidemia, DM, Smoking Uremia Related Increase ox-LDL, Free radicals, Uremic toxin Infection Bacterial and viral infection Proinflammatory cytokine release Endothelial dysfunction Systemic inflammatory respones Acute phase response Elevated CRP Binding LDL, cemplement activation, tissue factor secretion Accelerated ATHEROSCLEROSIS 12 LDL CD40L=CD40 ligand; TNF-α=tumor necrosis factor-alpha; IL=interleukin; VCAM=vascular cell adhesion molecule; ICAM=intercellular adhesion molecule. Cockerill GW et al. Arterioscler Thromb Vasc Biol. 1995;15:1987-1994; Andre P et al. Circulation. 2002;106:896-899; Libby P. Circulation. 2001;104:365-372; Libby P et al. Circulation. 2002;105:1135-1143; Ross R. N Engl J Med. 1999;340:115-126. Vessel lumen Monocyte Macrophage Adhesionmolecules (VCAM-1, ICAM-1) Inflammatory mediators (CRP, CD40/CD40L, TNF-α, IL-1, IL-6) Intima Foam cell INFLAMMATION PROMOTES PROGRESSION OF ATHEROSCLEROSIS Endothelium LDL Ox-LDL 13 14 Atherosclerosis is a fibroproliferative and inflammatory process occurring ins response to a variety of vascular insults The insults come from classical risk factors ( HT, dyslipidemia, endothelial dysfunction, smoking, menopause, diabetes etc) and novel risk factors (Hcy, LVH, Lp(a), TG, oxidative stress, fibrinogen etc) Endothelial dysfunction is regarded as the first abnormality leading to atherosclerosis This implies that modulation of endothelial function may be used as strategy to intervene the process. 15 Two theories gain more acceptance: (a) the lipid theory (b) inflammation theory Endothelial dysfunction is now regarded as the first abnormality leading to AS. More novel cardiovascular risk factors are known, e.g.: Fibrinogen b. PAI-1 Homocysteins d. AT-1 e. CRP f. Lp(a) g. small-dense LDL h. infectious agents i. and more are emerging 16 Acute Coronary Syndrome (endocrine viewpoints) atherosclerotic lesions vascular funtions b.1. inflammatory reaction b.2. thrombogeneity b.3. vasoreactivity b.4. plaque stability b.5. shoulder of plaque endothelium balance between c.1. vasodilating, antithrombotic, antiproliferative factors (NO, prostacyclin, C-natriuretic peptide, EDHF) c.2. vasoconstricting, prothrombotic, proliferative factors (ET, superoxide, thromoboxan A2) 17 NATURAL HISTORY OF CORONARY ATHEROSCLEROSIS Chatzizisis et all. JACC. 2007. Asymtomatic Stable Angina Acute Coronary Syndrome Early fibroatheroma Compensatory expansive remodeling Quiescent plaque Contrictive remodeling Stenotic plaque Exessive expansive remodeling Thin cap fibroatheroma Erosion Physiologic coronary artery Local factors, e.g. low ESS Systemic factors, e.g. hyperlipidemia Genetic factors Physiologic ESS Limited inflammation Fibroproliferation Microruptures 18 ATHEROSCLEROSIS IS AN INFLAMMATORY DISEASE Libby P. Circulation. 2001;104:365-372; Ross R. N Engl J Med. 1999;340:115-126. Monocyte LDL-C Adhesion molecule Macrophage Foam cell OxidizedLDL-C Plaque rupture Smooth muscle cells CRP Plaque instability and thrombus Oxidation Inflammation Endothelial dysfunction 19 20 Reverse Cholesterol Transport Monocyte CRP TXA2 PGI2 Thrombin LDL Platelets HDL HDL Ox-LDL MCP-1 Macrophage P-selectin CD 40L PDGF Foam cell MMP T cell E-selectins CD 40L VCAM-1 ICAM-1 IL-1 Reilly, et.all. 2005 21 THE ROLE OF Lp-PLA2 IN CHD LUMEN Monocytes Adhesion Molecules Oxidated LDL INTIMA MEDIA Lp-PLA2 Lyso-PC OxFA Cytokines Plaque Formation Foam Cell Macrophage 22 MC T T FC FC LDL Oxidation Lyso-PC Ox-chol Cytokines Cytokines ? C5a C’ MCP-1 F SMC 23 Intracelluler proteolysis and fusion of LDL Figure : Proposed Dual Action of Exocytosed Mast Cell Granules (The Granule Remnants) of Lipoprotein Metabolism in The Arterial Intima 24 HSCRP 25 26 GM-CSF VCAM-1 MPC-1 Transcription Factors : Endothelial Cell Pro-inflammatory Genes Oxidative Stress NF-xB AP-1 Leucocyte infiltration / activation Plaque Rupture Gibbons, 97 LEUCOCYTE ACTIVATION IN ATHEROGENESIS : IMPLICATIONS FOR ACUTE ISCHEMIC SYNDROMES 27 p38 c-Jun activation Caspases Apoptosis NIK ? ? MEKK1?   CKII IKK complex TNFR-1 TNFR-1 IL-1R Shear stress p65 p50 CBP/p300 Gene activation p65 p50 IB pKAc IB Ub Target genes : - IL-1, IL-8, IL-6, IFN  - TNF, MCP-1 - CSFs, c-myc - VCAM-1, ICAM-1, E-selectin - Tissue factor - Survival factor Thurberg and Collins : Curr Opin Lipidol 9:387-396,1998 Ub Ox-LDL ROIs ??? Lipid peroxides ? H2O2 Ubiquitination and proteosome degradation T R A D D R I P F A D D R I P T R A D D T R A F 2 T R A F 6 28 Visual Medica. 2009 29 Stockley. 2006 Cytokines : IL-6, TNF-α MACROPHAGE FOAM CELL Oxidized LDL CRP CRP Chemokines: MCO-1 Atherosclerotic plaque MONOCYTE Inflammatory Mediators: CRP Prothrombotic factors FCR Receptor 30 POTENTIAL MECHANISM OF CRP Stevens, R. 2005 CRP LDL opsonisation Monocyte infiltration Foam cell formation Increased MCP-1 and CAM EC activation Inflammatory cell recruitment Atherosclerosis plaque formation Complement activation EC sensitisation T-cell attack EC damage Atherosclerotic plaque rupture 31 Rheumatoid arthritis Atherosclerosis Multiple sclerosis Asthma Inflammatory bowel disease Helicobacter pylori-associated gastritis Systemic inflammatory response syndrome NF-KB ACTIVATION INFLAMMATORY DISEASE The Journal of Clinical Investigation, 2001 32 PROTEIN REGULATED BY NF-KB Inflammatory Enzyme Adhesion Molecule Inducible nitric oxide synthase Inducide cylooxigenase-2 5-Lipoxigenase Cytosolic phospolipase A2 ICAM-1 VCAM-1 E-selectin Receptor Interlekin-2 receptor (alpha chain) T-cell receptors (beta chain) NEJM, 1997 33 BIOMARKERS OF ACTIVITY STUDIED FOR CAD Cytokines (IL-1β, IL-6, IL-8, IL-10, TNF-α, sCD40 ligand, myeloperoxidase) Adhesion molecules (sICAM-1, sVCAM-1, p-selectin) Acute phase reactans (fibrinogen, AAS, CRP) White blood cells Erythrocyte sedimentation rate Neopterin Heat shock proteins Adiponectin Lipoprotein associated phospholipase A2 Placental growth factos Cystatin C Kaski, JC. 2006. 34 Are you hungry or sleepy ???? Sciences 35 The inflammatory cascade. IL indicates interleukin; ICAM, intercellular adhesion molecule; and HSP, heat shock protein. (Libby, Ridker; 1999) Pro-Inflammatory Risk Factors Primary Pro-Inflammatory Cytokines (eg. IL-1, TNF-) IL-6 “Mesenger” Cytokine CRP SAA Endothelium and other cells LIVER Circulation 36 (Ridker, 2004) MORE THAN A MARKER : DOES CRP PLAY A DIRECT ROLE IN ATHEROTHROMBOSIS ? CRP localizes in atherosclerotic but not normal intima CRP induced Complement activation CRP dependent monocyte recruitment into arterial wall CRP induced production of tissue factor in monocytes CRP based blunting of endothelial vasoreactivity CRP mediated LDL uptake by macrophages CRP triggered oxidation of LDL cholesterol CRP induced PAI-1 expression stabilizes PAI-1 mRNA CRP attenuates NO production and decreases eNOS expression CRP induced production of cell adhesion moleculas MCP-1, ET-1 37 ROLE OF INFLAMATORY MARKERS Interleukin-6 Total cholesterol LDL-cholesterol siCAM-1 Serum amyloid A Apolipoprotein B Total cholesterol: HDL-cholesterol Hs-CRP Hs-CRP + total cholesterol: HDL-cholesterol 0 1.0 2.0 4.0 6.0 Relative Risk (New England Journal of Medicine) 38 39 Weissberg, 1999 Inflammation Repair 40 REDOX REGULATION OF ENDOTHELIAL DYSFUNCTION & ACTIVATION O2– OH H2O2  NO Activity  G-Protein Function  Protein Kinase C Oxidation Endothelial Dysfunction (D. Sargowo) 41 ENDOTHELIAL DYSFUNCTION AND ACUTE CORONARY SYNDROMES Vasoconstriction Platelet Aggregation SMC Proliferation Leukocyte Adhesion LDL Oxidation Activation of MMPs Endothelial Dysfunction Plaque Rupture Thrombosis Matrix Remodeling (D. Sargowo) 42 ENDOTHELIAL DYSFUNCTION AND ACUTE CORONARY SYNDROMES Vasospasm Plaque Rupture Thrombosis Matrix Remodeling ACUTE CORONARY SYNDROMES (D. Sargowo) 43 44 Diabetes Smoking AII Oxidative Stress Endothelial Dysfunction and Smooth Muscle Activation Growth FactorsCytokinesMatrix Proteolysis Inflammation VCAM/1CAMCytokines EndothelinCatecholamines BP LDL  NO • ∆ Local Mediators •  Tissue ACE, AII PAI-1, Platelet Aggregation, Tissue Factor Vasoconstriction Thrombosis Inflammation Plaque Rupture Vascular Lesion and Remodeling Clinical Sequelae Risk Factors Reprinted with permission from Dzau VJ. Hypertension. 2001;37:1047–1052. 45 THERAPEUTICS : WHERE DO WE STAND TODAY ? Lipid lowering drugs ACEI / ARB Peroxisome proliferators-activated receptor (PPAR) Chemokine receptor antagonist TNF Inhibitor MMP Inhibitor 46 BIOCHEMICAL PARAMETER FOR ENDOTHELIAL DYSFUNCTION - vWF - Thrombomodulin - E-Selection - ICAM-1 - VCAM-1 - NO - Microalbuminuria - PAI-1 (D. Sargowo) - Ox LDL – MDA – F2 - Isoprostane - LP – PLA2 - Lyso-PC OxFA BIOCHEMICAL PARAMETER FOR ENDOTHELIAL DYSFUNCTION - vWF - Thrombomodulin - E-Selection - NO - Microalbuminuria - PAI-1 - Ox LDL – MDA – F2 - Isoprostane - LP – PLA2 - Lyso-PC OxFA 47 INFLAMMATORY MARKERS FOR CONSIDERATION AS PREDICTORS OF CARDIOVASCULAR RISK Adhesion molecules Cytokines Acute-phase reactants Fibrinogen SAA CRP WBC count Other (eg, erytrocyte sedimentation rate) (Pearson et al, 2003) 48 SURREGATE BIOMARKERS FOR ACS HS CRP MMP Stromelysin Kalogenase Elastase INFj, TNF, IL1 Gelatinase LDH CPK MBCK Troponin T-I Fibrinogen Albuminuri D. Sargowo 49 Rudolf Virchow Inflammation-based arterial changes as a mechanism of primary importance in atherogenesis mid 19th century Lamond, B. The American Journal of Pathology. 2008 SUMMARY 50 51 Thank You 52 The Role of Lp-PLA2 in CHD LUMEN Monocytes Adhesion Molecules Oxidated LDL INTIMA MEDIA Lp-PLA2 Lyso-PC OxFA Cytokines Plaque Formation Foam Cell Macrophage 53 Intracelluler proteolysis and fusion of LDL Figure : Proposed Dual Action of Exocytosed Mast Cell Granules (The Granule Remnants) of Lipoprotein Metabolism in The Arterial Intima 54 55 24.7% 29.9% Coronary disease 7.4% ATHEROTHROMBOSIS IS COMMONLY FOUND IN MORE THAN ONE ARTERIAL BED IN AN INDIVIDUAL PATIENT* Cerebrovascular disease Peripheral arterial disease 3.8% 11.8% 19.2% * Data from CAPRIE study (n=19,185) Coccheri S. Eur Heart J 1998; 19(suppl): P1268. 3.3%
Slide 56 - 1 Nama : Prof. Dr. H. Djanggan Sargowo, dr., SpPD., SpJP(K), FIHA, FACC, FESC, FCAPC, FASCC Tempat/Tgl lahir : Sragen, 21 September 1947 Alamat : Wilis Indah E-10 Malang, Telp. 0341-552395 Pendidikan : Lulus Dokter dari UGM, tahun 1974 Lulus Cardiologist dari Univ. Indonesia, tahun 1983 Lulus Internist dari Univ. Airlangga, tahun 1986 Lulus Doktor, Univ. Airlangga, tahun 1996 Advanced Cardiology Course, Univ. Hongkong, tahun 1984 Senior Visiting Program, Institut Jantung Negara, Kualalumpur, 1996 Fellow American College of Cardiology (FACC), September 2006. Fellow Collage Asia Pacific Society of Cardiology (FCAPC), Desember 2007 Fellow European Sociaty of Cardiology (FESC), 2008 Fellow Asean Collage of Cardiology (FASCC), 2008 Jabatan : Dosen Pengajar Program Pascasarjana Universitas Brawijaya Ketua MKEK Ikatan Dokter Indonesia Cabang Malang Raya Ketua PERKI Cabang Malang Raya Anggota Kolegium Kardiovaskuler Indonesia Dekan Fak. Kedokteran Univ. Wijaya Kusuma Surabaya Ketua Dewan Pengawas Rumah Sakit Pendidikan Ketua Program Studi Kardiovascular Fak. Kedokteran Univ. Brawijaya Curriculum Vitae 2 Djanggan Sargowo Surabaya, 15 April 2012 INFLAMMATION IN ATHEROSCLEROSIS : FROM BENCH TO BEDSIDE 3 4 RUDOLF VIRCHOW Inflammation-based arterial changes as a mechanism of primary importance in atherogenesis mid 19th century Lamond, B. The American Journal of Pathology. 2008 5 Atherosclerosis Start from very young To Old age ? 6 Atherothrombosis* is aLeading Cause of Death Worldwide1† The World Health Report, 2002, WHO Geneva, 2002 28.7 17.8 12.6 9.1 6 5.1 0 5 10 15 20 25 30 Atherothrombosis* Infectious disease Cancer Injuries Pulmonary disease AIDS Mortality (%) * Ischemic heart disease, cerebrovascular disease, inflammatory heart disease and hypertensive heart disease † Worldwide defined as Member States by WHO Region (Africa, Americas, Eastern Mediterranean, European, South-East Asia and Western Pacific) 7 MAJOR CLINICAL MANIFESTATIONS OF ATHEROTHROMBOSIS Adapted from: Drouet L. Cerebrovasc Dis 2002; 13(suppl 1): 1–6. Transient ischemic attack Angina: Stable Unstable Ischemic stroke Myocardial infarction Peripheral arterial disease: Intermittent claudication Rest Pain Gangrene Necrosis 8  Dyslipidemia  Endothelial dysfunction  Free radicals  Immunologic Atherosclerosis/CAD THEORY AND CONCEPT OF ATHEROSCLEROSIS Inflamation (Sargowo, 1996) 9 Free Radical ATHEROGENESIS (Sargowo, 1996) 10 IDENTIFYING THOSE AT RISK OF ATHEROTHROMBOSIS Yusuf S et al. Circulation 2001; 104: 2746–53. 2. Drouet L. Cerebrovasc Dis 2002;13(suppl 1):1–6. Lifestyle Smoking Diet Lack of exercise Genetic Genetic traits Gender Age Generalized disorders Obesity Diabetes Systemic conditions History of vascular events Hypertension Hyperlipidemia Hypercoagulable states Homocystinemia Local factors Elevated prothrombotic factors: fibrinogen, CRP, PAI-1 Blood flow patterns, vessel diameter, arterial wall structure Atherothrombosis manifestations (myocardial infarction, stroke, vascular death) 11 Arici. 2010 Risk Factors for Atherosclerosis Classic Hypertension, Hyper-lipidemia, DM, Smoking Uremia Related Increase ox-LDL, Free radicals, Uremic toxin Infection Bacterial and viral infection Proinflammatory cytokine release Endothelial dysfunction Systemic inflammatory respones Acute phase response Elevated CRP Binding LDL, cemplement activation, tissue factor secretion Accelerated ATHEROSCLEROSIS 12 LDL CD40L=CD40 ligand; TNF-α=tumor necrosis factor-alpha; IL=interleukin; VCAM=vascular cell adhesion molecule; ICAM=intercellular adhesion molecule. Cockerill GW et al. Arterioscler Thromb Vasc Biol. 1995;15:1987-1994; Andre P et al. Circulation. 