actually rupture! Challenges to the vulnerable plaque concept

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1 An Update on the Pathogenesis of the Acute Coronary Syndromes Peter Libby Brigham & Women s Hospital Harvard Medical School ADVANCES IN HEART DISEASE University of California San Francisco December 20, 2015 Peter Libby Brigham & Women s Hospital Harvard Medical School Dr. Libby does not accept payments from Pharma. He serves as an unpaid consultant and contributes to clinical trials sponsored by Pharma. ACS Stable demand angina Characteristics of Atherosclerotic Plaques Associated with Various Presentations of Coronary Artery Disease Libby P. N Engl J Med 2013;368: n engl j med 368;21 nejm.2004 org may 23, 2013 MMP = matrix metalloproteinase ACS N Engl J Med 2013;368: We tend to face today s battle prepared to fight the last war Is the vulnerable plaque a valid concept in 2015? Challenges to the vulnerable plaque concept Few thincapped plaques actually rupture! Page 1

2 Only 5% of thin-cap fibroatheromas cause events at a median follow-up of 3.4 Years (PROSPECT) Thin-cap fibroatheromas (TCFA) Minimal luminal area (MLA) Plaque burden (PB) Stone GW et al. N Engl J Med 2011;364: Challenges to the vulnerable plaque concept Thin capped, lipid-rich atheromata most often persist for years without causing a clinical event Thin capped, lipid-rich atheromata are not solitary, rather often multiple and affect several arterial beds in the same individual Challenges to the vulnerable plaque concept The risk profile and demographics of ACS patients is shifting worldwide (global burden, younger patients, more women, more insulin resistance/diabetes, more hypertriglyceridemia, less LDL excess) Challenges to the vulnerable plaque concept Statin treatment and other preventive measures have begun to modify atherosclerotic disease The character of human plaques is changing- Why? Statin use is on the rise ACS Treatments Changing with Time ASA Statins Dual anti-platelet Rx ACE-I or ARB β-blockers Swedish Registry:Hospital Survivors Receiving Specific Medications Jernberg et al. JAMA 2011;305: Page 2

3 Previous Use of Medication on an Outpatient Basis Population Trends in the Incidence and Outcomes of Acute Myocardial Infarction. Yeh RW et al. N Engl J Med 2010;362: Favorable Effects of Lipid Lowering in Experimentally Produced Atherosclerotic Plaques Libby P. N Engl J Med 2013;368: Challenges to the vulnerable plaque concept The character of human plaques is changing in the statin era Human plaques are getting less fatty in the statin era Human plaques are getting less inflammed in the statin era van Lammeren et al. Circulation. 2014;129: Page 3

4 Effects of intensive statin treatment on human atherosclerotic plaques Libby P. Eur Heart J 2015;eurheartj.ehu510 Meanwhile, the profile of ACS patients and presentations is changing STEMI is decreasing as NSTEMI rises as a proportion of ACS The Changing Face of the Acute Coronary Syndromes More NSTEMI, fewer STEMI Katz et al. Crit Care Med 2010; 38: Page 4

5 Incidence'rates'for'ST0segment'eleva5on'acute'myocardial'infarc5on'(STEMI)'and' non0st0segment'eleva5on'acute'myocardial'infarc5on'(nstemi)'by'study'year.' Recent'trends'in' the'incidence,' treatment,'and' outcomes'of' paaents'with' STEMI'and' NSTEMI. Age- and Sex-Adjusted Incidence Rates of Acute Myocardial Infarction, 1999 to 2008 'Am#J#Med.#2011;124(1):40147.' McManus'DD,' Gore'J,'Yarzebski' J,'Spencer'F,' Lessard'D,' Goldberg'RJ.'' Yeh RW et al. N Engl J Med 2010;362: We tend to face battle prepared to fight the last war Our current therapies likely contribute to the decline in STEMI by stabilizing so-called vulnerable plaques. We tend to face battle prepared to fight the last war Yet, despite statins, the residual burden of cardiovascular events even with contemporary preventive measures remains unacceptably high The Forgotten Majority: Residual Burden of Events in the Statin Megatrials Residual Major Coronary Events (%) Trial: 4S N: ΔLDL: % 62% LIPID % 75% 75% 78% CARE % Secondary PROVE-IT (Standard) % 74% 73% PROVE-IT (Aggressive) % Adapted from Libby. J Am Coll Cardiol. 2005;46: HPS 20,536-29% 69% High Risk WOS % 62% AFCAPS/ TexCAPS % Primary We tend to face battle prepared to fight the last war We understand the pathophysiology of plaque rupture We understand how lipid lowering limits plaque rupture Let s now address residual risk in statin-treated patients with the current risk factor profile Page 5

