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

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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.

Characteristics of Atherosclerotic Plaques Associated with Various Presentations of Coronary Artery Disease

Libby P. N Engl J Med 2013;368:2004-2013 ACS ACS

Stable demand angina

n engl j med 368;21 nejm.2004

• rg may 23, 2013

N Engl J Med 2013;368:2004-13.

MMP = matrix metalloproteinase

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 thin- capped plaques actually rupture!

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Only 5% of thin-cap fibroatheromas cause events at a median follow-up of 3.4 Years (PROSPECT)

Stone GW et al. N Engl J Med 2011;364:226-235

Thin-cap fibroatheromas (TCFA) Minimal luminal area (MLA) Plaque burden (PB)

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

• ther 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

Swedish Registry:Hospital Survivors Receiving Specific Medications

Jernberg et al. JAMA 2011;305:1677-1684 ASA Statins

Dual anti-platelet Rx

ACE-I or ARB β-blockers

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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 Experimentally Produced Atherosclerotic Plaques

Libby P. N Engl J Med 2013;368:2004-2013

Challenges to the “vulnerable plaque” concept

♥ The character of human plaques is changing in the statin era

van Lammeren et al. Circulation. 2014;129:2269-2276.

Human plaques are getting less fatty in the statin era

Human plaques

are getting less “inflammed” in the statin era

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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

More NSTEMI, fewer STEMI

The Changing Face of the

Acute Coronary Syndromes

Katz et al. Crit Care Med 2010; 38:375–381

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Incidence'rates'for'ST0segment'eleva5on'acute'myocardial'infarc5on'(STEMI)'and' non0ST0segment'eleva5on'acute'myocardial'infarc5on'(NSTEMI)'by'study'year.'

McManus'DD,' Gore'J,'Yarzebski' J,'Spencer'F,' Lessard'D,' Goldberg'RJ.''

Recent'trends'in' the'incidence,' treatment,'and'

• utcomes'of'

paAents'with' STEMI'and' NSTEMI.

'Am#J#Med.#2011;124(1):40147.'

Age- and Sex-Adjusted Incidence Rates of Acute Myocardial Infarction, 1999 to 2008

Yeh RW et al. N Engl J Med 2010;362:2155-2165

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

• f Events in the Statin Megatrials

62% 75% 75% 78% 74% 73% 69% 62% 20 40 60 80 100 AFCAPS/ TexCAPS 6605

• 27%

4S 4444

• 36%

LIPID 9014

• 25%

CARE 4159

• 28%

WOS 6595

• 26%

Trial: N: ΔLDL: HPS 20,536

• 29%

Secondary Primary High Risk Residual Major Coronary 
 Events (%)

Adapted from Libby. J Am Coll Cardiol. 2005;46:1225-1228.

PROVE-IT (Standard) 2063

• 10%

PROVE-IT (Aggressive) 2099

• 42%

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

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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?

The Acute Coronary Syndromes are Changing Before Our Eyes

Libby P. N Engl J Med 2013;368:2004-2013 ACS ACS

Stable demand angina

Fewer STEMI, more NSTEMI Less rupture, more erosion?

Superficial erosion of an atheroma causing thrombosis

Farb…Virmani Circulation 93:1354 (1996)

J Am Coll Cardiol. 2013;62:1748-1758.

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) cross- sectional images from proximal to distal of the culprit lesion indicate that no rupture is detected. Cross- sectional 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;62:1748-1758

In Vivo Diagnosis of Plaque Erosion and Calcified Nodule in Patients With Acute Coronary Syndrome by Intravascular Optical Coherence Tomography.

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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;62:1748-1758

STEMI

Rupture Erosion

NSTEMI

N=39 N=16 N=15 N=24

Plaque rupture causes primarily ST Segment Elevation MI (STEMI)

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;62:1748-1758.

The Changing Face of the Acute Coronary Syndromes

♥ What basic mechanisms drive superficial erosion?

αβ αβ αβ αβ αβ αβ

Basement membrane (type IV collagen rich)

MMP-2

Endothelial cell death (including apoptosis)

Endothelial cell desquamation due to lysis of the extracellular matrix

Libby P, Ganz P, Schoen FJ, Lee RT. The vascular biology of the acute coronary syndromes. In: Topol EJ, editor. Acute coronary syndromes, 2nd ed. New York: Marcel Dekker, Inc.; 2000. p. 33-57.

Hypotheses re Mechanisms of Superficial Erosion - 2000

Activated ECs can induce NETs and become susceptible to NETosis-mediated cell death

Fuchs et al, ATVB, 2012

Neutrophil extracellular traps (NETs)

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Human plaques with erosion characteristics associate with NETS

Quillard et al. EHJ, 2015

« Stable » « Erosion-prone » « Rupture-prone »

Neutrophil elastase Citrullinated histones

Neutrophil Extracellular Traps (NETs) in Human Atherosclerotic Plaques

DNA Citrullinated histone Neutrophil elastase Quillard et al. EHJ June 2015

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).

The innate immune receptor TLR2 promotes endothelial functions related to superficial erosion. Quillard et al. EHJ 2015

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

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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:10.1093/eurheartj/ehv349

Thanks!

Thibaut Quillard Haniel Araújo Grégory Franck Eugenia Schvarz Galina Sukhova Eduardo Folco

D.W. Reynolds Foundation

Thanks to the people who do the work



 
 Center for Excellence in Vascular Biology 2015