2002;106:896-899; Libby P. Circulation. 2001;104:365-372; Libby P et al. Circulation. 2002;105:1135-1143; Ross R. N Engl J Med. 1999;340:115-126. Vessel lumen Monocyte Macrophage Adhesionmolecules (VCAM-1, ICAM-1) Inflammatory mediators (CRP, CD40/CD40L, TNF-α, IL-1, IL-6) Intima Foam cell INFLAMMATION PROMOTES PROGRESSION OF ATHEROSCLEROSIS Endothelium LDL Ox-LDL 13 14 Atherosclerosis is a fibroproliferative and inflammatory process occurring ins response to a variety of vascular insults The insults come from classical risk factors ( HT, dyslipidemia, endothelial dysfunction, smoking, menopause, diabetes etc) and novel risk factors (Hcy, LVH, Lp(a), TG, oxidative stress, fibrinogen etc) Endothelial dysfunction is regarded as the first abnormality leading to atherosclerosis This implies that modulation of endothelial function may be used as strategy to intervene the process. 15 Two theories gain more acceptance: (a) the lipid theory (b) inflammation theory Endothelial dysfunction is now regarded as the first abnormality leading to AS. More novel cardiovascular risk factors are known, e.g.: Fibrinogen b. PAI-1 Homocysteins d. AT-1 e. CRP f. Lp(a) g. small-dense LDL h. infectious agents i. and more are emerging 16 Acute Coronary Syndrome (endocrine viewpoints) atherosclerotic lesions vascular funtions b.1. inflammatory reaction b.2. thrombogeneity b.3. vasoreactivity b.4. plaque stability b.5. shoulder of plaque endothelium balance between c.1. vasodilating, antithrombotic, antiproliferative factors (NO, prostacyclin, C-natriuretic peptide, EDHF) c.2. vasoconstricting, prothrombotic, proliferative factors (ET, superoxide, thromoboxan A2) 17 NATURAL HISTORY OF CORONARY ATHEROSCLEROSIS Chatzizisis et all. JACC. 2007. Asymtomatic Stable Angina Acute Coronary Syndrome Early fibroatheroma Compensatory expansive remodeling Quiescent plaque Contrictive remodeling Stenotic plaque Exessive expansive remodeling Thin cap fibroatheroma Erosion Physiologic coronary artery Local factors, e.g. low ESS Systemic factors, e.g. hyperlipidemia Genetic factors Physiologic ESS Limited inflammation Fibroproliferation Microruptures 18 ATHEROSCLEROSIS IS AN INFLAMMATORY DISEASE Libby P. Circulation. 2001;104:365-372; Ross R. N Engl J Med. 1999;340:115-126. Monocyte LDL-C Adhesion molecule Macrophage Foam cell OxidizedLDL-C Plaque rupture Smooth muscle cells CRP Plaque instability and thrombus Oxidation Inflammation Endothelial dysfunction 19 20 Reverse Cholesterol Transport Monocyte CRP TXA2 PGI2 Thrombin LDL Platelets HDL HDL Ox-LDL MCP-1 Macrophage P-selectin CD 40L PDGF Foam cell MMP T cell E-selectins CD 40L VCAM-1 ICAM-1 IL-1 Reilly, et.all. 2005 21 THE ROLE OF Lp-PLA2 IN CHD LUMEN Monocytes Adhesion Molecules Oxidated LDL INTIMA MEDIA Lp-PLA2 Lyso-PC OxFA Cytokines Plaque Formation Foam Cell Macrophage 22 MC T T FC FC LDL Oxidation Lyso-PC Ox-chol Cytokines Cytokines ? C5a C’ MCP-1 F SMC 23 Intracelluler proteolysis and fusion of LDL Figure : Proposed Dual Action of Exocytosed Mast Cell Granules (The Granule Remnants) of Lipoprotein Metabolism in The Arterial Intima 24 HSCRP 25 26 GM-CSF VCAM-1 MPC-1 Transcription Factors : Endothelial Cell Pro-inflammatory Genes Oxidative Stress NF-xB AP-1 Leucocyte infiltration / activation Plaque Rupture Gibbons, 97 LEUCOCYTE ACTIVATION IN ATHEROGENESIS : IMPLICATIONS FOR ACUTE ISCHEMIC SYNDROMES 27 p38 c-Jun activation Caspases Apoptosis NIK ? ? MEKK1?   CKII IKK complex TNFR-1 TNFR-1 IL-1R Shear stress p65 p50 CBP/p300 Gene activation p65 p50 IB pKAc IB Ub Target genes : - IL-1, IL-8, IL-6, IFN  - TNF, MCP-1 - CSFs, c-myc - VCAM-1, ICAM-1, E-selectin - Tissue factor - Survival factor Thurberg and Collins : Curr Opin Lipidol 9:387-396,1998 Ub Ox-LDL ROIs ??? Lipid peroxides ? H2O2 Ubiquitination and proteosome degradation T R A D D R I P F A D D R I P T R A D D T R A F 2 T R A F 6 28 Visual Medica. 2009 29 Stockley. 2006 Cytokines : IL-6, TNF-α MACROPHAGE FOAM CELL Oxidized LDL CRP CRP Chemokines: MCO-1 Atherosclerotic plaque MONOCYTE Inflammatory Mediators: CRP Prothrombotic factors FCR Receptor 30 POTENTIAL MECHANISM OF CRP Stevens, R. 2005 CRP LDL opsonisation Monocyte infiltration Foam cell formation Increased MCP-1 and CAM EC activation Inflammatory cell recruitment Atherosclerosis plaque formation Complement activation EC sensitisation T-cell attack EC damage Atherosclerotic plaque rupture 31 Rheumatoid arthritis Atherosclerosis Multiple sclerosis Asthma Inflammatory bowel disease Helicobacter pylori-associated gastritis Systemic inflammatory response syndrome NF-KB ACTIVATION INFLAMMATORY DISEASE The Journal of Clinical Investigation, 2001 32 PROTEIN REGULATED BY NF-KB Inflammatory Enzyme Adhesion Molecule Inducible nitric oxide synthase Inducide cylooxigenase-2 5-Lipoxigenase Cytosolic phospolipase A2 ICAM-1 VCAM-1 E-selectin Receptor Interlekin-2 receptor (alpha chain) T-cell receptors (beta chain) NEJM, 1997 33 BIOMARKERS OF ACTIVITY STUDIED FOR CAD Cytokines (IL-1β, IL-6, IL-8, IL-10, TNF-α, sCD40 ligand, myeloperoxidase) Adhesion molecules (sICAM-1, sVCAM-1, p-selectin) Acute phase reactans (fibrinogen, AAS, CRP) White blood cells Erythrocyte sedimentation rate Neopterin Heat shock proteins Adiponectin Lipoprotein associated phospholipase A2 Placental growth factos Cystatin C Kaski, JC. 2006. 34 Are you hungry or sleepy ???? Sciences 35 The inflammatory cascade. IL indicates interleukin; ICAM, intercellular adhesion molecule; and HSP, heat shock protein. (Libby, Ridker; 1999) Pro-Inflammatory Risk Factors Primary Pro-Inflammatory Cytokines (eg. IL-1, TNF-) IL-6 “Mesenger” Cytokine CRP SAA Endothelium and other cells LIVER Circulation 36 (Ridker, 2004) MORE THAN A MARKER : DOES CRP PLAY A DIRECT ROLE IN ATHEROTHROMBOSIS ? CRP localizes in atherosclerotic but not normal intima CRP induced Complement activation CRP dependent monocyte recruitment into arterial wall CRP induced production of tissue factor in monocytes CRP based blunting of endothelial vasoreactivity CRP mediated LDL uptake by macrophages CRP triggered oxidation of LDL cholesterol CRP induced PAI-1 expression stabilizes PAI-1 mRNA CRP attenuates NO production and decreases eNOS expression CRP induced production of cell adhesion moleculas MCP-1, ET-1 37 ROLE OF INFLAMATORY MARKERS Interleukin-6 Total cholesterol LDL-cholesterol siCAM-1 Serum amyloid A Apolipoprotein B Total cholesterol: HDL-cholesterol Hs-CRP Hs-CRP + total cholesterol: HDL-cholesterol 0 1.0 2.0 4.0 6.0 Relative Risk (New England Journal of Medicine) 38 39 Weissberg, 1999 Inflammation Repair 40 REDOX REGULATION OF ENDOTHELIAL DYSFUNCTION & ACTIVATION O2– OH H2O2  NO Activity  G-Protein Function  Protein Kinase C Oxidation Endothelial Dysfunction (D. Sargowo) 41 ENDOTHELIAL DYSFUNCTION AND ACUTE CORONARY SYNDROMES Vasoconstriction Platelet Aggregation SMC Proliferation Leukocyte Adhesion LDL Oxidation Activation of MMPs Endothelial Dysfunction Plaque Rupture Thrombosis Matrix Remodeling (D. Sargowo) 42 ENDOTHELIAL DYSFUNCTION AND ACUTE CORONARY SYNDROMES Vasospasm Plaque Rupture Thrombosis Matrix Remodeling ACUTE CORONARY SYNDROMES (D. Sargowo) 43 44 Diabetes Smoking AII Oxidative Stress Endothelial Dysfunction and Smooth Muscle Activation Growth FactorsCytokinesMatrix Proteolysis Inflammation VCAM/1CAMCytokines EndothelinCatecholamines BP LDL  NO • ∆ Local Mediators •  Tissue ACE, AII PAI-1, Platelet Aggregation, Tissue Factor Vasoconstriction Thrombosis Inflammation Plaque Rupture Vascular Lesion and Remodeling Clinical Sequelae Risk Factors Reprinted with permission from Dzau VJ. Hypertension. 2001;37:1047–1052. 45 THERAPEUTICS : WHERE DO WE STAND TODAY ? Lipid lowering drugs ACEI / ARB Peroxisome proliferators-activated receptor (PPAR) Chemokine receptor antagonist TNF Inhibitor MMP Inhibitor 46 BIOCHEMICAL PARAMETER FOR ENDOTHELIAL DYSFUNCTION - vWF - Thrombomodulin - E-Selection - ICAM-1 - VCAM-1 - NO - Microalbuminuria - PAI-1 (D. Sargowo) - Ox LDL – MDA – F2 - Isoprostane - LP – PLA2 - Lyso-PC OxFA BIOCHEMICAL PARAMETER FOR ENDOTHELIAL DYSFUNCTION - vWF - Thrombomodulin - E-Selection - NO - Microalbuminuria - PAI-1 - Ox LDL – MDA – F2 - Isoprostane - LP – PLA2 - Lyso-PC OxFA 47 INFLAMMATORY MARKERS FOR CONSIDERATION AS PREDICTORS OF CARDIOVASCULAR RISK Adhesion molecules Cytokines Acute-phase reactants Fibrinogen SAA CRP WBC count Other (eg, erytrocyte sedimentation rate) (Pearson et al, 2003) 48 SURREGATE BIOMARKERS FOR ACS HS CRP MMP Stromelysin Kalogenase Elastase INFj, TNF, IL1 Gelatinase LDH CPK MBCK Troponin T-I Fibrinogen Albuminuri D. Sargowo 49 Rudolf Virchow Inflammation-based arterial changes as a mechanism of primary importance in atherogenesis mid 19th century Lamond, B. The American Journal of Pathology. 2008 SUMMARY 50 51 Thank You 52 The Role of Lp-PLA2 in CHD LUMEN Monocytes Adhesion Molecules Oxidated LDL INTIMA MEDIA Lp-PLA2 Lyso-PC OxFA Cytokines Plaque Formation Foam Cell Macrophage 53 Intracelluler proteolysis and fusion of LDL Figure : Proposed Dual Action of Exocytosed Mast Cell Granules (The Granule Remnants) of Lipoprotein Metabolism in The Arterial Intima 54 55 24.7% 29.9% Coronary disease 7.4% ATHEROTHROMBOSIS IS COMMONLY FOUND IN MORE THAN ONE ARTERIAL BED IN AN INDIVIDUAL PATIENT* Cerebrovascular disease Peripheral arterial disease 3.8% 11.8% 19.2% * Data from CAPRIE study (n=19,185) Coccheri S. Eur Heart J 1998; 19(suppl): P1268. 3.3% 56 IKK- IKK IKK IKK Hemodynamic forces Matrix Cytokines LPS/LBP CD14 Oxidized lipids Ang II AGE RAGE AT1 SR TLR Cytokines receptor Integrin PLASMA MEMBRANE Chlamydia and virus Proteasome IKK complexes Inhibitors : IKB- IKB- IKB-r Bcl-3 (Ub)n P P IKB P65 P50 IKB P50 P65 P50 P65 NF-KB CYTOPLASM NUCLEUS
Slide 57 - 1 Nama : Prof. Dr. H. Djanggan Sargowo, dr., SpPD., SpJP(K), FIHA, FACC, FESC, FCAPC, FASCC Tempat/Tgl lahir : Sragen, 21 September 1947 Alamat : Wilis Indah E-10 Malang, Telp. 0341-552395 Pendidikan : Lulus Dokter dari UGM, tahun 1974 Lulus Cardiologist dari Univ. Indonesia, tahun 1983 Lulus Internist dari Univ. Airlangga, tahun 1986 Lulus Doktor, Univ. Airlangga, tahun 1996 Advanced Cardiology Course, Univ. Hongkong, tahun 1984 Senior Visiting Program, Institut Jantung Negara, Kualalumpur, 1996 Fellow American College of Cardiology (FACC), September 2006. Fellow Collage Asia Pacific Society of Cardiology (FCAPC), Desember 2007 Fellow European Sociaty of Cardiology (FESC), 2008 Fellow Asean Collage of Cardiology (FASCC), 2008 Jabatan : Dosen Pengajar Program Pascasarjana Universitas Brawijaya Ketua MKEK Ikatan Dokter Indonesia Cabang Malang Raya Ketua PERKI Cabang Malang Raya Anggota Kolegium Kardiovaskuler Indonesia Dekan Fak. Kedokteran Univ. Wijaya Kusuma Surabaya Ketua Dewan Pengawas Rumah Sakit Pendidikan Ketua Program Studi Kardiovascular Fak. Kedokteran Univ. Brawijaya Curriculum Vitae 2 Djanggan Sargowo Surabaya, 15 April 2012 INFLAMMATION IN ATHEROSCLEROSIS : FROM BENCH TO BEDSIDE 3 4 RUDOLF VIRCHOW Inflammation-based arterial changes as a mechanism of primary importance in atherogenesis mid 19th century Lamond, B. The American Journal of Pathology. 2008 5 Atherosclerosis Start from very young To Old age ? 6 Atherothrombosis* is aLeading Cause of Death Worldwide1† The World Health Report, 2002, WHO Geneva, 2002 28.7 17.8 12.6 9.1 6 5.1 0 5 10 15 20 25 30 Atherothrombosis* Infectious disease Cancer Injuries Pulmonary disease AIDS Mortality (%) * Ischemic heart disease, cerebrovascular disease, inflammatory heart disease and hypertensive heart disease † Worldwide defined as Member States by WHO Region (Africa, Americas, Eastern Mediterranean, European, South-East Asia and Western Pacific) 7 MAJOR CLINICAL MANIFESTATIONS OF ATHEROTHROMBOSIS Adapted from: Drouet L. Cerebrovasc Dis 2002; 13(suppl 1): 1–6. Transient ischemic attack Angina: Stable Unstable Ischemic stroke Myocardial infarction Peripheral arterial disease: Intermittent claudication Rest Pain Gangrene Necrosis 8  Dyslipidemia  Endothelial dysfunction  Free radicals  Immunologic Atherosclerosis/CAD THEORY AND CONCEPT OF ATHEROSCLEROSIS Inflamation (Sargowo, 1996) 9 Free Radical ATHEROGENESIS (Sargowo, 1996) 10 IDENTIFYING THOSE AT RISK OF ATHEROTHROMBOSIS Yusuf S et al. Circulation 2001; 104: 2746–53. 2. Drouet L. Cerebrovasc Dis 2002;13(suppl 1):1–6. Lifestyle Smoking Diet Lack of exercise Genetic Genetic traits Gender Age Generalized disorders Obesity Diabetes Systemic conditions History of vascular events Hypertension Hyperlipidemia Hypercoagulable states Homocystinemia Local factors Elevated prothrombotic factors: fibrinogen, CRP, PAI-1 Blood flow patterns, vessel diameter, arterial wall structure Atherothrombosis manifestations (myocardial infarction, stroke, vascular death) 11 Arici. 2010 Risk Factors for Atherosclerosis Classic Hypertension, Hyper-lipidemia, DM, Smoking Uremia Related Increase ox-LDL, Free radicals, Uremic toxin Infection Bacterial and viral infection Proinflammatory cytokine release Endothelial dysfunction Systemic inflammatory respones Acute phase response Elevated CRP Binding LDL, cemplement activation, tissue factor secretion Accelerated ATHEROSCLEROSIS 12 LDL CD40L=CD40 ligand; TNF-α=tumor necrosis factor-alpha; IL=interleukin; VCAM=vascular cell adhesion molecule; ICAM=intercellular adhesion molecule. Cockerill GW et al. Arterioscler Thromb Vasc Biol. 1995;15:1987-1994; Andre P et al. Circulation. 