6 The Changing Face of the Acute Coronary Syndromes What mechanisms beyond plaque rupture may contribute to the residual burden of events in the current era? ACS Stable demand angina ACS The Acute Coronary Syndromes are Changing Before Our Eyes Fewer STEMI, more NSTEMI Less rupture, more erosion? Libby P. N Engl J Med 2013;368: Superficial erosion of an atheroma causing thrombosis Farb Virmani Circulation 93:1354 (1996) Representative Case of Plaque Rupture. A 57-year-old man presenting with ST-segment elevation myocardial infarction was treated with thrombolysis. (A) The coronary angiogram shows the culprit lesion in the mid left anterior descending coronary artery (dashed line indicates the ruptured site corresponding to B). Plaque rupture is identified on cross-sectional (B) and longitudinal (C) optical coherence tomography images by the disrupted fibrous-cap (arrowheads) and a cavity ( ) formation inside the plaque. In Vivo Diagnosis of Plaque Erosion and Calcified Nodule in Patients With Acute Coronary Syndrome by Intravascular Optical Coherence Tomography. Representative Case of Definite OCT-Erosion A 31-year-old man presented with non ST-segment elevation myocardial infarction. Angiographic image (bottom panel) shows a moderate stenosis in the proximal left anterior descending coronary artery. Serial optical coherence tomography (OCT) crosssectional images from proximal to distal of the culprit lesion indicate that no rupture is detected. Crosssectional images indicate fibrous plaque (homogeneous high signal region) proximal (A) and distal (D) to thrombus. OCT-erosion is identified as an irregular lumen surface with attached mural thrombus (arrows) overlying a fibrous plaque (B and C). J Am Coll Cardiol. 2013;62: In Vivo Diagnosis of Plaque Erosion and Calcified Nodule in Patients With Acute Coronary Syndrome by Intravascular Optical Coherence Tomography. J Am Coll Cardiol. 2013;62: Page 6

7 In Vivo Diagnosis of Plaque Erosion and Calcified Nodule in Patients With Acute Coronary Syndrome by Intravascular Optical Coherence Tomography Incidence of Plaque Rupture, OCT-Erosion, and OCT-CN in Patients With ACS. Among the 126 culprit lesions, 55 (44%) lesions were classified as plaque rupture, 39 (31%) lesions were classified as optical coherence tomography (OCT)-erosion, 10 (8%) lesions were classified as OCT-calcified nodule (CN), and 22 (17%) lesions were classified as others. ACS = acute coronary syndrome. J Am Coll Cardiol. 2013;62: Plaque rupture causes primarily ST Segment Elevation MI (STEMI) STEMI N=39 Rupture Erosion NSTEMI N=16 N=15 N=24 After: In Vivo Diagnosis of Plaque Erosion and Calcified Nodule in Patients With Acute Coronary Syndrome by Intravascular Optical Coherence Tomography. J Am Coll Cardiol. 2013;62: The Changing Face of the Acute Coronary Syndromes What basic mechanisms drive superficial erosion? Hypotheses re Mechanisms of Superficial Erosion Endothelial cell desquamation due to lysis of the extracellular matrix MMP-2 αβ αβ αβ Basement membrane (type IV collagen rich) Endothelial cell death (including apoptosis) Libby P, Ganz P, Schoen FJ, Lee RT. The vascular biology of the acute coronary syndromes. In: Topol EJ, editor. Acute coronary syndromes, 2 nd ed. New York: Marcel Dekker, Inc.; p Activated ECs can induce NETs and become susceptible to NETosis-mediated cell death Neutrophil extracellular traps (NETs) Fuchs et al, ATVB, 2012 Page 7

8 Human plaques with erosion characteristics associate with NETS «Stable» «Erosion-prone» «Rupture-prone» Neutrophil elastase Citrullinated histones Neutrophil Extracellular Traps (NETs) in Human Atherosclerotic Plaques Quillard et al. EHJ, 2015 Quillard et al. EHJ June 2015 DNA Citrullinated histone Neutrophil elastase EC apoptosis associates with luminal PMNs and TLR2 expression only in SMC-rich lesions Quillard et al. EHJ, 2015 The frond-like processes extending into the lumen from the intimal surface of a human carotid atheroma exemplify neutrophil extracellular traps (NETs) derived from DNA extruded by dying granulocytes. This merged immunofluorescent micrograph shows neutrophil elastase (green), citrullinated histone-4 (red), and nuclei (blue). Implication of the Innate Immune Receptor TLR2 in Plaque Superficial Erosion The innate immune receptor TLR2 promotes endothelial functions related to superficial erosion. Quillard et al. EHJ 2015 Promotes endothelial (EC) death Promotes EC desquamation Impairs EC monolayer healing Sets the stage for formation of neutrophil extracellular traps Page 8

9 The Changing Face of the Acute Coronary Syndromes Superficial erosion appears on the rise in the statin era and may account for some of the residual burden of risk Contrasts between superficial erosion and fibrous cap rupture as causes of arterial thrombosis Requiem for the vulnerable plaque Peter Libby and Gerard Pasterkamp European Heart Journal doi: /eurheartj/ehv349 D.W. Reynolds Foundation Thanks! Thibaut Quillard Haniel Araújo Grégory Franck Eugenia Schvarz Galina Sukhova Eduardo Folco Thanks to the people who do the work Center for Excellence in Vascular Biology 2015 Page 9