Few thin- vulnerable capped plaques plaque a valid actually - PDF document

An Update on the Pathogenesis of Peter Libby Brigham & Women’s Hospital the Acute Coronary Syndromes Harvard Medical School Dr. Libby does not accept payments Peter Libby from Pharma. He Brigham & Women’s Hospital serves as an Harvard Medical School unpaid consultant and contributes to ADVANCES IN HEART DISEASE clinical trials sponsored by University of California San Francisco December 20, 2015 Pharma. MMP = matrix metalloproteinase n engl j med 368;21 nejm.2004 Characteristics of Atherosclerotic org may 23, 2013 Plaques Associated with ACS Various Presentations of Coronary Artery Disease Stable demand angina Libby P. N Engl J Med 2013;368:2004-2013 ACS N Engl J Med 2013;368:2004-13. We tend to face today’s battle Challenges to the prepared to fight the last war “vulnerable plaque” concept ♥ Is the ♥ Few thin- “vulnerable capped plaques plaque” a valid actually rupture! concept in 2015? Page 1

Only 5% of thin-cap fibroatheromas cause Challenges to the events at a median follow-up of 3.4 Years “vulnerable plaque” concept (PROSPECT) � 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 Thin-cap fibroatheromas (TCFA) and affect several arterial beds in Minimal luminal area (MLA) Plaque burden (PB) the same individual Stone GW et al. N Engl J Med 2011;364:226-235 Challenges to the “vulnerable Challenges to the “vulnerable plaque” concept plaque” concept � Statin treatment and � The risk profile and demographics of ACS patients is other preventive shifting worldwide (global burden, measures have begun younger patients, more women, to modify more insulin resistance/diabetes, more hypertriglyceridemia, less atherosclerotic disease LDL excess) ACS Treatments Changing with Time The character of human Dual anti-platelet Rx plaques is changing- Why? ASA β -blockers ♥ Statin use Statins Swedish ACE-I or ARB Registry:Hospital is on the rise Survivors Receiving Specific Medications Jernberg et al. JAMA 2011;305:1677-1684 Page 2

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;362:2155-2165 Favorable Effects of Lipid Lowering in Challenges to the Experimentally Produced Atherosclerotic Plaques “vulnerable plaque” concept ♥ The character of human plaques is changing in the statin era Libby P. N Engl J Med 2013;368:2004-2013 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;129:2269-2276. Page 3

Effects of intensive statin treatment on human atherosclerotic plaques Libby P. Eur Heart J 2015;eurheartj.ehu510 Meanwhile, the profile of ACS The Changing Face of the patients and presentations is Acute Coronary Syndromes changing ♥ STEMI is decreasing as NSTEMI rises as a More NSTEMI, fewer STEMI proportion of ACS Katz et al. Crit Care Med 2010; 38:375–381 Page 4

Incidence'rates'for'ST0segment'eleva5on'acute'myocardial'infarc5on'(STEMI)'and' Age- and Sex-Adjusted Incidence Rates of non0ST0segment'eleva5on'acute'myocardial'infarc5on'(NSTEMI)'by'study'year.' Acute Myocardial Infarction, 1999 to 2008 Recent'trends'in' the'incidence,' treatment,'and' outcomes'of' paAents'with' STEMI'and' NSTEMI. McManus'DD,' Gore'J,'Yarzebski' J,'Spencer'F,' Lessard'D,' Goldberg'RJ.'' ' Am#J#Med.#2011;124(1):40147. ' Yeh RW et al. N Engl J Med 2010;362:2155-2165 We tend to face battle We tend to face battle prepared to fight the last war prepared to fight the last war ♥ Yet, despite statins, the ♥ Our current therapies residual burden of likely contribute to the cardiovascular events even decline in STEMI by with contemporary “stabilizing” so-called preventive measures “vulnerable plaques.” remains unacceptably high The Forgotten Majority: Residual Burden We tend to face battle of Events in the Statin � Megatrials � prepared to fight the last war Residual Major Coronary 
 100 78% 75% 75% 74% 80 73% ♥ We understand the 69% Events (%) 62% 62% 60 pathophysiology of plaque rupture 40 ♥ We understand how lipid lowering 20 limits plaque rupture 0 Trial: 4S LIPID CARE PROVE-IT PROVE-IT HPS WOS AFCAPS/ TexCAPS ( Standard ) ( Aggressive ) ♥ Let’s now address residual risk in 6605 N: 4444 9014 4159 2063 2099 20,536 6595 Δ LDL: -36% -25% -28% -10% -42% -29% -26% -27% statin-treated patients with the Secondary High Risk Primary current risk factor profile Adapted from Libby. J Am Coll Cardiol. 2005;46:1225-1228. Page 5

