Abstract-Observational studies of necrotic core progression identify intraplaque hemorrhage as a critical factor in atherosclerotic plaque growth and destabilization. The rapid accumulation of erythrocyte membranes causes an abrupt change in plaque substrate characterized by increased free cholesterol within the lipid core and excessive macrophage infiltration. Neoangiogenesis is associated closely with plaque progression, and microvascular incompetence is a likely source of intraplaque hemorrhage. Intimal neovascularization is predominantly thought to arise from the adventitia, where there are a plethora of pre-existing vasa vasorum. In lesions that have early necrotic cores, the majority of vessels invading from the adventitia occur at specific sites of medial wall disruption. A breech in the medial wall likely facilitates the rapid in-growth of microvessels from the adventitia, and exposure to an atherosclerotic environment stimulates abnormal vascular development characterized by disorganized branching and immature endothelial tubes with "leaky" imperfect linings. This network of immature blood vessels is a viable source of intraplaque hemorrhage providing erythrocyte-derived phospholipids and free cholesterol. The rapid change in plaque substrate caused by the excessive accumulation of erythrocytes may promote the transition from a stable to an unstable lesion. This review discusses the potential role of intraplaque vasa vasorum in lesion instability as it relates to plaque rupture. Key Words: angiogenesis Ⅲ plaque rupture Ⅲ sudden coronary death Ⅲ free cholesterol Ⅲ hemorrhage T he causes of coronary lesion progression from an asymptomatic fibroatheromatous plaque to a lesion at high risk for rupture (thin cap fibroatheroma or "vulnerable plaque") are not fully understood. Recently, our laboratory showed that intraplaque hemorrhage is an important process in the progression of asymptomatic plaques into high-risk unstable lesions. 1 Red blood cell (RBC) membranes are rich in phospholipids and free cholesterol, and their accumulation within plaques plays a key role in promoting lesion instability through necrotic core expansion and inflammatory cell infiltration. The source of RBCs within coronary lesions is likely provided by inherently leaky immature blood vessels that surround and invade the plaque. Understanding the mechanisms by which plaque angiogenesis and hemorrhage occurs may ultimately help prevent the transition from a stable to an unstable lesion. Plaque Rupture Is the Dominant Cause of Acute Coronary ThrombosisPlaque rupture is the principal cause of luminal thrombosis in acute coronary syndromes occurring in 75% of patients dying of an acute myocardial infarction. 2 The plaques that are vulnerable to rupture are characterized by the same histopathologic signatures, except that they still have an intact fibrous cap, albeit thin. [3][4][5] The fibrous cap is focally interrupted in plaque ruptures, allowing circulating blood to come in direct contact with the thrombogenic contents of the lipid-ric...

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