2002;106:896-899; Libby P. Circulation. 2001;104:365-372; Libby P et al. Circulation. 2002;105:1135-1143; Ross R. N Engl J Med. 1999;340:115-126. Vessel lumen Monocyte Macrophage Adhesionmolecules (VCAM-1, ICAM-1) Inflammatory mediators (CRP, CD40/CD40L, TNF-α, IL-1, IL-6) Intima Foam cell INFLAMMATION PROMOTES PROGRESSION OF ATHEROSCLEROSIS Endothelium LDL Ox-LDL 13 14 Atherosclerosis is a fibroproliferative and inflammatory process occurring ins response to a variety of vascular insults The insults come from classical risk factors ( HT, dyslipidemia, endothelial dysfunction, smoking, menopause, diabetes etc) and novel risk factors (Hcy, LVH, Lp(a), TG, oxidative stress, fibrinogen etc) Endothelial dysfunction is regarded as the first abnormality leading to atherosclerosis This implies that modulation of endothelial function may be used as strategy to intervene the process. 15 Two theories gain more acceptance: (a) the lipid theory (b) inflammation theory Endothelial dysfunction is now regarded as the first abnormality leading to AS. More novel cardiovascular risk factors are known, e.g.: Fibrinogen b. PAI-1 Homocysteins d. AT-1 e. CRP f. Lp(a) g. small-dense LDL h. infectious agents i. and more are emerging 16 Acute Coronary Syndrome (endocrine viewpoints) atherosclerotic lesions vascular funtions b.1. inflammatory reaction b.2. thrombogeneity b.3. vasoreactivity b.4. plaque stability b.5. shoulder of plaque endothelium balance between c.1. vasodilating, antithrombotic, antiproliferative factors (NO, prostacyclin, C-natriuretic peptide, EDHF) c.2. vasoconstricting, prothrombotic, proliferative factors (ET, superoxide, thromoboxan A2) 17 NATURAL HISTORY OF CORONARY ATHEROSCLEROSIS Chatzizisis et all. JACC. 2007. Asymtomatic Stable Angina Acute Coronary Syndrome Early fibroatheroma Compensatory expansive remodeling Quiescent plaque Contrictive remodeling Stenotic plaque Exessive expansive remodeling Thin cap fibroatheroma Erosion Physiologic coronary artery Local factors, e.g. low ESS Systemic factors, e.g. hyperlipidemia Genetic factors Physiologic ESS Limited inflammation Fibroproliferation Microruptures 18 ATHEROSCLEROSIS IS AN INFLAMMATORY DISEASE Libby P. Circulation. 2001;104:365-372; Ross R. N Engl J Med. 1999;340:115-126. Monocyte LDL-C Adhesion molecule Macrophage Foam cell OxidizedLDL-C Plaque rupture Smooth muscle cells CRP Plaque instability and thrombus Oxidation Inflammation Endothelial dysfunction 19 20 Reverse Cholesterol Transport Monocyte CRP TXA2 PGI2 Thrombin LDL Platelets HDL HDL Ox-LDL MCP-1 Macrophage P-selectin CD 40L PDGF Foam cell MMP T cell E-selectins CD 40L VCAM-1 ICAM-1 IL-1 Reilly, et.all. 2005 21 THE ROLE OF Lp-PLA2 IN CHD LUMEN Monocytes Adhesion Molecules Oxidated LDL INTIMA MEDIA Lp-PLA2 Lyso-PC OxFA Cytokines Plaque Formation Foam Cell Macrophage 22 MC T T FC FC LDL Oxidation Lyso-PC Ox-chol Cytokines Cytokines ? C5a C’ MCP-1 F SMC 23 Intracelluler proteolysis and fusion of LDL Figure : Proposed Dual Action of Exocytosed Mast Cell Granules (The Granule Remnants) of Lipoprotein Metabolism in The Arterial Intima 24 HSCRP 25 26 GM-CSF VCAM-1 MPC-1 Transcription Factors : Endothelial Cell Pro-inflammatory Genes Oxidative Stress NF-xB AP-1 Leucocyte infiltration / activation Plaque Rupture Gibbons, 97 LEUCOCYTE ACTIVATION IN ATHEROGENESIS : IMPLICATIONS FOR ACUTE ISCHEMIC SYNDROMES 27 p38 c-Jun activation Caspases Apoptosis NIK ? ? MEKK1?   CKII IKK complex TNFR-1 TNFR-1 IL-1R Shear stress p65 p50 CBP/p300 Gene activation p65 p50 IB pKAc IB Ub Target genes : - IL-1, IL-8, IL-6, IFN  - TNF, MCP-1 - CSFs, c-myc - VCAM-1, ICAM-1, E-selectin - Tissue factor - Survival factor Thurberg and Collins : Curr Opin Lipidol 9:387-396,1998 Ub Ox-LDL ROIs ??? Lipid peroxides ? H2O2 Ubiquitination and proteosome degradation T R A D D R I P F A D D R I P T R A D D T R A F 2 T R A F 6 28 Visual Medica. 2009 29 Stockley. 2006 Cytokines : IL-6, TNF-α MACROPHAGE FOAM CELL Oxidized LDL CRP CRP Chemokines: MCO-1 Atherosclerotic plaque MONOCYTE Inflammatory Mediators: CRP Prothrombotic factors FCR Receptor 30 POTENTIAL MECHANISM OF CRP Stevens, R. 2005 CRP LDL opsonisation Monocyte infiltration Foam cell formation Increased MCP-1 and CAM EC activation Inflammatory cell recruitment Atherosclerosis plaque formation Complement activation EC sensitisation T-cell attack EC damage Atherosclerotic plaque rupture 31 Rheumatoid arthritis Atherosclerosis Multiple sclerosis Asthma Inflammatory bowel disease Helicobacter pylori-associated gastritis Systemic inflammatory response syndrome NF-KB ACTIVATION INFLAMMATORY DISEASE The Journal of Clinical Investigation, 2001 32 PROTEIN REGULATED BY NF-KB Inflammatory Enzyme Adhesion Molecule Inducible nitric oxide synthase Inducide cylooxigenase-2 5-Lipoxigenase Cytosolic phospolipase A2 ICAM-1 VCAM-1 E-selectin Receptor Interlekin-2 receptor (alpha chain) T-cell receptors (beta chain) NEJM, 1997 33 BIOMARKERS OF ACTIVITY STUDIED FOR CAD Cytokines (IL-1β, IL-6, IL-8, IL-10, TNF-α, sCD40 ligand, myeloperoxidase) Adhesion molecules (sICAM-1, sVCAM-1, p-selectin) Acute phase reactans (fibrinogen, AAS, CRP) White blood cells Erythrocyte sedimentation rate Neopterin Heat shock proteins Adiponectin Lipoprotein associated phospholipase A2 Placental growth factos Cystatin C Kaski, JC. 2006. 34 Are you hungry or sleepy ???? Sciences 35 The inflammatory cascade. IL indicates interleukin; ICAM, intercellular adhesion molecule; and HSP, heat shock protein. (Libby, Ridker; 1999) Pro-Inflammatory Risk Factors Primary Pro-Inflammatory Cytokines (eg. IL-1, TNF-) IL-6 “Mesenger” Cytokine CRP SAA Endothelium and other cells LIVER Circulation 36 (Ridker, 2004) MORE THAN A MARKER : DOES CRP PLAY A DIRECT ROLE IN ATHEROTHROMBOSIS ? CRP localizes in atherosclerotic but not normal intima CRP induced Complement activation CRP dependent monocyte recruitment into arterial wall CRP induced production of tissue factor in monocytes CRP based blunting of endothelial vasoreactivity CRP mediated LDL uptake by macrophages CRP triggered oxidation of LDL cholesterol CRP induced PAI-1 expression stabilizes PAI-1 mRNA CRP attenuates NO production and decreases eNOS expression CRP induced production of cell adhesion moleculas MCP-1, ET-1 37 ROLE OF INFLAMATORY MARKERS Interleukin-6 Total cholesterol LDL-cholesterol siCAM-1 Serum amyloid A Apolipoprotein B Total cholesterol: HDL-cholesterol Hs-CRP Hs-CRP + total cholesterol: HDL-cholesterol 0 1.0 2.0 4.0 6.0 Relative Risk (New England Journal of Medicine) 38 39 Weissberg, 1999 Inflammation Repair 40 REDOX REGULATION OF ENDOTHELIAL DYSFUNCTION & ACTIVATION O2– OH H2O2  NO Activity  G-Protein Function  Protein Kinase C Oxidation Endothelial Dysfunction (D. Sargowo) 41 ENDOTHELIAL DYSFUNCTION AND ACUTE CORONARY SYNDROMES Vasoconstriction Platelet Aggregation SMC Proliferation Leukocyte Adhesion LDL Oxidation Activation of MMPs Endothelial Dysfunction Plaque Rupture Thrombosis Matrix Remodeling (D. Sargowo) 42 ENDOTHELIAL DYSFUNCTION AND ACUTE CORONARY SYNDROMES Vasospasm Plaque Rupture Thrombosis Matrix Remodeling ACUTE CORONARY SYNDROMES (D. Sargowo) 43 44 Diabetes Smoking AII Oxidative Stress Endothelial Dysfunction and Smooth Muscle Activation Growth FactorsCytokinesMatrix Proteolysis Inflammation VCAM/1CAMCytokines EndothelinCatecholamines BP LDL  NO • ∆ Local Mediators •  Tissue ACE, AII PAI-1, Platelet Aggregation, Tissue Factor Vasoconstriction Thrombosis Inflammation Plaque Rupture Vascular Lesion and Remodeling Clinical Sequelae Risk Factors Reprinted with permission from Dzau VJ. Hypertension. 2001;37:1047–1052. 45 THERAPEUTICS : WHERE DO WE STAND TODAY ? Lipid lowering drugs ACEI / ARB Peroxisome proliferators-activated receptor (PPAR) Chemokine receptor antagonist TNF Inhibitor MMP Inhibitor 46 BIOCHEMICAL PARAMETER FOR ENDOTHELIAL DYSFUNCTION - vWF - Thrombomodulin - E-Selection - ICAM-1 - VCAM-1 - NO - Microalbuminuria - PAI-1 (D. Sargowo) - Ox LDL – MDA – F2 - Isoprostane - LP – PLA2 - Lyso-PC OxFA BIOCHEMICAL PARAMETER FOR ENDOTHELIAL DYSFUNCTION - vWF - Thrombomodulin - E-Selection - NO - Microalbuminuria - PAI-1 - Ox LDL – MDA – F2 - Isoprostane - LP – PLA2 - Lyso-PC OxFA 47 INFLAMMATORY MARKERS FOR CONSIDERATION AS PREDICTORS OF CARDIOVASCULAR RISK Adhesion molecules Cytokines Acute-phase reactants Fibrinogen SAA CRP WBC count Other (eg, erytrocyte sedimentation rate) (Pearson et al, 2003) 48 SURREGATE BIOMARKERS FOR ACS HS CRP MMP Stromelysin Kalogenase Elastase INFj, TNF, IL1 Gelatinase LDH CPK MBCK Troponin T-I Fibrinogen Albuminuri D. Sargowo 49 Rudolf Virchow Inflammation-based arterial changes as a mechanism of primary importance in atherogenesis mid 19th century Lamond, B. The American Journal of Pathology. 2008 SUMMARY 50 51 Thank You 52 The Role of Lp-PLA2 in CHD LUMEN Monocytes Adhesion Molecules Oxidated LDL INTIMA MEDIA Lp-PLA2 Lyso-PC OxFA Cytokines Plaque Formation Foam Cell Macrophage 53 Intracelluler proteolysis and fusion of LDL Figure : Proposed Dual Action of Exocytosed Mast Cell Granules (The Granule Remnants) of Lipoprotein Metabolism in The Arterial Intima 54 55 24.7% 29.9% Coronary disease 7.4% ATHEROTHROMBOSIS IS COMMONLY FOUND IN MORE THAN ONE ARTERIAL BED IN AN INDIVIDUAL PATIENT* Cerebrovascular disease Peripheral arterial disease 3.8% 11.8% 19.2% * Data from CAPRIE study (n=19,185) Coccheri S. Eur Heart J 1998; 19(suppl): P1268. 3.3% 56 IKK- IKK IKK IKK Hemodynamic forces Matrix Cytokines LPS/LBP CD14 Oxidized lipids Ang II AGE RAGE AT1 SR TLR Cytokines receptor Integrin PLASMA MEMBRANE Chlamydia and virus Proteasome IKK complexes Inhibitors : IKB- IKB- IKB-r Bcl-3 (Ub)n P P IKB P65 P50 IKB P50 P65 P50 P65 NF-KB CYTOPLASM NUCLEUS 57
Slide 58 - 1 Nama : Prof. Dr. H. Djanggan Sargowo, dr., SpPD., SpJP(K), FIHA, FACC, FESC, FCAPC, FASCC Tempat/Tgl lahir : Sragen, 21 September 1947 Alamat : Wilis Indah E-10 Malang, Telp. 0341-552395 Pendidikan : Lulus Dokter dari UGM, tahun 1974 Lulus Cardiologist dari Univ. Indonesia, tahun 1983 Lulus Internist dari Univ. Airlangga, tahun 1986 Lulus Doktor, Univ. Airlangga, tahun 1996 Advanced Cardiology Course, Univ. Hongkong, tahun 1984 Senior Visiting Program, Institut Jantung Negara, Kualalumpur, 1996 Fellow American College of Cardiology (FACC), September 2006. Fellow Collage Asia Pacific Society of Cardiology (FCAPC), Desember 2007 Fellow European Sociaty of Cardiology (FESC), 2008 Fellow Asean Collage of Cardiology (FASCC), 2008 Jabatan : Dosen Pengajar Program Pascasarjana Universitas Brawijaya Ketua MKEK Ikatan Dokter Indonesia Cabang Malang Raya Ketua PERKI Cabang Malang Raya Anggota Kolegium Kardiovaskuler Indonesia Dekan Fak. Kedokteran Univ. Wijaya Kusuma Surabaya Ketua Dewan Pengawas Rumah Sakit Pendidikan Ketua Program Studi Kardiovascular Fak. Kedokteran Univ. Brawijaya Curriculum Vitae 2 Djanggan Sargowo Surabaya, 15 April 2012 INFLAMMATION IN ATHEROSCLEROSIS : FROM BENCH TO BEDSIDE 3 4 RUDOLF VIRCHOW Inflammation-based arterial changes as a mechanism of primary importance in atherogenesis mid 19th century Lamond, B. The American Journal of Pathology. 2008 5 Atherosclerosis Start from very young To Old age ? 6 Atherothrombosis* is aLeading Cause of Death Worldwide1† The World Health Report, 2002, WHO Geneva, 2002 28.7 17.8 12.6 9.1 6 5.1 0 5 10 15 20 25 30 Atherothrombosis* Infectious disease Cancer Injuries Pulmonary disease AIDS Mortality (%) * Ischemic heart disease, cerebrovascular disease, inflammatory heart disease and hypertensive heart disease † Worldwide defined as Member States by WHO Region (Africa, Americas, Eastern Mediterranean, European, South-East Asia and Western Pacific) 7 MAJOR CLINICAL MANIFESTATIONS OF ATHEROTHROMBOSIS Adapted from: Drouet L. Cerebrovasc Dis 2002; 13(suppl 1): 1–6. Transient ischemic attack Angina: Stable Unstable Ischemic stroke Myocardial infarction Peripheral arterial disease: Intermittent claudication Rest Pain Gangrene Necrosis 8  Dyslipidemia  Endothelial dysfunction  Free radicals  Immunologic Atherosclerosis/CAD THEORY AND CONCEPT OF ATHEROSCLEROSIS Inflamation (Sargowo, 1996) 9 Free Radical ATHEROGENESIS (Sargowo, 1996) 10 IDENTIFYING THOSE AT RISK OF ATHEROTHROMBOSIS Yusuf S et al. Circulation 2001; 104: 2746–53. 2. Drouet L. Cerebrovasc Dis 2002;13(suppl 1):1–6. Lifestyle Smoking Diet Lack of exercise Genetic Genetic traits Gender Age Generalized disorders Obesity Diabetes Systemic conditions History of vascular events Hypertension Hyperlipidemia Hypercoagulable states Homocystinemia Local factors Elevated prothrombotic factors: fibrinogen, CRP, PAI-1 Blood flow patterns, vessel diameter, arterial wall structure Atherothrombosis manifestations (myocardial infarction, stroke, vascular death) 11 Arici. 2010 Risk Factors for Atherosclerosis Classic Hypertension, Hyper-lipidemia, DM, Smoking Uremia Related Increase ox-LDL, Free radicals, Uremic toxin Infection Bacterial and viral infection Proinflammatory cytokine release Endothelial dysfunction Systemic inflammatory respones Acute phase response Elevated CRP Binding LDL, cemplement activation, tissue factor secretion Accelerated ATHEROSCLEROSIS 12 LDL CD40L=CD40 ligand; TNF-α=tumor necrosis factor-alpha; IL=interleukin; VCAM=vascular cell adhesion molecule; ICAM=intercellular adhesion molecule. Cockerill GW et al. Arterioscler Thromb Vasc Biol. 1995;15:1987-1994; Andre P et al. Circulation. 