The Acute The Changing Face of the Coronary Acute Coronary Syndromes Syndromes are Changing Before Our Eyes ACS ♥ What mechanisms � Fewer STEMI, beyond plaque rupture more NSTEMI Stable � Less rupture, may contribute to the demand angina more erosion? residual burden of events Libby P. N Engl J Med 2013;368:2004-2013 in the current era? ACS 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 Representative Case of � Definite OCT-Erosion �� A 31-year-old man presented with non–ST-segment infarction was treated with thrombolysis. (A) The coronary angiogram shows the culprit lesion in the mid left anterior elevation myocardial infarction. Angiographic image (bottom panel) shows a moderate stenosis in the descending coronary artery (dashed line indicates the ruptured site corresponding to B). Plaque rupture is identified on proximal left anterior descending coronary artery. Serial optical coherence tomography (OCT) cross- cross-sectional (B) and longitudinal (C) optical coherence tomography images by the disrupted fibrous-cap sectional images from proximal to distal of the culprit lesion indicate that no rupture is detected. Cross- (arrowheads) and a cavity ( � ) formation inside the plaque. sectional images indicate fibrous plaque (homogeneous high signal region) proximal (A) and distal (D) In Vivo Diagnosis of Plaque Erosion and to thrombus. OCT-erosion is identified as an irregular lumen surface with attached mural thrombus Calcified Nodule in Patients With Acute (arrows) overlying a fibrous plaque (B and C). Coronary Syndrome by Intravascular Optical Coherence Tomography. In Vivo Diagnosis of Plaque Erosion and Calcified Nodule in Patients With Acute J Am Coll Cardiol. Coronary Syndrome by 2013;62:1748-1758 Intravascular Optical J Am Coll Cardiol. Coherence 2013;62:1748-1758. Tomography. Page 6

In Vivo Diagnosis of Plaque Erosion and Calcified Nodule in Patients With Acute Plaque rupture causes primarily Coronary Syndrome by Intravascular Optical Coherence Tomography J Am Coll Cardiol. 2013;62:1748-1758 ST Segment Elevation MI (STEMI) NSTEMI STEMI N=16 N=15 N=39 N=24 Rupture Erosion Incidence of Plaque Rupture, OCT-Erosion, and OCT-CN in Patients With ACS. Among the 126 culprit lesions, 55 (44%) lesions were After: In Vivo Diagnosis of Plaque Erosion and Calcified Nodule in Patients With Acute Coronary classified as plaque rupture, 39 (31%) lesions were classified as optical coherence tomography (OCT)-erosion, 10 (8%) lesions were Syndrome by Intravascular Optical Coherence Tomography. J Am Coll Cardiol. 2013;62:1748-1758. classified as OCT-calcified nodule (CN), and 22 (17%) lesions were classified as others. ACS = acute coronary syndrome. Hypotheses re Mechanisms of The Changing Face of the Superficial Erosion - 2000 Acute Coronary Syndromes Endothelial cell desquamation due to Endothelial cell death lysis of the extracellular matrix (including apoptosis) ♥ What basic mechanisms αβ αβ αβ αβ αβ αβ MMP-2 drive superficial Basement membrane (type IV collagen rich) Libby P, Ganz P, Schoen FJ, Lee RT. The vascular biology of the erosion? acute coronary syndromes. In: Topol EJ, editor. Acute coronary syndromes, 2 nd ed. New York: Marcel Dekker, Inc.; 2000. p. 33-57. Activated ECs can induce NETs and become susceptible to NETosis-mediated cell death Neutrophil extracellular traps (NETs) Fuchs et al, ATVB, 2012 Page 7

Human plaques with erosion Neutrophil Extracellular Traps (NETs) characteristics associate with NETS in Human Atherosclerotic Plaques « Stable » « Erosion-prone » « Rupture-prone » Neutrophil elastase Citrullinated histones DNA Citrullinated histone Quillard et al. EHJ June 2015 Neutrophil elastase Quillard et al. EHJ, 2015 EC apoptosis associates with luminal PMNs and TLR2 The frond-like processes expression only in SMC-rich lesions extending into the lumen from the intimal surface of a human carotid atheroma exemplify neutrophil Quillard et al. EHJ, 2015 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 ♥ Promotes endothelial (EC) death ♥ Promotes EC desquamation ♥ Impairs EC monolayer healing ♥ Sets the stage for formation of neutrophil extracellular traps The innate immune receptor TLR2 promotes endothelial functions related to superficial erosion. Quillard et al. EHJ 2015 Page 8