CRT 2016 February 21 2016 Plaque vulnerability From

CRT 2016 February 21, 2016 Plaque vulnerability: From discovery to clinical characterization (“Twenty Years After”) Zorina S. Galis, Ph. D. Chief, Vascular Biology and Hypertension Branch Division of Cardiovascular Sciences National Heart, Lung, and Blood Institute (NHLBI) National Institutes of Health

Conflict disclosures § No financial conflicts § Note: The opinions presented do not necessarily represent the opinions of the National Heart, Lung, and Blood Institute (NHLBI)

Natural history of atherosclerosis Lipid core Vulnerable shoulder Occluding Thrombus M. Davies Cca 1990…

The “Vulnerable Plaque” Concept - Publications (Web of Science) Published Every Year Search topics: “vulnerable plaque”/“vulnerable shoulder”/“vulnerability” + atherosclerosis • • • 1990 - Little WC, Angiographic Assessment of The Culprit Coronary-artery Lesion Before Acute Myocardial-infarction 1992 - Falk E, Why Do Plaques Rupture 1992 - Davies et al, Lipid and Cellular-constituents of Unstable Human Aortic Plaques 1993 - Brown BG, Lipid-lowering Therapy for the Stabilization of the Vulnerable Atherosclerotic Plaque 1994 - Muller et al. , Triggers, Acute Risk-factors and Vulnerable Plaques - The Lexicon of a New Frontier 1994 - Galis et al, Increased Expression of Matrix Metalloproteinases and Matrix-degrading Activity in Vulnerable Regions of Human Atherosclerotic Plaques 4

New mechanistic concept, new suspects: Matrix metalloproteinases (MMPs) Normal Atherosclerotic “Vulnerable shoulder” Lumen Fibrous cap Hypothesis (cca 1994): Acute plaque failure is a consequence of MMP-3 remodeling. MMP-3 arterial Galis point. et al. 1994, JCI Plaque rupture is the tipping

Clinical imaging detects strain in plaque shoulders vulnerability IVUS Elastography Strain % Finite model of stress Characteristics of vulnerable shoulder (Lee et al. 1996, ATVB) Macrophages Schaar et al, Circulation. 2003; 108: 2636 Absence of Collagen

In vivo molecular imaging: MMPs MRI with MMP-targeted P 947 in Apo. E KO mice (Fayad, Galis, and co. , 2009) Probe Targeted Scrambled Nonspecific

How did pathological observations and experimental research benefit development of the vulnerable plaque concept and clinical strategies?

Changing investigative methods for patients at risk Angiography IVUS The “silent killer” (outward remodeling) ►“The new image” of atherosclerosis!!!

Changed the paradigm of human atherosclerosis: “the donut vs. the hole”

Vascular remodeling as a basis for the complex presentation of atherosclerotic plaques Inward remodeling Outward remodeling Pasterkamp, Galis, de Kleijn, ATVB 2004 11

Pathologic basis for new atherosclerosis imaging techniques (2003) Task Force #2 of the 34 th Bethesda Conference “Can atherosclerosis imaging techniques improve the detection of patients at risk for ischemic heart disease? ” § Plaque characteristics - Thickness of fibrous cap - Size of necrotic core - Active inflammation § Vessel wall - Compensatory/outward remodeling (Burke at al, JACC 2003)

Systematic classification of vulnerable plaques characteristics: imaging & pathology (2008) Narula J et al. (2008) Arithmetic of Vulnerable Plaques For Noninvasive Imaging Nat Clin Pract Cardiovasc Med doi: 10. 1038/ncpcardio 1247 13

Vulnerable plaque features have guided development of new imaging modalities IVUS : Plaque burden, outward remodeling IVUS Echogenicity: Lipid content IVUS Palpography: Mechanical stress areas Virtual histology: Plaque composition Optical Coherence Tomography: Fibrous cap thickness, macrophage infiltration Intravascular MRI: Plaque composition Thermography: Temperature = Inflammation

The “Vulnerable Plaque” Concept - Publications (Web of Science) Cited Every Year 15

Evolution of the “Vulnerable Plaque” Concept Pathological/Clinical puzzle Targeted clinical observations “Back to the bench” New concepts “Vulnerable Plaque” “Vulnerable shoulder” “Back to the bedside” New molecular mechanisms New animal models Fleiner et al. , 2004 Clinical associations New concepts “Vulnerable Patient” New clinical diagnosis/management

NHLBI investments targeted to imaging of vulnerable plaques “Development of Molecular Imaging Agents and Methods to Detect High Risk Atherosclerotic Plaque” (2014 solicitation) SBIR fast-track mechanism to support the development of target-specific molecular imaging agents in combination with existing imaging modalities to detect high risk atherosclerotic plaque § * Ocean Nanotech, LLC. - Manganese-based MRI Contrast Agent for Rick Stratification of Atherosclerotic Plaque * Collagen Medical, LLC. – PET-imaging of fibrin in high risk atherosclerotic plaque Nanohybrids, Inc. - Molecularly Targeted Liposomes for Detection of Macrophages in High Risk Atherosclerotic Plaque Sib. Tech, Inc. – Imaging VEGFR to detect vulnerable plaques Molecular Targeting Technologies, Inc. - PE-specific SPECT molecular imaging probe for detection of high-risk atherosclerotic plaque Nuv. Ox Pharma, LLC. - Novel Ultrasound Contrast Agent for Vulnerable Plaque § § § Thanks: Dr. Simhan Danthi, NHLBI 17