2002;106:896-899; Libby P. Circulation. 2001;104:365-372; Libby P et al. Circulation. 2002;105:1135-1143; Ross R. N Engl J Med. 1999;340:115-126. Vessel lumen Monocyte Macrophage Adhesionmolecules (VCAM-1, ICAM-1) Inflammatory mediators (CRP, CD40/CD40L, TNF-α, IL-1, IL-6) Intima Foam cell INFLAMMATION PROMOTES PROGRESSION OF ATHEROSCLEROSIS Endothelium LDL Ox-LDL 13 14 Atherosclerosis is a fibroproliferative and inflammatory process occurring ins response to a variety of vascular insults The insults come from classical risk factors ( HT, dyslipidemia, endothelial dysfunction, smoking, menopause, diabetes etc) and novel risk factors (Hcy, LVH, Lp(a), TG, oxidative stress, fibrinogen etc) Endothelial dysfunction is regarded as the first abnormality leading to atherosclerosis This implies that modulation of endothelial function may be used as strategy to intervene the process. 15 Two theories gain more acceptance: (a) the lipid theory (b) inflammation theory Endothelial dysfunction is now regarded as the first abnormality leading to AS. More novel cardiovascular risk factors are known, e.g.: Fibrinogen b. PAI-1 Homocysteins d. AT-1 e. CRP f. Lp(a) g. small-dense LDL h. infectious agents i. and more are emerging 16 Acute Coronary Syndrome (endocrine viewpoints) atherosclerotic lesions vascular funtions b.1. inflammatory reaction b.2. thrombogeneity b.3. vasoreactivity b.4. plaque stability b.5. shoulder of plaque endothelium balance between c.1. vasodilating, antithrombotic, antiproliferative factors (NO, prostacyclin, C-natriuretic peptide, EDHF) c.2. vasoconstricting, prothrombotic, proliferative factors (ET, superoxide, thromoboxan A2) 17 NATURAL HISTORY OF CORONARY ATHEROSCLEROSIS Chatzizisis et all. JACC. 2007. Asymtomatic Stable Angina Acute Coronary Syndrome Early fibroatheroma Compensatory expansive remodeling Quiescent plaque Contrictive remodeling Stenotic plaque Exessive expansive remodeling Thin cap fibroatheroma Erosion Physiologic coronary artery Local factors, e.g. low ESS Systemic factors, e.g. hyperlipidemia Genetic factors Physiologic ESS Limited inflammation Fibroproliferation Microruptures 18 ATHEROSCLEROSIS IS AN INFLAMMATORY DISEASE Libby P. Circulation. 2001;104:365-372; Ross R. N Engl J Med. 1999;340:115-126. Monocyte LDL-C Adhesion molecule Macrophage Foam cell OxidizedLDL-C Plaque rupture Smooth muscle cells CRP Plaque instability and thrombus Oxidation Inflammation Endothelial dysfunction 19 20 Reverse Cholesterol Transport Monocyte CRP TXA2 PGI2 Thrombin LDL Platelets HDL HDL Ox-LDL MCP-1 Macrophage P-selectin CD 40L PDGF Foam cell MMP T cell E-selectins CD 40L VCAM-1 ICAM-1 IL-1 Reilly, et.all. 2005 21 THE ROLE OF Lp-PLA2 IN CHD LUMEN Monocytes Adhesion Molecules Oxidated LDL INTIMA MEDIA Lp-PLA2 Lyso-PC OxFA Cytokines Plaque Formation Foam Cell Macrophage 22 MC T T FC FC LDL Oxidation Lyso-PC Ox-chol Cytokines Cytokines ? C5a C’ MCP-1 F SMC 23 Intracelluler proteolysis and fusion of LDL Figure : Proposed Dual Action of Exocytosed Mast Cell Granules (The Granule Remnants) of Lipoprotein Metabolism in The Arterial Intima 24 HSCRP 25 26 GM-CSF VCAM-1 MPC-1 Transcription Factors : Endothelial Cell Pro-inflammatory Genes Oxidative Stress NF-xB AP-1 Leucocyte infiltration / activation Plaque Rupture Gibbons, 97 LEUCOCYTE ACTIVATION IN ATHEROGENESIS : IMPLICATIONS FOR ACUTE ISCHEMIC SYNDROMES 27 p38 c-Jun activation Caspases Apoptosis NIK ? ? MEKK1?   CKII IKK complex TNFR-1 TNFR-1 IL-1R Shear stress p65 p50 CBP/p300 Gene activation p65 p50 IB pKAc IB Ub Target genes : - IL-1, IL-8, IL-6, IFN  - TNF, MCP-1 - CSFs, c-myc - VCAM-1, ICAM-1, E-selectin - Tissue factor - Survival factor Thurberg and Collins : Curr Opin Lipidol 9:387-396,1998 Ub Ox-LDL ROIs ??? Lipid peroxides ? H2O2 Ubiquitination and proteosome degradation T R A D D R I P F A D D R I P T R A D D T R A F 2 T R A F 6 28 Visual Medica. 2009 29 Stockley. 2006 Cytokines : IL-6, TNF-α MACROPHAGE FOAM CELL Oxidized LDL CRP CRP Chemokines: MCO-1 Atherosclerotic plaque MONOCYTE Inflammatory Mediators: CRP Prothrombotic factors FCR Receptor 30 POTENTIAL MECHANISM OF CRP Stevens, R. 2005 CRP LDL opsonisation Monocyte infiltration Foam cell formation Increased MCP-1 and CAM EC activation Inflammatory cell recruitment Atherosclerosis plaque formation Complement activation EC sensitisation T-cell attack EC damage Atherosclerotic plaque rupture 31 Rheumatoid arthritis Atherosclerosis Multiple sclerosis Asthma Inflammatory bowel disease Helicobacter pylori-associated gastritis Systemic inflammatory response syndrome NF-KB ACTIVATION INFLAMMATORY DISEASE The Journal of Clinical Investigation, 2001 32 PROTEIN REGULATED BY NF-KB Inflammatory Enzyme Adhesion Molecule Inducible nitric oxide synthase Inducide cylooxigenase-2 5-Lipoxigenase Cytosolic phospolipase A2 ICAM-1 VCAM-1 E-selectin Receptor Interlekin-2 receptor (alpha chain) T-cell receptors (beta chain) NEJM, 1997 33 BIOMARKERS OF ACTIVITY STUDIED FOR CAD Cytokines (IL-1β, IL-6, IL-8, IL-10, TNF-α, sCD40 ligand, myeloperoxidase) Adhesion molecules (sICAM-1, sVCAM-1, p-selectin) Acute phase reactans (fibrinogen, AAS, CRP) White blood cells Erythrocyte sedimentation rate Neopterin Heat shock proteins Adiponectin Lipoprotein associated phospholipase A2 Placental growth factos Cystatin C Kaski, JC. 2006. 34 Are you hungry or sleepy ???? Sciences 35 The inflammatory cascade. IL indicates interleukin; ICAM, intercellular adhesion molecule; and HSP, heat shock protein. (Libby, Ridker; 1999) Pro-Inflammatory Risk Factors Primary Pro-Inflammatory Cytokines (eg. IL-1, TNF-) IL-6 “Mesenger” Cytokine CRP SAA Endothelium and other cells LIVER Circulation 36 (Ridker, 2004) MORE THAN A MARKER : DOES CRP PLAY A DIRECT ROLE IN ATHEROTHROMBOSIS ? CRP localizes in atherosclerotic but not normal intima CRP induced Complement activation CRP dependent monocyte recruitment into arterial wall CRP induced production of tissue factor in monocytes CRP based blunting of endothelial vasoreactivity CRP mediated LDL uptake by macrophages CRP triggered oxidation of LDL cholesterol CRP induced PAI-1 expression stabilizes PAI-1 mRNA CRP attenuates NO production and decreases eNOS expression CRP induced production of cell adhesion moleculas MCP-1, ET-1 37 ROLE OF INFLAMATORY MARKERS Interleukin-6 Total cholesterol LDL-cholesterol siCAM-1 Serum amyloid A Apolipoprotein B Total cholesterol: HDL-cholesterol Hs-CRP Hs-CRP + total cholesterol: HDL-cholesterol 0 1.0 2.0 4.0 6.0 Relative Risk (New England Journal of Medicine) 38 39 Weissberg, 1999 Inflammation Repair 40 REDOX REGULATION OF ENDOTHELIAL DYSFUNCTION & ACTIVATION O2– OH H2O2  NO Activity  G-Protein Function  Protein Kinase C Oxidation Endothelial Dysfunction (D. Sargowo) 41 ENDOTHELIAL DYSFUNCTION AND ACUTE CORONARY SYNDROMES Vasoconstriction Platelet Aggregation SMC Proliferation Leukocyte Adhesion LDL Oxidation Activation of MMPs Endothelial Dysfunction Plaque Rupture Thrombosis Matrix Remodeling (D. Sargowo) 42 ENDOTHELIAL DYSFUNCTION AND ACUTE CORONARY SYNDROMES Vasospasm Plaque Rupture Thrombosis Matrix Remodeling ACUTE CORONARY SYNDROMES (D. Sargowo) 43 44 Diabetes Smoking AII Oxidative Stress Endothelial Dysfunction and Smooth Muscle Activation Growth FactorsCytokinesMatrix Proteolysis Inflammation VCAM/1CAMCytokines EndothelinCatecholamines BP LDL  NO • ∆ Local Mediators •  Tissue ACE, AII PAI-1, Platelet Aggregation, Tissue Factor Vasoconstriction Thrombosis Inflammation Plaque Rupture Vascular Lesion and Remodeling Clinical Sequelae Risk Factors Reprinted with permission from Dzau VJ. Hypertension. 2001;37:1047–1052. 45 THERAPEUTICS : WHERE DO WE STAND TODAY ? Lipid lowering drugs ACEI / ARB Peroxisome proliferators-activated receptor (PPAR) Chemokine receptor antagonist TNF Inhibitor MMP Inhibitor 46 BIOCHEMICAL PARAMETER FOR ENDOTHELIAL DYSFUNCTION - vWF - Thrombomodulin - E-Selection - ICAM-1 - VCAM-1 - NO - Microalbuminuria - PAI-1 (D. Sargowo) - Ox LDL – MDA – F2 - Isoprostane - LP – PLA2 - Lyso-PC OxFA BIOCHEMICAL PARAMETER FOR ENDOTHELIAL DYSFUNCTION - vWF - Thrombomodulin - E-Selection - NO - Microalbuminuria - PAI-1 - Ox LDL – MDA – F2 - Isoprostane - LP – PLA2 - Lyso-PC OxFA 47 INFLAMMATORY MARKERS FOR CONSIDERATION AS PREDICTORS OF CARDIOVASCULAR RISK Adhesion molecules Cytokines Acute-phase reactants Fibrinogen SAA CRP WBC count Other (eg, erytrocyte sedimentation rate) (Pearson et al, 2003) 48 SURREGATE BIOMARKERS FOR ACS HS CRP MMP Stromelysin Kalogenase Elastase INFj, TNF, IL1 Gelatinase LDH CPK MBCK Troponin T-I Fibrinogen Albuminuri D. Sargowo 49 Rudolf Virchow Inflammation-based arterial changes as a mechanism of primary importance in atherogenesis mid 19th century Lamond, B. The American Journal of Pathology. 2008 SUMMARY 50 51 Thank You 52 The Role of Lp-PLA2 in CHD LUMEN Monocytes Adhesion Molecules Oxidated LDL INTIMA MEDIA Lp-PLA2 Lyso-PC OxFA Cytokines Plaque Formation Foam Cell Macrophage 53 Intracelluler proteolysis and fusion of LDL Figure : Proposed Dual Action of Exocytosed Mast Cell Granules (The Granule Remnants) of Lipoprotein Metabolism in The Arterial Intima 54 55 24.7% 29.9% Coronary disease 7.4% ATHEROTHROMBOSIS IS COMMONLY FOUND IN MORE THAN ONE ARTERIAL BED IN AN INDIVIDUAL PATIENT* Cerebrovascular disease Peripheral arterial disease 3.8% 11.8% 19.2% * Data from CAPRIE study (n=19,185) Coccheri S. Eur Heart J 1998; 19(suppl): P1268. 3.3% 56 IKK- IKK IKK IKK Hemodynamic forces Matrix Cytokines LPS/LBP CD14 Oxidized lipids Ang II AGE RAGE AT1 SR TLR Cytokines receptor Integrin PLASMA MEMBRANE Chlamydia and virus Proteasome IKK complexes Inhibitors : IKB- IKB- IKB-r Bcl-3 (Ub)n P P IKB P65 P50 IKB P50 P65 P50 P65 NF-KB CYTOPLASM NUCLEUS 57 58 The Role of T-Lymphocyte in Atherogenesis Libby, P. 2002
Slide 59 - 1 Nama : Prof. Dr. H. Djanggan Sargowo, dr., SpPD., SpJP(K), FIHA, FACC, FESC, FCAPC, FASCC Tempat/Tgl lahir : Sragen, 21 September 1947 Alamat : Wilis Indah E-10 Malang, Telp. 0341-552395 Pendidikan : Lulus Dokter dari UGM, tahun 1974 Lulus Cardiologist dari Univ. Indonesia, tahun 1983 Lulus Internist dari Univ. Airlangga, tahun 1986 Lulus Doktor, Univ. Airlangga, tahun 1996 Advanced Cardiology Course, Univ. Hongkong, tahun 1984 Senior Visiting Program, Institut Jantung Negara, Kualalumpur, 1996 Fellow American College of Cardiology (FACC), September 2006. Fellow Collage Asia Pacific Society of Cardiology (FCAPC), Desember 2007 Fellow European Sociaty of Cardiology (FESC), 2008 Fellow Asean Collage of Cardiology (FASCC), 2008 Jabatan : Dosen Pengajar Program Pascasarjana Universitas Brawijaya Ketua MKEK Ikatan Dokter Indonesia Cabang Malang Raya Ketua PERKI Cabang Malang Raya Anggota Kolegium Kardiovaskuler Indonesia Dekan Fak. Kedokteran Univ. Wijaya Kusuma Surabaya Ketua Dewan Pengawas Rumah Sakit Pendidikan Ketua Program Studi Kardiovascular Fak. Kedokteran Univ. Brawijaya Curriculum Vitae 2 Djanggan Sargowo Surabaya, 15 April 2012 INFLAMMATION IN ATHEROSCLEROSIS : FROM BENCH TO BEDSIDE 3 4 RUDOLF VIRCHOW Inflammation-based arterial changes as a mechanism of primary importance in atherogenesis mid 19th century Lamond, B. The American Journal of Pathology. 2008 5 Atherosclerosis Start from very young To Old age ? 6 Atherothrombosis* is aLeading Cause of Death Worldwide1† The World Health Report, 2002, WHO Geneva, 2002 28.7 17.8 12.6 9.1 6 5.1 0 5 10 15 20 25 30 Atherothrombosis* Infectious disease Cancer Injuries Pulmonary disease AIDS Mortality (%) * Ischemic heart disease, cerebrovascular disease, inflammatory heart disease and hypertensive heart disease † Worldwide defined as Member States by WHO Region (Africa, Americas, Eastern Mediterranean, European, South-East Asia and Western Pacific) 7 MAJOR CLINICAL MANIFESTATIONS OF ATHEROTHROMBOSIS Adapted from: Drouet L. Cerebrovasc Dis 2002; 13(suppl 1): 1–6. Transient ischemic attack Angina: Stable Unstable Ischemic stroke Myocardial infarction Peripheral arterial disease: Intermittent claudication Rest Pain Gangrene Necrosis 8  Dyslipidemia  Endothelial dysfunction  Free radicals  Immunologic Atherosclerosis/CAD THEORY AND CONCEPT OF ATHEROSCLEROSIS Inflamation (Sargowo, 1996) 9 Free Radical ATHEROGENESIS (Sargowo, 1996) 10 IDENTIFYING THOSE AT RISK OF ATHEROTHROMBOSIS Yusuf S et al. Circulation 2001; 104: 2746–53. 2. Drouet L. Cerebrovasc Dis 2002;13(suppl 1):1–6. Lifestyle Smoking Diet Lack of exercise Genetic Genetic traits Gender Age Generalized disorders Obesity Diabetes Systemic conditions History of vascular events Hypertension Hyperlipidemia Hypercoagulable states Homocystinemia Local factors Elevated prothrombotic factors: fibrinogen, CRP, PAI-1 Blood flow patterns, vessel diameter, arterial wall structure Atherothrombosis manifestations (myocardial infarction, stroke, vascular death) 11 Arici. 