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...

By contributing to the deposition of free cholesterol, macrophage infiltration, and enlargement of the necrotic core, the accumulation of erythrocyte membranes within an atherosclerotic plaque may represent a potent atherogenic stimulus. These factors may increase the risk of plaque destabilization.

Abstract-Polymer-based sirolimus-(Cypher) and paclitaxel-eluting (Taxus) drug eluting stents have become the treatment of choice for patients with symptomatic coronary artery disease undergoing percutaneous coronary intervention (PCI).Although these stents reduce rates of restenosis compared with bare metal stents (BMS), late thrombosis, a life threatening complication, has emerged as a major safety concern. Our understanding of the pathophysiology of late DES thrombosis is derived from animal and human pathologic samples taken after implantation of these devices. These data indicate that both DES cause substantial impairment in arterial healing characterized by lack of complete reendothelialization and persistence of fibrin when compared with BMS. This delayed healing is the primary substrate underlying all cases of late DES thrombosis at autopsy. Several additional risk factors for late stent thrombosis such as penetration of necrotic core, malapposition, overlapping stent placement, excessive stent length, and bifurcation lesions represent additional barriers to healing and should be avoided if DES are to be used to minimize the risk of late thrombosis.Because the time course of complete healing with DES in man is unknown, the optimal duration of antiplatelet treatment remains to be determined. Key Words: stents Ⅲ thrombosis Ⅲ endothelium P olymer-based sirolimus (Cypher) and paclitaxel (Taxus) drug eluting stents (DES) have reduced rates of restenosis and target lesion revascularization (TLR) compared with bare metal stents (BMS) and launched a revolution in the interventional treatment of symptomatic coronary artery disease. However, enthusiasm for this technology has recently been dampened by concerns about late thrombosis (ie, stent thrombosis occurring more than 30 days after percutaneous coronary intervention), an event with oftencatastrophic consequences.Our understanding of the pathophysiology of late DES thrombosis is derived from the histological examination of animal and human arteries containing these devices. This review will focus on the cellular response that occurs when the drug and polymer contained in these devices interact with the vessel wall, especially as it relates to the process of late stent thrombosis. Preclinical Evaluation of DESPreclinical testing in both the porcine and rabbit models is an important part of the regulatory process used to determine the safety and efficacy of devices before human use. Comparative preclinical histological studies remain the most effective method of assessing the vascular responses to these devices before their introduction into humans. Although it is wellrecognized that arterial repair after stent placement in animals occurs more rapidly than in man, the sequence of biological events associated with healing are remarkably similar. 1 We will discuss below why the predictive value of the vascular healing responses for humans has for the most part not been shown. Sirolimus and Paclitaxel and Their Effects on the Arterial WallDrug choice and release kin...

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The Cypher and Taxus DES result in delayed arterial healing when compared with BMS of similar implant duration. The cause of DES LST is multifactorial with delayed healing in combination with other clinical and procedural risk factors playing a role.

The present study marks the first comparator analysis of endothelial coverage in leading polymeric DES, supporting disparities in arterial healing based on endothelial regrowth and recovery, favoring newer designs over the current generation of FDA-approved stents.

Background-The long-term safety of drug-eluting stents (DES) for acute myocardial infarction (AMI) remains uncertain.Using autopsy data, we evaluated the pathological responses of the stented segment in patients treated with DES for AMI and compared with patients with stable angina. Methods and Results-From the CVPath Registry of 138 DES autopsies, we identified 25 patients who presented with AMI and had an underlying necrotic core with a ruptured fibrous cap. Twenty-six patients who had stable angina with thick-cap fibroatheroma treated by DES were selected as controls. Histomorphometric analysis was performed in patients with Ͼ30-day stent duration. We compared the response to stenting at the culprit site in these 2 groups and to nonculprit sites within each stent.

While the concept of plaque 'vulnerability' implies a propensity towards thrombosis, the term vulnerable was originally intended to provide a morphologic description consistent with plaques that are prone to rupture. It is now known that the etiology of coronary thrombi is diverse and can arise from entities of plaque erosion or calcified nodules. These findings have prompted the search for more definitive terminology to describe precursor lesions associated with rupture, now referred to as thin-cap fibroatheromas. This review focuses on the thin-cap fibroatheroma, as a specific cause of acute coronary syndromes. To put these issues into current perspective, we need to revisit some of the older literature describing plaque morphology in stable and unstable angina, acute myocardial infarction, and sudden coronary death. The morphology, frequency, and precise location of these thin-cap fibroatheromas are further discussed in detail. Potential mechanisms of fibrous cap thinning are also addressed, in particular emerging data, which suggests the role of cell death "apoptosis" in cap atrophy.