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December 3, 2019 1857 Mark Brezinski, MD, PhD Frank Willard, PhD Maria Rupnick, MD, PhD I t is a widely believed paradigm that intimal angiogenesis in coronary atherosclerosis contributes to plaque instability through both hemorrhagic plaque expansion and cholesterol deposition.1 However, this article supports an alternative concept in which angiogenesis is actually essential for plaque stabilization and healing.2,3 The prevailing paradigm has its origins primarily in histopathology work from the 1980s by Barger’s group reported by Kamat et al.4 We argue that misinterpretation of their results has skewed the understanding of vulnerable plaque for >35 years. This misconception still endures in recent plaque angiogenesis reviews, affecting understanding of acute coronary syndromes (ACS) pathophysiology.1 Most coronary plaque ruptures/erosions do not lead to ACS. ACS research focuses primarily on vessel breakdown through mechanisms such as inflammation. We have instead proposed that vessel repair mechanisms that oppose instability fail, leading to ACS.3 ACS is then a double hit of rupture/erosion and failed vascular healing. Here, we assert that intimal angiogenesis, needed to maintain cellular reparative functions (ie, healing), if inadequate, leads to coronary plaque instability. Angiogenesis is the supply line to reparative cells in healing regions. In plaques with long necrotic cores, this supply line to compromised regions may not be reliably established. In their 1984 report, Barger’s group injected silicone into human coronary arteries in vitro and filmed the flow into mural microvessels.4 They described a primarily short centripetal angiogenesis pattern from the vasa vasorum to the intima. Their discussion linked angiogenesis to plaque hemorrhage with rapid plaque expansion as a trigger for ACS. Our data and literature analysis, including re-examination of the results of Barger and colleagues, do not support primarily centripetal angiogenesis. Instead, we find axial angiogenesis extending many millimeters yet perhaps remaining insufficient to reach compromised intima. We acknowledge that leaky immature microvessels lead to small intimal hemorrhages that contribute red blood cell cholesterol.2 However, hemorrhage is not a significant source of coronary plaque rapid expansion.2 This is unlike human carotid arteries or most animal arteries, often used as models in intimal angiogenesis research, in which hemorrhagic plaque expansion is common.1 We instead propose that coronary angiogenesis is a critical stabilizing factor. Our conclusions are derived from an examination of human coronary plaque in the long axis rather than in conventional cross section, as well as re-evaluating published data, including the work by Barger and colleagues. These conclusions are also supported by data that angiogenesis inhibitors (eg, sunitinib and sorafenib) increase, not decrease, the risk of vascular occlusion in humans. Examining plaques axially rather than in conventional cross section was critical in our questioning of the current paradigms. The most common morphology found after ACS is thin-walled plaques with a large necrotic core by cross © 2019 American Heart Association, Inc. ON MY MIND