2010 Risk Factors for Atherosclerosis Classic Hypertension, Hyper-lipidemia, DM, Smoking Uremia Related Increase ox-LDL, Free radicals, Uremic toxin Infection Bacterial and viral infection Proinflammatory cytokine release Endothelial dysfunction Systemic inflammatory respones Acute phase response Elevated CRP Binding LDL, cemplement activation, tissue factor secretion Accelerated ATHEROSCLEROSIS 12 LDL CD40L=CD40 ligand; TNF-α=tumor necrosis factor-alpha; IL=interleukin; VCAM=vascular cell adhesion molecule; ICAM=intercellular adhesion molecule. Cockerill GW et al. Arterioscler Thromb Vasc Biol. 1995;15:1987-1994; Andre P et al. Circulation. 2002;106:896-899; Libby P. Circulation. 2001;104:365-372; Libby P et al. Circulation. 2002;105:1135-1143; Ross R. N Engl J Med. 1999;340:115-126. Vessel lumen Monocyte Macrophage Adhesionmolecules (VCAM-1, ICAM-1) Inflammatory mediators (CRP, CD40/CD40L, TNF-α, IL-1, IL-6) Intima Foam cell INFLAMMATION PROMOTES PROGRESSION OF ATHEROSCLEROSIS Endothelium LDL Ox-LDL 13 14 Atherosclerosis is a fibroproliferative and inflammatory process occurring ins response to a variety of vascular insults The insults come from classical risk factors ( HT, dyslipidemia, endothelial dysfunction, smoking, menopause, diabetes etc) and novel risk factors (Hcy, LVH, Lp(a), TG, oxidative stress, fibrinogen etc) Endothelial dysfunction is regarded as the first abnormality leading to atherosclerosis This implies that modulation of endothelial function may be used as strategy to intervene the process. 15 Two theories gain more acceptance: (a) the lipid theory (b) inflammation theory Endothelial dysfunction is now regarded as the first abnormality leading to AS. More novel cardiovascular risk factors are known, e.g.: Fibrinogen b. PAI-1 Homocysteins d. AT-1 e. CRP f. Lp(a) g. small-dense LDL h. infectious agents i. and more are emerging 16 Acute Coronary Syndrome (endocrine viewpoints) atherosclerotic lesions vascular funtions b.1. inflammatory reaction b.2. thrombogeneity b.3. vasoreactivity b.4. plaque stability b.5. shoulder of plaque endothelium balance between c.1. vasodilating, antithrombotic, antiproliferative factors (NO, prostacyclin, C-natriuretic peptide, EDHF) c.2. vasoconstricting, prothrombotic, proliferative factors (ET, superoxide, thromoboxan A2) 17 NATURAL HISTORY OF CORONARY ATHEROSCLEROSIS Chatzizisis et all. JACC. 2007. Asymtomatic Stable Angina Acute Coronary Syndrome Early fibroatheroma Compensatory expansive remodeling Quiescent plaque Contrictive remodeling Stenotic plaque Exessive expansive remodeling Thin cap fibroatheroma Erosion Physiologic coronary artery Local factors, e.g. low ESS Systemic factors, e.g. hyperlipidemia Genetic factors Physiologic ESS Limited inflammation Fibroproliferation Microruptures 18 ATHEROSCLEROSIS IS AN INFLAMMATORY DISEASE Libby P. Circulation. 2001;104:365-372; Ross R. N Engl J Med. 1999;340:115-126. Monocyte LDL-C Adhesion molecule Macrophage Foam cell OxidizedLDL-C Plaque rupture Smooth muscle cells CRP Plaque instability and thrombus Oxidation Inflammation Endothelial dysfunction 19 20 Reverse Cholesterol Transport Monocyte CRP TXA2 PGI2 Thrombin LDL Platelets HDL HDL Ox-LDL MCP-1 Macrophage P-selectin CD 40L PDGF Foam cell MMP T cell E-selectins CD 40L VCAM-1 ICAM-1 IL-1 Reilly, et.all. 2005 21 THE ROLE OF Lp-PLA2 IN CHD LUMEN Monocytes Adhesion Molecules Oxidated LDL INTIMA MEDIA Lp-PLA2 Lyso-PC OxFA Cytokines Plaque Formation Foam Cell Macrophage 22 MC T T FC FC LDL Oxidation Lyso-PC Ox-chol Cytokines Cytokines ? C5a C’ MCP-1 F SMC 23 Intracelluler proteolysis and fusion of LDL Figure : Proposed Dual Action of Exocytosed Mast Cell Granules (The Granule Remnants) of Lipoprotein Metabolism in The Arterial Intima 24 HSCRP 25 26 GM-CSF VCAM-1 MPC-1 Transcription Factors : Endothelial Cell Pro-inflammatory Genes Oxidative Stress NF-xB AP-1 Leucocyte infiltration / activation Plaque Rupture Gibbons, 97 LEUCOCYTE ACTIVATION IN ATHEROGENESIS : IMPLICATIONS FOR ACUTE ISCHEMIC SYNDROMES 27 p38 c-Jun activation Caspases Apoptosis NIK ? ? MEKK1?   CKII IKK complex TNFR-1 TNFR-1 IL-1R Shear stress p65 p50 CBP/p300 Gene activation p65 p50 IB pKAc IB Ub Target genes : - IL-1, IL-8, IL-6, IFN  - TNF, MCP-1 - CSFs, c-myc - VCAM-1, ICAM-1, E-selectin - Tissue factor - Survival factor Thurberg and Collins : Curr Opin Lipidol 9:387-396,1998 Ub Ox-LDL ROIs ??? Lipid peroxides ? H2O2 Ubiquitination and proteosome degradation T R A D D R I P F A D D R I P T R A D D T R A F 2 T R A F 6 28 Visual Medica. 2009 29 Stockley. 2006 Cytokines : IL-6, TNF-α MACROPHAGE FOAM CELL Oxidized LDL CRP CRP Chemokines: MCO-1 Atherosclerotic plaque MONOCYTE Inflammatory Mediators: CRP Prothrombotic factors FCR Receptor 30 POTENTIAL MECHANISM OF CRP Stevens, R. 2005 CRP LDL opsonisation Monocyte infiltration Foam cell formation Increased MCP-1 and CAM EC activation Inflammatory cell recruitment Atherosclerosis plaque formation Complement activation EC sensitisation T-cell attack EC damage Atherosclerotic plaque rupture 31 Rheumatoid arthritis Atherosclerosis Multiple sclerosis Asthma Inflammatory bowel disease Helicobacter pylori-associated gastritis Systemic inflammatory response syndrome NF-KB ACTIVATION INFLAMMATORY DISEASE The Journal of Clinical Investigation, 2001 32 PROTEIN REGULATED BY NF-KB Inflammatory Enzyme Adhesion Molecule Inducible nitric oxide synthase Inducide cylooxigenase-2 5-Lipoxigenase Cytosolic phospolipase A2 ICAM-1 VCAM-1 E-selectin Receptor Interlekin-2 receptor (alpha chain) T-cell receptors (beta chain) NEJM, 1997 33 BIOMARKERS OF ACTIVITY STUDIED FOR CAD Cytokines (IL-1β, IL-6, IL-8, IL-10, TNF-α, sCD40 ligand, myeloperoxidase) Adhesion molecules (sICAM-1, sVCAM-1, p-selectin) Acute phase reactans (fibrinogen, AAS, CRP) White blood cells Erythrocyte sedimentation rate Neopterin Heat shock proteins Adiponectin Lipoprotein associated phospholipase A2 Placental growth factos Cystatin C Kaski, JC. 2006. 34 Are you hungry or sleepy ???? Sciences 35 The inflammatory cascade. IL indicates interleukin; ICAM, intercellular adhesion molecule; and HSP, heat shock protein. (Libby, Ridker; 1999) Pro-Inflammatory Risk Factors Primary Pro-Inflammatory Cytokines (eg. IL-1, TNF-) IL-6 “Mesenger” Cytokine CRP SAA Endothelium and other cells LIVER Circulation 36 (Ridker, 2004) MORE THAN A MARKER : DOES CRP PLAY A DIRECT ROLE IN ATHEROTHROMBOSIS ? CRP localizes in atherosclerotic but not normal intima CRP induced Complement activation CRP dependent monocyte recruitment into arterial wall CRP induced production of tissue factor in monocytes CRP based blunting of endothelial vasoreactivity CRP mediated LDL uptake by macrophages CRP triggered oxidation of LDL cholesterol CRP induced PAI-1 expression stabilizes PAI-1 mRNA CRP attenuates NO production and decreases eNOS expression CRP induced production of cell adhesion moleculas MCP-1, ET-1 37 ROLE OF INFLAMATORY MARKERS Interleukin-6 Total cholesterol LDL-cholesterol siCAM-1 Serum amyloid A Apolipoprotein B Total cholesterol: HDL-cholesterol Hs-CRP Hs-CRP + total cholesterol: HDL-cholesterol 0 1.0 2.0 4.0 6.0 Relative Risk (New England Journal of Medicine) 38 39 Weissberg, 1999 Inflammation Repair 40 REDOX REGULATION OF ENDOTHELIAL DYSFUNCTION & ACTIVATION O2– OH H2O2  NO Activity  G-Protein Function  Protein Kinase C Oxidation Endothelial Dysfunction (D. Sargowo) 41 ENDOTHELIAL DYSFUNCTION AND ACUTE CORONARY SYNDROMES Vasoconstriction Platelet Aggregation SMC Proliferation Leukocyte Adhesion LDL Oxidation Activation of MMPs Endothelial Dysfunction Plaque Rupture Thrombosis Matrix Remodeling (D. Sargowo) 42 ENDOTHELIAL DYSFUNCTION AND ACUTE CORONARY SYNDROMES Vasospasm Plaque Rupture Thrombosis Matrix Remodeling ACUTE CORONARY SYNDROMES (D. Sargowo) 43 44 Diabetes Smoking AII Oxidative Stress Endothelial Dysfunction and Smooth Muscle Activation Growth FactorsCytokinesMatrix Proteolysis Inflammation VCAM/1CAMCytokines EndothelinCatecholamines BP LDL  NO • ∆ Local Mediators •  Tissue ACE, AII PAI-1, Platelet Aggregation, Tissue Factor Vasoconstriction Thrombosis Inflammation Plaque Rupture Vascular Lesion and Remodeling Clinical Sequelae Risk Factors Reprinted with permission from Dzau VJ. Hypertension. 2001;37:1047–1052. 45 THERAPEUTICS : WHERE DO WE STAND TODAY ? Lipid lowering drugs ACEI / ARB Peroxisome proliferators-activated receptor (PPAR) Chemokine receptor antagonist TNF Inhibitor MMP Inhibitor 46 BIOCHEMICAL PARAMETER FOR ENDOTHELIAL DYSFUNCTION - vWF - Thrombomodulin - E-Selection - ICAM-1 - VCAM-1 - NO - Microalbuminuria - PAI-1 (D. Sargowo) - Ox LDL – MDA – F2 - Isoprostane - LP – PLA2 - Lyso-PC OxFA BIOCHEMICAL PARAMETER FOR ENDOTHELIAL DYSFUNCTION - vWF - Thrombomodulin - E-Selection - NO - Microalbuminuria - PAI-1 - Ox LDL – MDA – F2 - Isoprostane - LP – PLA2 - Lyso-PC OxFA 47 INFLAMMATORY MARKERS FOR CONSIDERATION AS PREDICTORS OF CARDIOVASCULAR RISK Adhesion molecules Cytokines Acute-phase reactants Fibrinogen SAA CRP WBC count Other (eg, erytrocyte sedimentation rate) (Pearson et al, 2003) 48 SURREGATE BIOMARKERS FOR ACS HS CRP MMP Stromelysin Kalogenase Elastase INFj, TNF, IL1 Gelatinase LDH CPK MBCK Troponin T-I Fibrinogen Albuminuri D. Sargowo 49 Rudolf Virchow Inflammation-based arterial changes as a mechanism of primary importance in atherogenesis mid 19th century Lamond, B. The American Journal of Pathology. 2008 SUMMARY 50 51 Thank You 52 The Role of Lp-PLA2 in CHD LUMEN Monocytes Adhesion Molecules Oxidated LDL INTIMA MEDIA Lp-PLA2 Lyso-PC OxFA Cytokines Plaque Formation Foam Cell Macrophage 53 Intracelluler proteolysis and fusion of LDL Figure : Proposed Dual Action of Exocytosed Mast Cell Granules (The Granule Remnants) of Lipoprotein Metabolism in The Arterial Intima 54 55 24.7% 29.9% Coronary disease 7.4% ATHEROTHROMBOSIS IS COMMONLY FOUND IN MORE THAN ONE ARTERIAL BED IN AN INDIVIDUAL PATIENT* Cerebrovascular disease Peripheral arterial disease 3.8% 11.8% 19.2% * Data from CAPRIE study (n=19,185) Coccheri S. Eur Heart J 1998; 19(suppl): P1268. 3.3% 56 IKK- IKK IKK IKK Hemodynamic forces Matrix Cytokines LPS/LBP CD14 Oxidized lipids Ang II AGE RAGE AT1 SR TLR Cytokines receptor Integrin PLASMA MEMBRANE Chlamydia and virus Proteasome IKK complexes Inhibitors : IKB- IKB- IKB-r Bcl-3 (Ub)n P P IKB P65 P50 IKB P50 P65 P50 P65 NF-KB CYTOPLASM NUCLEUS 57 58 The Role of T-Lymphocyte in Atherogenesis Libby, P. 2002 59 p38 c-Jun activation Caspases Apoptosis NIK ? ? MEKK1?   CKII IKK complex TNFR-1 TNFR-1 IL-1R Shear stress p65 p50 CBP/p300 Gene activation IB Ub Target genes : - IL-1, IL-8, IL-6, IFN  - TNF, MCP-1 - CSFs, c-myc - VCAM-1, ICAM-1, E-selectin - Tissue factor - Survival factor Thurberg and Collins : Curr Opin Lipidol 9:387-396,1998 Ub Ox-LDL ROIs ??? Lipid peroxides ? H2O2 Ubiquitination and proteosome degradation
Slide 60 - 1 Nama : Prof. Dr. H. Djanggan Sargowo, dr., SpPD., SpJP(K), FIHA, FACC, FESC, FCAPC, FASCC Tempat/Tgl lahir : Sragen, 21 September 1947 Alamat : Wilis Indah E-10 Malang, Telp. 0341-552395 Pendidikan : Lulus Dokter dari UGM, tahun 1974 Lulus Cardiologist dari Univ. Indonesia, tahun 1983 Lulus Internist dari Univ. Airlangga, tahun 1986 Lulus Doktor, Univ. Airlangga, tahun 1996 Advanced Cardiology Course, Univ. Hongkong, tahun 1984 Senior Visiting Program, Institut Jantung Negara, Kualalumpur, 1996 Fellow American College of Cardiology (FACC), September 2006. Fellow Collage Asia Pacific Society of Cardiology (FCAPC), Desember 2007 Fellow European Sociaty of Cardiology (FESC), 2008 Fellow Asean Collage of Cardiology (FASCC), 2008 Jabatan : Dosen Pengajar Program Pascasarjana Universitas Brawijaya Ketua MKEK Ikatan Dokter Indonesia Cabang Malang Raya Ketua PERKI Cabang Malang Raya Anggota Kolegium Kardiovaskuler Indonesia Dekan Fak. Kedokteran Univ. Wijaya Kusuma Surabaya Ketua Dewan Pengawas Rumah Sakit Pendidikan Ketua Program Studi Kardiovascular Fak. Kedokteran Univ. Brawijaya Curriculum Vitae 2 Djanggan Sargowo Surabaya, 15 April 2012 INFLAMMATION IN ATHEROSCLEROSIS : FROM BENCH TO BEDSIDE 3 4 RUDOLF VIRCHOW Inflammation-based arterial changes as a mechanism of primary importance in atherogenesis mid 19th century Lamond, B. The American Journal of Pathology. 2008 5 Atherosclerosis Start from very young To Old age ? 6 Atherothrombosis* is aLeading Cause of Death Worldwide1† The World Health Report, 2002, WHO Geneva, 2002 28.7 17.8 12.6 9.1 6 5.1 0 5 10 15 20 25 30 Atherothrombosis* Infectious disease Cancer Injuries Pulmonary disease AIDS Mortality (%) * Ischemic heart disease, cerebrovascular disease, inflammatory heart disease and hypertensive heart disease † Worldwide defined as Member States by WHO Region (Africa, Americas, Eastern Mediterranean, European, South-East Asia and Western Pacific) 7 MAJOR CLINICAL MANIFESTATIONS OF ATHEROTHROMBOSIS Adapted from: Drouet L. Cerebrovasc Dis 2002; 13(suppl 1): 1–6. Transient ischemic attack Angina: Stable Unstable Ischemic stroke Myocardial infarction Peripheral arterial disease: Intermittent claudication Rest Pain Gangrene Necrosis 8  Dyslipidemia  Endothelial dysfunction  Free radicals  Immunologic Atherosclerosis/CAD THEORY AND CONCEPT OF ATHEROSCLEROSIS Inflamation (Sargowo, 1996) 9 Free Radical ATHEROGENESIS (Sargowo, 1996) 10 IDENTIFYING THOSE AT RISK OF ATHEROTHROMBOSIS Yusuf S et al. Circulation 2001; 104: 2746–53. 2. Drouet L. Cerebrovasc Dis 2002;13(suppl 1):1–6. Lifestyle Smoking Diet Lack of exercise Genetic Genetic traits Gender Age Generalized disorders Obesity Diabetes Systemic conditions History of vascular events Hypertension Hyperlipidemia Hypercoagulable states Homocystinemia Local factors Elevated prothrombotic factors: fibrinogen, CRP, PAI-1 Blood flow patterns, vessel diameter, arterial wall structure Atherothrombosis manifestations (myocardial infarction, stroke, vascular death) 11 Arici. 2010 Risk Factors for Atherosclerosis Classic Hypertension, Hyper-lipidemia, DM, Smoking Uremia Related Increase ox-LDL, Free radicals, Uremic toxin Infection Bacterial and viral infection Proinflammatory cytokine release Endothelial dysfunction Systemic inflammatory respones Acute phase response Elevated CRP Binding LDL, cemplement activation, tissue factor secretion Accelerated ATHEROSCLEROSIS 12 LDL CD40L=CD40 ligand; TNF-α=tumor necrosis factor-alpha; IL=interleukin; VCAM=vascular cell adhesion molecule; ICAM=intercellular adhesion molecule. Cockerill GW et al. Arterioscler Thromb Vasc Biol. 1995;15:1987-1994; Andre P et al. Circulation. 2002;106:896-899; Libby P. Circulation. 2001;104:365-372; Libby P et al. Circulation. 2002;105:1135-1143; Ross R. N Engl J Med. 1999;340:115-126. Vessel lumen Monocyte Macrophage Adhesionmolecules (VCAM-1, ICAM-1) Inflammatory mediators (CRP, CD40/CD40L, TNF-α, IL-1, IL-6) Intima Foam cell INFLAMMATION PROMOTES PROGRESSION OF ATHEROSCLEROSIS Endothelium LDL Ox-LDL 13 14 Atherosclerosis is a fibroproliferative and inflammatory process occurring ins response to a variety of vascular insults The insults come from classical risk factors ( HT, dyslipidemia, endothelial dysfunction, smoking, menopause, diabetes etc) and novel risk factors (Hcy, LVH, Lp(a), TG, oxidative stress, fibrinogen etc) Endothelial dysfunction is regarded as the first abnormality leading to atherosclerosis This implies that modulation of endothelial function may be used as strategy to intervene the process. 15 Two theories gain more acceptance: (a) the lipid theory (b) inflammation theory Endothelial dysfunction is now regarded as the first abnormality leading to AS. More novel cardiovascular risk factors are known, e.g.: Fibrinogen b. PAI-1 Homocysteins d. AT-1 e. CRP f. Lp(a) g. small-dense LDL h. infectious agents i. and more are emerging 16 Acute Coronary Syndrome (endocrine viewpoints) atherosclerotic lesions vascular funtions b.1. inflammatory reaction b.2. thrombogeneity b.3. vasoreactivity b.4. plaque stability b.5. shoulder of plaque endothelium balance between c.1. vasodilating, antithrombotic, antiproliferative factors (NO, prostacyclin, C-natriuretic peptide, EDHF) c.2. vasoconstricting, prothrombotic, proliferative factors (ET, superoxide, thromoboxan A2) 17 NATURAL HISTORY OF CORONARY ATHEROSCLEROSIS Chatzizisis et all. JACC. 2007. Asymtomatic Stable Angina Acute Coronary Syndrome Early fibroatheroma Compensatory expansive remodeling Quiescent plaque Contrictive remodeling Stenotic plaque Exessive expansive remodeling Thin cap fibroatheroma Erosion Physiologic coronary artery Local factors, e.g. low ESS Systemic factors, e.g. hyperlipidemia Genetic factors Physiologic ESS Limited inflammation Fibroproliferation Microruptures 18 ATHEROSCLEROSIS IS AN INFLAMMATORY DISEASE Libby P. Circulation. 2001;104:365-372; Ross R. N Engl J Med. 1999;340:115-126. Monocyte LDL-C Adhesion molecule Macrophage Foam cell OxidizedLDL-C Plaque rupture Smooth muscle cells CRP Plaque instability and thrombus Oxidation Inflammation Endothelial dysfunction 19 20 Reverse Cholesterol Transport Monocyte CRP TXA2 PGI2 Thrombin LDL Platelets HDL HDL Ox-LDL MCP-1 Macrophage P-selectin CD 40L PDGF Foam cell MMP T cell E-selectins CD 40L VCAM-1 ICAM-1 IL-1 Reilly, et.all. 2005 21 THE ROLE OF Lp-PLA2 IN CHD LUMEN Monocytes Adhesion Molecules Oxidated LDL INTIMA MEDIA Lp-PLA2 Lyso-PC OxFA Cytokines Plaque Formation Foam Cell Macrophage 22 MC T T FC FC LDL Oxidation Lyso-PC Ox-chol Cytokines Cytokines ? C5a C’ MCP-1 F SMC 23 Intracelluler proteolysis and fusion of LDL Figure : Proposed Dual Action of Exocytosed Mast Cell Granules (The Granule Remnants) of Lipoprotein Metabolism in The Arterial Intima 24 HSCRP 25 26 GM-CSF VCAM-1 MPC-1 Transcription Factors : Endothelial Cell Pro-inflammatory Genes Oxidative Stress NF-xB AP-1 Leucocyte infiltration / activation Plaque Rupture Gibbons, 97 LEUCOCYTE ACTIVATION IN ATHEROGENESIS : IMPLICATIONS FOR ACUTE ISCHEMIC SYNDROMES 27 p38 c-Jun activation Caspases Apoptosis NIK ? ? MEKK1?   CKII IKK complex TNFR-1 TNFR-1 IL-1R Shear stress p65 p50 CBP/p300 Gene activation p65 p50 IB pKAc IB Ub Target genes : - IL-1, IL-8, IL-6, IFN  - TNF, MCP-1 - CSFs, c-myc - VCAM-1, ICAM-1, E-selectin - Tissue factor - Survival factor Thurberg and Collins : Curr Opin Lipidol 9:387-396,1998 Ub Ox-LDL ROIs ??? Lipid peroxides ? H2O2 Ubiquitination and proteosome degradation T R A D D R I P F A D D R I P T R A D D T R A F 2 T R A F 6 28 Visual Medica. 2009 29 Stockley. 2006 Cytokines : IL-6, TNF-α MACROPHAGE FOAM CELL Oxidized LDL CRP CRP Chemokines: MCO-1 Atherosclerotic plaque MONOCYTE Inflammatory Mediators: CRP Prothrombotic factors FCR Receptor 30 POTENTIAL MECHANISM OF CRP Stevens, R. 2005 CRP LDL opsonisation Monocyte infiltration Foam cell formation Increased MCP-1 and CAM EC activation Inflammatory cell recruitment Atherosclerosis plaque formation Complement activation EC sensitisation T-cell attack EC damage Atherosclerotic plaque rupture 31 Rheumatoid arthritis Atherosclerosis Multiple sclerosis Asthma Inflammatory bowel disease Helicobacter pylori-associated gastritis Systemic inflammatory response syndrome NF-KB ACTIVATION INFLAMMATORY DISEASE The Journal of Clinical Investigation, 2001 32 PROTEIN REGULATED BY NF-KB Inflammatory Enzyme Adhesion Molecule Inducible nitric oxide synthase Inducide cylooxigenase-2 5-Lipoxigenase Cytosolic phospolipase A2 ICAM-1 VCAM-1 E-selectin Receptor Interlekin-2 receptor (alpha chain) T-cell receptors (beta chain) NEJM, 1997 33 BIOMARKERS OF ACTIVITY STUDIED FOR CAD Cytokines (IL-1β, IL-6, IL-8, IL-10, TNF-α, sCD40 ligand, myeloperoxidase) Adhesion molecules (sICAM-1, sVCAM-1, p-selectin) Acute phase reactans (fibrinogen, AAS, CRP) White blood cells Erythrocyte sedimentation rate Neopterin Heat shock proteins Adiponectin Lipoprotein associated phospholipase A2 Placental growth factos Cystatin C Kaski, JC. 2006. 34 Are you hungry or sleepy ???? Sciences 35 The inflammatory cascade. IL indicates interleukin; ICAM, intercellular adhesion molecule; and HSP, heat shock protein. (Libby, Ridker; 1999) Pro-Inflammatory Risk Factors Primary Pro-Inflammatory Cytokines (eg. IL-1, TNF-) IL-6 “Mesenger” Cytokine CRP SAA Endothelium and other cells LIVER Circulation 36 (Ridker, 2004) MORE THAN A MARKER : DOES CRP PLAY A DIRECT ROLE IN ATHEROTHROMBOSIS ? CRP localizes in atherosclerotic but not normal intima CRP induced Complement activation CRP dependent monocyte recruitment into arterial wall CRP induced production of tissue factor in monocytes CRP based blunting of endothelial vasoreactivity CRP mediated LDL uptake by macrophages CRP triggered oxidation of LDL cholesterol CRP induced PAI-1 expression stabilizes PAI-1 mRNA CRP attenuates NO production and decreases eNOS expression CRP induced production of cell adhesion moleculas MCP-1, ET-1 37 ROLE OF INFLAMATORY MARKERS Interleukin-6 Total cholesterol LDL-cholesterol siCAM-1 Serum amyloid A Apolipoprotein B Total cholesterol: HDL-cholesterol Hs-CRP Hs-CRP + total cholesterol: HDL-cholesterol 0 1.0 2.0 4.0 6.0 Relative Risk (New England Journal of Medicine) 38 39 Weissberg, 1999 Inflammation Repair 40 REDOX REGULATION OF ENDOTHELIAL DYSFUNCTION & ACTIVATION O2– OH H2O2  NO Activity  G-Protein Function  Protein Kinase C Oxidation Endothelial Dysfunction (D. Sargowo) 41 ENDOTHELIAL DYSFUNCTION AND ACUTE CORONARY SYNDROMES Vasoconstriction Platelet Aggregation SMC Proliferation Leukocyte Adhesion LDL Oxidation Activation of MMPs Endothelial Dysfunction Plaque Rupture Thrombosis Matrix Remodeling (D. Sargowo) 42 ENDOTHELIAL DYSFUNCTION AND ACUTE CORONARY SYNDROMES Vasospasm Plaque Rupture Thrombosis Matrix Remodeling ACUTE CORONARY SYNDROMES (D. Sargowo) 43 44 Diabetes Smoking AII Oxidative Stress Endothelial Dysfunction and Smooth Muscle Activation Growth FactorsCytokinesMatrix Proteolysis Inflammation VCAM/1CAMCytokines EndothelinCatecholamines BP LDL  NO • ∆ Local Mediators •  Tissue ACE, AII PAI-1, Platelet Aggregation, Tissue Factor Vasoconstriction Thrombosis Inflammation Plaque Rupture Vascular Lesion and Remodeling Clinical Sequelae Risk Factors Reprinted with permission from Dzau VJ. Hypertension. 2001;37:1047–1052. 45 THERAPEUTICS : WHERE DO WE STAND TODAY ? Lipid lowering drugs ACEI / ARB Peroxisome proliferators-activated receptor (PPAR) Chemokine receptor antagonist TNF Inhibitor MMP Inhibitor 46 BIOCHEMICAL PARAMETER FOR ENDOTHELIAL DYSFUNCTION - vWF - Thrombomodulin - E-Selection - ICAM-1 - VCAM-1 - NO - Microalbuminuria - PAI-1 (D. Sargowo) - Ox LDL – MDA – F2 - Isoprostane - LP – PLA2 - Lyso-PC OxFA BIOCHEMICAL PARAMETER FOR ENDOTHELIAL DYSFUNCTION - vWF - Thrombomodulin - E-Selection - NO - Microalbuminuria - PAI-1 - Ox LDL – MDA – F2 - Isoprostane - LP – PLA2 - Lyso-PC OxFA 47 INFLAMMATORY MARKERS FOR CONSIDERATION AS PREDICTORS OF CARDIOVASCULAR RISK Adhesion molecules Cytokines Acute-phase reactants Fibrinogen SAA CRP WBC count Other (eg, erytrocyte sedimentation rate) (Pearson et al, 2003) 48 SURREGATE BIOMARKERS FOR ACS HS CRP MMP Stromelysin Kalogenase Elastase INFj, TNF, IL1 Gelatinase LDH CPK MBCK Troponin T-I Fibrinogen Albuminuri D. Sargowo 49 Rudolf Virchow Inflammation-based arterial changes as a mechanism of primary importance in atherogenesis mid 19th century Lamond, B. The American Journal of Pathology. 2008 SUMMARY 50 51 Thank You 52 The Role of Lp-PLA2 in CHD LUMEN Monocytes Adhesion Molecules Oxidated LDL INTIMA MEDIA Lp-PLA2 Lyso-PC OxFA Cytokines Plaque Formation Foam Cell Macrophage 53 Intracelluler proteolysis and fusion of LDL Figure : Proposed Dual Action of Exocytosed Mast Cell Granules (The Granule Remnants) of Lipoprotein Metabolism in The Arterial Intima 54 55 24.7% 29.9% Coronary disease 7.4% ATHEROTHROMBOSIS IS COMMONLY FOUND IN MORE THAN ONE ARTERIAL BED IN AN INDIVIDUAL PATIENT* Cerebrovascular disease Peripheral arterial disease 3.8% 11.8% 19.2% * Data from CAPRIE study (n=19,185) Coccheri S. Eur Heart J 1998; 19(suppl): P1268. 3.3% 56 IKK- IKK IKK IKK Hemodynamic forces Matrix Cytokines LPS/LBP CD14 Oxidized lipids Ang II AGE RAGE AT1 SR TLR Cytokines receptor Integrin PLASMA MEMBRANE Chlamydia and virus Proteasome IKK complexes Inhibitors : IKB- IKB- IKB-r Bcl-3 (Ub)n P P IKB P65 P50 IKB P50 P65 P50 P65 NF-KB CYTOPLASM NUCLEUS 57 58 The Role of T-Lymphocyte in Atherogenesis Libby, P. 2002 59 p38 c-Jun activation Caspases Apoptosis NIK ? ? MEKK1?   CKII IKK complex TNFR-1 TNFR-1 IL-1R Shear stress p65 p50 CBP/p300 Gene activation IB Ub Target genes : - IL-1, IL-8, IL-6, IFN  - TNF, MCP-1 - CSFs, c-myc - VCAM-1, ICAM-1, E-selectin - Tissue factor - Survival factor Thurberg and Collins : Curr Opin Lipidol 9:387-396,1998 Ub Ox-LDL ROIs ??? Lipid peroxides ? H2O2 Ubiquitination and proteosome degradation 60 GM-CSF VCAM-1 MPC-1 Transcription Factors : Endothelial Cell Pro-inflammatory Genes Oxidative Stress NF-xB AP-1 Leucocyte infiltration / activation Plaque Rupture Gibbons, 97 Leucocyte Activation in Atherogenesis : Implications for Acute Ischemic Syndromes
Slide 61 - 1 Nama : Prof. Dr. H. Djanggan Sargowo, dr., SpPD., SpJP(K), FIHA, FACC, FESC, FCAPC, FASCC Tempat/Tgl lahir : Sragen, 21 September 1947 Alamat : Wilis Indah E-10 Malang, Telp. 0341-552395 Pendidikan : Lulus Dokter dari UGM, tahun 1974 Lulus Cardiologist dari Univ. Indonesia, tahun 1983 Lulus Internist dari Univ. Airlangga, tahun 1986 Lulus Doktor, Univ. Airlangga, tahun 1996 Advanced Cardiology Course, Univ. Hongkong, tahun 1984 Senior Visiting Program, Institut Jantung Negara, Kualalumpur, 1996 Fellow American College of Cardiology (FACC), September 2006. Fellow Collage Asia Pacific Society of Cardiology (FCAPC), Desember 2007 Fellow European Sociaty of Cardiology (FESC), 2008 Fellow Asean Collage of Cardiology (FASCC), 2008 Jabatan : Dosen Pengajar Program Pascasarjana Universitas Brawijaya Ketua MKEK Ikatan Dokter Indonesia Cabang Malang Raya Ketua PERKI Cabang Malang Raya Anggota Kolegium Kardiovaskuler Indonesia Dekan Fak. Kedokteran Univ. Wijaya Kusuma Surabaya Ketua Dewan Pengawas Rumah Sakit Pendidikan Ketua Program Studi Kardiovascular Fak. Kedokteran Univ. Brawijaya Curriculum Vitae 2 Djanggan Sargowo Surabaya, 15 April 2012 INFLAMMATION IN ATHEROSCLEROSIS : FROM BENCH TO BEDSIDE 3 4 RUDOLF VIRCHOW Inflammation-based arterial changes as a mechanism of primary importance in atherogenesis mid 19th century Lamond, B. The American Journal of Pathology. 2008 5 Atherosclerosis Start from very young To Old age ? 6 Atherothrombosis* is aLeading Cause of Death Worldwide1† The World Health Report, 2002, WHO Geneva, 2002 28.7 17.8 12.6 9.1 6 5.1 0 5 10 15 20 25 30 Atherothrombosis* Infectious disease Cancer Injuries Pulmonary disease AIDS Mortality (%) * Ischemic heart disease, cerebrovascular disease, inflammatory heart disease and hypertensive heart disease † Worldwide defined as Member States by WHO Region (Africa, Americas, Eastern Mediterranean, European, South-East Asia and Western Pacific) 7 MAJOR CLINICAL MANIFESTATIONS OF ATHEROTHROMBOSIS Adapted from: Drouet L. Cerebrovasc Dis 2002; 13(suppl 1): 1–6. Transient ischemic attack Angina: Stable Unstable Ischemic stroke Myocardial infarction Peripheral arterial disease: Intermittent claudication Rest Pain Gangrene Necrosis 8  Dyslipidemia  Endothelial dysfunction  Free radicals  Immunologic Atherosclerosis/CAD THEORY AND CONCEPT OF ATHEROSCLEROSIS Inflamation (Sargowo, 1996) 9 Free Radical ATHEROGENESIS (Sargowo, 1996) 10 IDENTIFYING THOSE AT RISK OF ATHEROTHROMBOSIS Yusuf S et al. Circulation 2001; 104: 2746–53. 2. Drouet L. Cerebrovasc Dis 2002;13(suppl 1):1–6. Lifestyle Smoking Diet Lack of exercise Genetic Genetic traits Gender Age Generalized disorders Obesity Diabetes Systemic conditions History of vascular events Hypertension Hyperlipidemia Hypercoagulable states Homocystinemia Local factors Elevated prothrombotic factors: fibrinogen, CRP, PAI-1 Blood flow patterns, vessel diameter, arterial wall structure Atherothrombosis manifestations (myocardial infarction, stroke, vascular death) 11 Arici. 2010 Risk Factors for Atherosclerosis Classic Hypertension, Hyper-lipidemia, DM, Smoking Uremia Related Increase ox-LDL, Free radicals, Uremic toxin Infection Bacterial and viral infection Proinflammatory cytokine release Endothelial dysfunction Systemic inflammatory respones Acute phase response Elevated CRP Binding LDL, cemplement activation, tissue factor secretion Accelerated ATHEROSCLEROSIS 12 LDL CD40L=CD40 ligand; TNF-α=tumor necrosis factor-alpha; IL=interleukin; VCAM=vascular cell adhesion molecule; ICAM=intercellular adhesion molecule. Cockerill GW et al. Arterioscler Thromb Vasc Biol. 1995;15:1987-1994; Andre P et al. Circulation. 2002;106:896-899; Libby P. Circulation. 2001;104:365-372; Libby P et al. Circulation. 2002;105:1135-1143; Ross R. N Engl J Med. 1999;340:115-126. Vessel lumen Monocyte Macrophage Adhesionmolecules (VCAM-1, ICAM-1) Inflammatory mediators (CRP, CD40/CD40L, TNF-α, IL-1, IL-6) Intima Foam cell INFLAMMATION PROMOTES PROGRESSION OF ATHEROSCLEROSIS Endothelium LDL Ox-LDL 13 14 Atherosclerosis is a fibroproliferative and inflammatory process occurring ins response to a variety of vascular insults The insults come from classical risk factors ( HT, dyslipidemia, endothelial dysfunction, smoking, menopause, diabetes etc) and novel risk factors (Hcy, LVH, Lp(a), TG, oxidative stress, fibrinogen etc) Endothelial dysfunction is regarded as the first abnormality leading to atherosclerosis This implies that modulation of endothelial function may be used as strategy to intervene the process. 15 Two theories gain more acceptance: (a) the lipid theory (b) inflammation theory Endothelial dysfunction is now regarded as the first abnormality leading to AS. More novel cardiovascular risk factors are known, e.g.: Fibrinogen b. PAI-1 Homocysteins d. AT-1 e. CRP f. Lp(a) g. small-dense LDL h. infectious agents i. and more are emerging 16 Acute Coronary Syndrome (endocrine viewpoints) atherosclerotic lesions vascular funtions b.1. inflammatory reaction b.2. thrombogeneity b.3. vasoreactivity b.4. plaque stability b.5. shoulder of plaque endothelium balance between c.1. vasodilating, antithrombotic, antiproliferative factors (NO, prostacyclin, C-natriuretic peptide, EDHF) c.2. vasoconstricting, prothrombotic, proliferative factors (ET, superoxide, thromoboxan A2) 17 NATURAL HISTORY OF CORONARY ATHEROSCLEROSIS Chatzizisis et all. JACC. 2007. Asymtomatic Stable Angina Acute Coronary Syndrome Early fibroatheroma Compensatory expansive remodeling Quiescent plaque Contrictive remodeling Stenotic plaque Exessive expansive remodeling Thin cap fibroatheroma Erosion Physiologic coronary artery Local factors, e.g. low ESS Systemic factors, e.g. hyperlipidemia Genetic factors Physiologic ESS Limited inflammation Fibroproliferation Microruptures 18 ATHEROSCLEROSIS IS AN INFLAMMATORY DISEASE Libby P. Circulation. 2001;104:365-372; Ross R. N Engl J Med. 1999;340:115-126. Monocyte LDL-C Adhesion molecule Macrophage Foam cell OxidizedLDL-C Plaque rupture Smooth muscle cells CRP Plaque instability and thrombus Oxidation Inflammation Endothelial dysfunction 19 20 Reverse Cholesterol Transport Monocyte CRP TXA2 PGI2 Thrombin LDL Platelets HDL HDL Ox-LDL MCP-1 Macrophage P-selectin CD 40L PDGF Foam cell MMP T cell E-selectins CD 40L VCAM-1 ICAM-1 IL-1 Reilly, et.all. 2005 21 THE ROLE OF Lp-PLA2 IN CHD LUMEN Monocytes Adhesion Molecules Oxidated LDL INTIMA MEDIA Lp-PLA2 Lyso-PC OxFA Cytokines Plaque Formation Foam Cell Macrophage 22 MC T T FC FC LDL Oxidation Lyso-PC Ox-chol Cytokines Cytokines ? C5a C’ MCP-1 F SMC 23 Intracelluler proteolysis and fusion of LDL Figure : Proposed Dual Action of Exocytosed Mast Cell Granules (The Granule Remnants) of Lipoprotein Metabolism in The Arterial Intima 24 HSCRP 25 26 GM-CSF VCAM-1 MPC-1 Transcription Factors : Endothelial Cell Pro-inflammatory Genes Oxidative Stress NF-xB AP-1 Leucocyte infiltration / activation Plaque Rupture Gibbons, 97 LEUCOCYTE ACTIVATION IN ATHEROGENESIS : IMPLICATIONS FOR ACUTE ISCHEMIC SYNDROMES 27 p38 c-Jun activation Caspases Apoptosis NIK ? ? MEKK1?   CKII IKK complex TNFR-1 TNFR-1 IL-1R Shear stress p65 p50 CBP/p300 Gene activation p65 p50 IB pKAc IB Ub Target genes : - IL-1, IL-8, IL-6, IFN  - TNF, MCP-1 - CSFs, c-myc - VCAM-1, ICAM-1, E-selectin - Tissue factor - Survival factor Thurberg and Collins : Curr Opin Lipidol 9:387-396,1998 Ub Ox-LDL ROIs ??? Lipid peroxides ? H2O2 Ubiquitination and proteosome degradation T R A D D R I P F A D D R I P T R A D D T R A F 2 T R A F 6 28 Visual Medica. 2009 29 Stockley. 2006 Cytokines : IL-6, TNF-α MACROPHAGE FOAM CELL Oxidized LDL CRP CRP Chemokines: MCO-1 Atherosclerotic plaque MONOCYTE Inflammatory Mediators: CRP Prothrombotic factors FCR Receptor 30 POTENTIAL MECHANISM OF CRP Stevens, R. 2005 CRP LDL opsonisation Monocyte infiltration Foam cell formation Increased MCP-1 and CAM EC activation Inflammatory cell recruitment Atherosclerosis plaque formation Complement activation EC sensitisation T-cell attack EC damage Atherosclerotic plaque rupture 31 Rheumatoid arthritis Atherosclerosis Multiple sclerosis Asthma Inflammatory bowel disease Helicobacter pylori-associated gastritis Systemic inflammatory response syndrome NF-KB ACTIVATION INFLAMMATORY DISEASE The Journal of Clinical Investigation, 2001 32 PROTEIN REGULATED BY NF-KB Inflammatory Enzyme Adhesion Molecule Inducible nitric oxide synthase Inducide cylooxigenase-2 5-Lipoxigenase Cytosolic phospolipase A2 ICAM-1 VCAM-1 E-selectin Receptor Interlekin-2 receptor (alpha chain) T-cell receptors (beta chain) NEJM, 1997 33 BIOMARKERS OF ACTIVITY STUDIED FOR CAD Cytokines (IL-1β, IL-6, IL-8, IL-10, TNF-α, sCD40 ligand, myeloperoxidase) Adhesion molecules (sICAM-1, sVCAM-1, p-selectin) Acute phase reactans (fibrinogen, AAS, CRP) White blood cells Erythrocyte sedimentation rate Neopterin Heat shock proteins Adiponectin Lipoprotein associated phospholipase A2 Placental growth factos Cystatin C Kaski, JC. 2006. 34 Are you hungry or sleepy ???? Sciences 35 The inflammatory cascade. IL indicates interleukin; ICAM, intercellular adhesion molecule; and HSP, heat shock protein. (Libby, Ridker; 1999) Pro-Inflammatory Risk Factors Primary Pro-Inflammatory Cytokines (eg. IL-1, TNF-) IL-6 “Mesenger” Cytokine CRP SAA Endothelium and other cells LIVER Circulation 36 (Ridker, 2004) MORE THAN A MARKER : DOES CRP PLAY A DIRECT ROLE IN ATHEROTHROMBOSIS ? CRP localizes in atherosclerotic but not normal intima CRP induced Complement activation CRP dependent monocyte recruitment into arterial wall CRP induced production of tissue factor in monocytes CRP based blunting of endothelial vasoreactivity CRP mediated LDL uptake by macrophages CRP triggered oxidation of LDL cholesterol CRP induced PAI-1 expression stabilizes PAI-1 mRNA CRP attenuates NO production and decreases eNOS expression CRP induced production of cell adhesion moleculas MCP-1, ET-1 37 ROLE OF INFLAMATORY MARKERS Interleukin-6 Total cholesterol LDL-cholesterol siCAM-1 Serum amyloid A Apolipoprotein B Total cholesterol: HDL-cholesterol Hs-CRP Hs-CRP + total cholesterol: HDL-cholesterol 0 1.0 2.0 4.0 6.0 Relative Risk (New England Journal of Medicine) 38 39 Weissberg, 1999 Inflammation Repair 40 REDOX REGULATION OF ENDOTHELIAL DYSFUNCTION & ACTIVATION O2– OH H2O2  NO Activity  G-Protein Function  Protein Kinase C Oxidation Endothelial Dysfunction (D. Sargowo) 41 ENDOTHELIAL DYSFUNCTION AND ACUTE CORONARY SYNDROMES Vasoconstriction Platelet Aggregation SMC Proliferation Leukocyte Adhesion LDL Oxidation Activation of MMPs Endothelial Dysfunction Plaque Rupture Thrombosis Matrix Remodeling (D. Sargowo) 42 ENDOTHELIAL DYSFUNCTION AND ACUTE CORONARY SYNDROMES Vasospasm Plaque Rupture Thrombosis Matrix Remodeling ACUTE CORONARY SYNDROMES (D. Sargowo) 43 44 Diabetes Smoking AII Oxidative Stress Endothelial Dysfunction and Smooth Muscle Activation Growth FactorsCytokinesMatrix Proteolysis Inflammation VCAM/1CAMCytokines EndothelinCatecholamines BP LDL  NO • ∆ Local Mediators •  Tissue ACE, AII PAI-1, Platelet Aggregation, Tissue Factor Vasoconstriction Thrombosis Inflammation Plaque Rupture Vascular Lesion and Remodeling Clinical Sequelae Risk Factors Reprinted with permission from Dzau VJ. Hypertension. 2001;37:1047–1052. 45 THERAPEUTICS : WHERE DO WE STAND TODAY ? Lipid lowering drugs ACEI / ARB Peroxisome proliferators-activated receptor (PPAR) Chemokine receptor antagonist TNF Inhibitor MMP Inhibitor 46 BIOCHEMICAL PARAMETER FOR ENDOTHELIAL DYSFUNCTION - vWF - Thrombomodulin - E-Selection - ICAM-1 - VCAM-1 - NO - Microalbuminuria - PAI-1 (D. Sargowo) - Ox LDL – MDA – F2 - Isoprostane - LP – PLA2 - Lyso-PC OxFA BIOCHEMICAL PARAMETER FOR ENDOTHELIAL DYSFUNCTION - vWF - Thrombomodulin - E-Selection - NO - Microalbuminuria - PAI-1 - Ox LDL – MDA – F2 - Isoprostane - LP – PLA2 - Lyso-PC OxFA 47 INFLAMMATORY MARKERS FOR CONSIDERATION AS PREDICTORS OF CARDIOVASCULAR RISK Adhesion molecules Cytokines Acute-phase reactants Fibrinogen SAA CRP WBC count Other (eg, erytrocyte sedimentation rate) (Pearson et al, 2003) 48 SURREGATE BIOMARKERS FOR ACS HS CRP MMP Stromelysin Kalogenase Elastase INFj, TNF, IL1 Gelatinase LDH CPK MBCK Troponin T-I Fibrinogen Albuminuri D. Sargowo 49 Rudolf Virchow Inflammation-based arterial changes as a mechanism of primary importance in atherogenesis mid 19th century Lamond, B. The American Journal of Pathology. 2008 SUMMARY 50 51 Thank You 52 The Role of Lp-PLA2 in CHD LUMEN Monocytes Adhesion Molecules Oxidated LDL INTIMA MEDIA Lp-PLA2 Lyso-PC OxFA Cytokines Plaque Formation Foam Cell Macrophage 53 Intracelluler proteolysis and fusion of LDL Figure : Proposed Dual Action of Exocytosed Mast Cell Granules (The Granule Remnants) of Lipoprotein Metabolism in The Arterial Intima 54 55 24.7% 29.9% Coronary disease 7.4% ATHEROTHROMBOSIS IS COMMONLY FOUND IN MORE THAN ONE ARTERIAL BED IN AN INDIVIDUAL PATIENT* Cerebrovascular disease Peripheral arterial disease 3.8% 11.8% 19.2% * Data from CAPRIE study (n=19,185) Coccheri S. Eur Heart J 1998; 19(suppl): P1268. 3.3% 56 IKK- IKK IKK IKK Hemodynamic forces Matrix Cytokines LPS/LBP CD14 Oxidized lipids Ang II AGE RAGE AT1 SR TLR Cytokines receptor Integrin PLASMA MEMBRANE Chlamydia and virus Proteasome IKK complexes Inhibitors : IKB- IKB- IKB-r Bcl-3 (Ub)n P P IKB P65 P50 IKB P50 P65 P50 P65 NF-KB CYTOPLASM NUCLEUS 57 58 The Role of T-Lymphocyte in Atherogenesis Libby, P. 2002 59 p38 c-Jun activation Caspases Apoptosis NIK ? ? MEKK1?   CKII IKK complex TNFR-1 TNFR-1 IL-1R Shear stress p65 p50 CBP/p300 Gene activation IB Ub Target genes : - IL-1, IL-8, IL-6, IFN  - TNF, MCP-1 - CSFs, c-myc - VCAM-1, ICAM-1, E-selectin - Tissue factor - Survival factor Thurberg and Collins : Curr Opin Lipidol 9:387-396,1998 Ub Ox-LDL ROIs ??? Lipid peroxides ? H2O2 Ubiquitination and proteosome degradation 60 GM-CSF VCAM-1 MPC-1 Transcription Factors : Endothelial Cell Pro-inflammatory Genes Oxidative Stress NF-xB AP-1 Leucocyte infiltration / activation Plaque Rupture Gibbons, 97 Leucocyte Activation in Atherogenesis : Implications for Acute Ischemic Syndromes 61 Protein Regulated by NF-kB Proinflammatory Cytokine Chemokine TNF-α IL-1 β IL-2 IL-6 Granulocyte-macrophage colony stimulating factor Macrophage colony stimulating factor Granulocyte colony stimulating factor IL-8 Macrophage inflammatory protein 1 alpha MCP-1 Gro α, β dan γ NEJM, 1997
Slide 62 - 1 Nama : Prof. Dr. H. Djanggan Sargowo, dr., SpPD., SpJP(K), FIHA, FACC, FESC, FCAPC, FASCC Tempat/Tgl lahir : Sragen, 21 September 1947 Alamat : Wilis Indah E-10 Malang, Telp. 0341-552395 Pendidikan : Lulus Dokter dari UGM, tahun 1974 Lulus Cardiologist dari Univ. Indonesia, tahun 1983 Lulus Internist dari Univ. Airlangga, tahun 1986 Lulus Doktor, Univ. Airlangga, tahun 1996 Advanced Cardiology Course, Univ. Hongkong, tahun 1984 Senior Visiting Program, Institut Jantung Negara, Kualalumpur, 1996 Fellow American College of Cardiology (FACC), September 2006. Fellow Collage Asia Pacific Society of Cardiology (FCAPC), Desember 2007 Fellow European Sociaty of Cardiology (FESC), 2008 Fellow Asean Collage of Cardiology (FASCC), 2008 Jabatan : Dosen Pengajar Program Pascasarjana Universitas Brawijaya Ketua MKEK Ikatan Dokter Indonesia Cabang Malang Raya Ketua PERKI Cabang Malang Raya Anggota Kolegium Kardiovaskuler Indonesia Dekan Fak. Kedokteran Univ. Wijaya Kusuma Surabaya Ketua Dewan Pengawas Rumah Sakit Pendidikan Ketua Program Studi Kardiovascular Fak. Kedokteran Univ. Brawijaya Curriculum Vitae 2 Djanggan Sargowo Surabaya, 15 April 2012 INFLAMMATION IN ATHEROSCLEROSIS : FROM BENCH TO BEDSIDE 3 4 RUDOLF VIRCHOW Inflammation-based arterial changes as a mechanism of primary importance in atherogenesis mid 19th century Lamond, B. The American Journal of Pathology. 2008 5 Atherosclerosis Start from very young To Old age ? 6 Atherothrombosis* is aLeading Cause of Death Worldwide1† The World Health Report, 2002, WHO Geneva, 2002 28.7 17.8 12.6 9.1 6 5.1 0 5 10 15 20 25 30 Atherothrombosis* Infectious disease Cancer Injuries Pulmonary disease AIDS Mortality (%) * Ischemic heart disease, cerebrovascular disease, inflammatory heart disease and hypertensive heart disease † Worldwide defined as Member States by WHO Region (Africa, Americas, Eastern Mediterranean, European, South-East Asia and Western Pacific) 7 MAJOR CLINICAL MANIFESTATIONS OF ATHEROTHROMBOSIS Adapted from: Drouet L. Cerebrovasc Dis 2002; 13(suppl 1): 1–6. Transient ischemic attack Angina: Stable Unstable Ischemic stroke Myocardial infarction Peripheral arterial disease: Intermittent claudication Rest Pain Gangrene Necrosis 8  Dyslipidemia  Endothelial dysfunction  Free radicals  Immunologic Atherosclerosis/CAD THEORY AND CONCEPT OF ATHEROSCLEROSIS Inflamation (Sargowo, 1996) 9 Free Radical ATHEROGENESIS (Sargowo, 1996) 10 IDENTIFYING THOSE AT RISK OF ATHEROTHROMBOSIS Yusuf S et al. Circulation 2001; 104: 2746–53. 2. Drouet L. Cerebrovasc Dis 2002;13(suppl 1):1–6. Lifestyle Smoking Diet Lack of exercise Genetic Genetic traits Gender Age Generalized disorders Obesity Diabetes Systemic conditions History of vascular events Hypertension Hyperlipidemia Hypercoagulable states Homocystinemia Local factors Elevated prothrombotic factors: fibrinogen, CRP, PAI-1 Blood flow patterns, vessel diameter, arterial wall structure Atherothrombosis manifestations (myocardial infarction, stroke, vascular death) 11 Arici. 2010 Risk Factors for Atherosclerosis Classic Hypertension, Hyper-lipidemia, DM, Smoking Uremia Related Increase ox-LDL, Free radicals, Uremic toxin Infection Bacterial and viral infection Proinflammatory cytokine release Endothelial dysfunction Systemic inflammatory respones Acute phase response Elevated CRP Binding LDL, cemplement activation, tissue factor secretion Accelerated ATHEROSCLEROSIS 12 LDL CD40L=CD40 ligand; TNF-α=tumor necrosis factor-alpha; IL=interleukin; VCAM=vascular cell adhesion molecule; ICAM=intercellular adhesion molecule. Cockerill GW et al. Arterioscler Thromb Vasc Biol. 1995;15:1987-1994; Andre P et al. Circulation. 2002;106:896-899; Libby P. Circulation. 2001;104:365-372; Libby P et al. Circulation. 2002;105:1135-1143; Ross R. N Engl J Med. 1999;340:115-126. Vessel lumen Monocyte Macrophage Adhesionmolecules (VCAM-1, ICAM-1) Inflammatory mediators (CRP, CD40/CD40L, TNF-α, IL-1, IL-6) Intima Foam cell INFLAMMATION PROMOTES PROGRESSION OF ATHEROSCLEROSIS Endothelium LDL Ox-LDL 13 14 Atherosclerosis is a fibroproliferative and inflammatory process occurring ins response to a variety of vascular insults The insults come from classical risk factors ( HT, dyslipidemia, endothelial dysfunction, smoking, menopause, diabetes etc) and novel risk factors (Hcy, LVH, Lp(a), TG, oxidative stress, fibrinogen etc) Endothelial dysfunction is regarded as the first abnormality leading to atherosclerosis This implies that modulation of endothelial function may be used as strategy to intervene the process. 15 Two theories gain more acceptance: (a) the lipid theory (b) inflammation theory Endothelial dysfunction is now regarded as the first abnormality leading to AS. More novel cardiovascular risk factors are known, e.g.: Fibrinogen b. PAI-1 Homocysteins d. AT-1 e. CRP f. Lp(a) g. small-dense LDL h. infectious agents i. and more are emerging 16 Acute Coronary Syndrome (endocrine viewpoints) atherosclerotic lesions vascular funtions b.1. inflammatory reaction b.2. thrombogeneity b.3. vasoreactivity b.4. plaque stability b.5. shoulder of plaque endothelium balance between c.1. vasodilating, antithrombotic, antiproliferative factors (NO, prostacyclin, C-natriuretic peptide, EDHF) c.2. vasoconstricting, prothrombotic, proliferative factors (ET, superoxide, thromoboxan A2) 17 NATURAL HISTORY OF CORONARY ATHEROSCLEROSIS Chatzizisis et all. JACC. 2007. Asymtomatic Stable Angina Acute Coronary Syndrome Early fibroatheroma Compensatory expansive remodeling Quiescent plaque Contrictive remodeling Stenotic plaque Exessive expansive remodeling Thin cap fibroatheroma Erosion Physiologic coronary artery Local factors, e.g. low ESS Systemic factors, e.g. hyperlipidemia Genetic factors Physiologic ESS Limited inflammation Fibroproliferation Microruptures 18 ATHEROSCLEROSIS IS AN INFLAMMATORY DISEASE Libby P. Circulation. 2001;104:365-372; Ross R. N Engl J Med. 1999;340:115-126. Monocyte LDL-C Adhesion molecule Macrophage Foam cell OxidizedLDL-C Plaque rupture Smooth muscle cells CRP Plaque instability and thrombus Oxidation Inflammation Endothelial dysfunction 19 20 Reverse Cholesterol Transport Monocyte CRP TXA2 PGI2 Thrombin LDL Platelets HDL HDL Ox-LDL MCP-1 Macrophage P-selectin CD 40L PDGF Foam cell MMP T cell E-selectins CD 40L VCAM-1 ICAM-1 IL-1 Reilly, et.all. 2005 21 THE ROLE OF Lp-PLA2 IN CHD LUMEN Monocytes Adhesion Molecules Oxidated LDL INTIMA MEDIA Lp-PLA2 Lyso-PC OxFA Cytokines Plaque Formation Foam Cell Macrophage 22 MC T T FC FC LDL Oxidation Lyso-PC Ox-chol Cytokines Cytokines ? C5a C’ MCP-1 F SMC 23 Intracelluler proteolysis and fusion of LDL Figure : Proposed Dual Action of Exocytosed Mast Cell Granules (The Granule Remnants) of Lipoprotein Metabolism in The Arterial Intima 24 HSCRP 25 26 GM-CSF VCAM-1 MPC-1 Transcription Factors : Endothelial Cell Pro-inflammatory Genes Oxidative Stress NF-xB AP-1 Leucocyte infiltration / activation Plaque Rupture Gibbons, 97 LEUCOCYTE ACTIVATION IN ATHEROGENESIS : IMPLICATIONS FOR ACUTE ISCHEMIC SYNDROMES 27 p38 c-Jun activation Caspases Apoptosis NIK ? ? MEKK1?   CKII IKK complex TNFR-1 TNFR-1 IL-1R Shear stress p65 p50 CBP/p300 Gene activation p65 p50 IB pKAc IB Ub Target genes : - IL-1, IL-8, IL-6, IFN  - TNF, MCP-1 - CSFs, c-myc - VCAM-1, ICAM-1, E-selectin - Tissue factor - Survival factor Thurberg and Collins : Curr Opin Lipidol 9:387-396,1998 Ub Ox-LDL ROIs ??? Lipid peroxides ? H2O2 Ubiquitination and proteosome degradation T R A D D R I P F A D D R I P T R A D D T R A F 2 T R A F 6 28 Visual Medica. 2009 29 Stockley. 2006 Cytokines : IL-6, TNF-α MACROPHAGE FOAM CELL Oxidized LDL CRP CRP Chemokines: MCO-1 Atherosclerotic plaque MONOCYTE Inflammatory Mediators: CRP Prothrombotic factors FCR Receptor 30 POTENTIAL MECHANISM OF CRP Stevens, R. 2005 CRP LDL opsonisation Monocyte infiltration Foam cell formation Increased MCP-1 and CAM EC activation Inflammatory cell recruitment Atherosclerosis plaque formation Complement activation EC sensitisation T-cell attack EC damage Atherosclerotic plaque rupture 31 Rheumatoid arthritis Atherosclerosis Multiple sclerosis Asthma Inflammatory bowel disease Helicobacter pylori-associated gastritis Systemic inflammatory response syndrome NF-KB ACTIVATION INFLAMMATORY DISEASE The Journal of Clinical Investigation, 2001 32 PROTEIN REGULATED BY NF-KB Inflammatory Enzyme Adhesion Molecule Inducible nitric oxide synthase Inducide cylooxigenase-2 5-Lipoxigenase Cytosolic phospolipase A2 ICAM-1 VCAM-1 E-selectin Receptor Interlekin-2 receptor (alpha chain) T-cell receptors (beta chain) NEJM, 1997 33 BIOMARKERS OF ACTIVITY STUDIED FOR CAD Cytokines (IL-1β, IL-6, IL-8, IL-10, TNF-α, sCD40 ligand, myeloperoxidase) Adhesion molecules (sICAM-1, sVCAM-1, p-selectin) Acute phase reactans (fibrinogen, AAS, CRP) White blood cells Erythrocyte sedimentation rate Neopterin Heat shock proteins Adiponectin Lipoprotein associated phospholipase A2 Placental growth factos Cystatin C Kaski, JC. 2006. 34 Are you hungry or sleepy ???? Sciences 35 The inflammatory cascade. IL indicates interleukin; ICAM, intercellular adhesion molecule; and HSP, heat shock protein. (Libby, Ridker; 1999) Pro-Inflammatory Risk Factors Primary Pro-Inflammatory Cytokines (eg. IL-1, TNF-) IL-6 “Mesenger” Cytokine CRP SAA Endothelium and other cells LIVER Circulation 36 (Ridker, 2004) MORE THAN A MARKER : DOES CRP PLAY A DIRECT ROLE IN ATHEROTHROMBOSIS ? CRP localizes in atherosclerotic but not normal intima CRP induced Complement activation CRP dependent monocyte recruitment into arterial wall CRP induced production of tissue factor in monocytes CRP based blunting of endothelial vasoreactivity CRP mediated LDL uptake by macrophages CRP triggered oxidation of LDL cholesterol CRP induced PAI-1 expression stabilizes PAI-1 mRNA CRP attenuates NO production and decreases eNOS expression CRP induced production of cell adhesion moleculas MCP-1, ET-1 37 ROLE OF INFLAMATORY MARKERS Interleukin-6 Total cholesterol LDL-cholesterol siCAM-1 Serum amyloid A Apolipoprotein B Total cholesterol: HDL-cholesterol Hs-CRP Hs-CRP + total cholesterol: HDL-cholesterol 0 1.0 2.0 4.0 6.0 Relative Risk (New England Journal of Medicine) 38 39 Weissberg, 1999 Inflammation Repair 40 REDOX REGULATION OF ENDOTHELIAL DYSFUNCTION & ACTIVATION O2– OH H2O2  NO Activity  G-Protein Function  Protein Kinase C Oxidation Endothelial Dysfunction (D. Sargowo) 41 ENDOTHELIAL DYSFUNCTION AND ACUTE CORONARY SYNDROMES Vasoconstriction Platelet Aggregation SMC Proliferation Leukocyte Adhesion LDL Oxidation Activation of MMPs Endothelial Dysfunction Plaque Rupture Thrombosis Matrix Remodeling (D. Sargowo) 42 ENDOTHELIAL DYSFUNCTION AND ACUTE CORONARY SYNDROMES Vasospasm Plaque Rupture Thrombosis Matrix Remodeling ACUTE CORONARY SYNDROMES (D. Sargowo) 43 44 Diabetes Smoking AII Oxidative Stress Endothelial Dysfunction and Smooth Muscle Activation Growth FactorsCytokinesMatrix Proteolysis Inflammation VCAM/1CAMCytokines EndothelinCatecholamines BP LDL  NO • ∆ Local Mediators •  Tissue ACE, AII PAI-1, Platelet Aggregation, Tissue Factor Vasoconstriction Thrombosis Inflammation Plaque Rupture Vascular Lesion and Remodeling Clinical Sequelae Risk Factors Reprinted with permission from Dzau VJ. Hypertension. 2001;37:1047–1052. 45 THERAPEUTICS : WHERE DO WE STAND TODAY ? Lipid lowering drugs ACEI / ARB Peroxisome proliferators-activated receptor (PPAR) Chemokine receptor antagonist TNF Inhibitor MMP Inhibitor 46 BIOCHEMICAL PARAMETER FOR ENDOTHELIAL DYSFUNCTION - vWF - Thrombomodulin - E-Selection - ICAM-1 - VCAM-1 - NO - Microalbuminuria - PAI-1 (D. Sargowo) - Ox LDL – MDA – F2 - Isoprostane - LP – PLA2 - Lyso-PC OxFA BIOCHEMICAL PARAMETER FOR ENDOTHELIAL DYSFUNCTION - vWF - Thrombomodulin - E-Selection - NO - Microalbuminuria - PAI-1 - Ox LDL – MDA – F2 - Isoprostane - LP – PLA2 - Lyso-PC OxFA 47 INFLAMMATORY MARKERS FOR CONSIDERATION AS PREDICTORS OF CARDIOVASCULAR RISK Adhesion molecules Cytokines Acute-phase reactants Fibrinogen SAA CRP WBC count Other (eg, erytrocyte sedimentation rate) (Pearson et al, 2003) 48 SURREGATE BIOMARKERS FOR ACS HS CRP MMP Stromelysin Kalogenase Elastase INFj, TNF, IL1 Gelatinase LDH CPK MBCK Troponin T-I Fibrinogen Albuminuri D. Sargowo 49 Rudolf Virchow Inflammation-based arterial changes as a mechanism of primary importance in atherogenesis mid 19th century Lamond, B. The American Journal of Pathology. 2008 SUMMARY 50 51 Thank You 52 The Role of Lp-PLA2 in CHD LUMEN Monocytes Adhesion Molecules Oxidated LDL INTIMA MEDIA Lp-PLA2 Lyso-PC OxFA Cytokines Plaque Formation Foam Cell Macrophage 53 Intracelluler proteolysis and fusion of LDL Figure : Proposed Dual Action of Exocytosed Mast Cell Granules (The Granule Remnants) of Lipoprotein Metabolism in The Arterial Intima 54 55 24.7% 29.9% Coronary disease 7.4% ATHEROTHROMBOSIS IS COMMONLY FOUND IN MORE THAN ONE ARTERIAL BED IN AN INDIVIDUAL PATIENT* Cerebrovascular disease Peripheral arterial disease 3.8% 11.8% 19.2% * Data from CAPRIE study (n=19,185) Coccheri S. Eur Heart J 1998; 19(suppl): P1268. 3.3% 56 IKK- IKK IKK IKK Hemodynamic forces Matrix Cytokines LPS/LBP CD14 Oxidized lipids Ang II AGE RAGE AT1 SR TLR Cytokines receptor Integrin PLASMA MEMBRANE Chlamydia and virus Proteasome IKK complexes Inhibitors : IKB- IKB- IKB-r Bcl-3 (Ub)n P P IKB P65 P50 IKB P50 P65 P50 P65 NF-KB CYTOPLASM NUCLEUS 57 58 The Role of T-Lymphocyte in Atherogenesis Libby, P. 2002 59 p38 c-Jun activation Caspases Apoptosis NIK ? ? MEKK1?   CKII IKK complex TNFR-1 TNFR-1 IL-1R Shear stress p65 p50 CBP/p300 Gene activation IB Ub Target genes : - IL-1, IL-8, IL-6, IFN  - TNF, MCP-1 - CSFs, c-myc - VCAM-1, ICAM-1, E-selectin - Tissue factor - Survival factor Thurberg and Collins : Curr Opin Lipidol 9:387-396,1998 Ub Ox-LDL ROIs ??? Lipid peroxides ? H2O2 Ubiquitination and proteosome degradation 60 GM-CSF VCAM-1 MPC-1 Transcription Factors : Endothelial Cell Pro-inflammatory Genes Oxidative Stress NF-xB AP-1 Leucocyte infiltration / activation Plaque Rupture Gibbons, 97 Leucocyte Activation in Atherogenesis : Implications for Acute Ischemic Syndromes 61 Protein Regulated by NF-kB Proinflammatory Cytokine Chemokine TNF-α IL-1 β IL-2 IL-6 Granulocyte-macrophage colony stimulating factor Macrophage colony stimulating factor Granulocyte colony stimulating factor IL-8 Macrophage inflammatory protein 1 alpha MCP-1 Gro α, β dan γ NEJM, 1997 62 Thank You