Section 4: Plaque dynamics and stenosis Atherosclerosis timeline Content Points: The degeneration of healthy endothelium via the pathogenesis of atherosclerosis occurs slowly over decades.27 It appears to begin with a subtle form of endothelial injury that alters function. Foam cells are the earliest sign of endothelial dysfunction. They are macrophages that contain Ox LDL-C and are most frequent in infants and children. Foam cells may then infiltrate the vessel, progressing to a fatty streak. As the lesion progresses to an intermediate lesion, small pools of extracellular lipid form within the smooth muscle layers, disrupting the intimal lining of the vessel. Progression to an advanced lesion occurs when the accumulated lipid, cells and other components of the plaque disrupt the artery wall. This lesion is termed an atheroma. Once the plaque becomes fibrous, it is primed to rupture. This type of advanced lesion can be found from the fourth decade of life onward. The endothelium itself appears to participate in some of this remodeling through secretion of specific compounds.5

Some features of vulnerable plaque Content Points: Plaques are more vulnerable in their earlier stages than later in their development. Pathologic studies have suggested that coronary arteries undergo dilation (remodeling) of the lamina in the early stages of atherosclerosis to compensate for the progressive accumulation of plaque.28 Thus, vulnerable plaques are characterized by a well-preserved lumen (and may appear angiographically normal).29 There is also a substantial lipid core and a thin fibrous cap separating this core from the bloodstream.29 The presence of HLA-DR antigen at sites of lesion disruption indicates activation of smooth muscle cells. Activation of macrophages and smooth muscle cells by inflammatory mediators may result in weakening of the fibrous cap, increasing the risk of plaque rupture.

Patients dying with stable versus unstable coronary syndromes: Atheromas have varying composition Content Points: In a landmark study, Davies and colleagues assessed the histology of aortic plaques of men who had died suddenly (within 6 hours of onset of symptoms) of ischemic heart disease.30 Stable plaques were defined as those with a smooth, apparently intact intimal surface, while unstable plaques were defined as those with an area of thrombosis and focal ulceration at one end that left most of the plaque intact. The investigators analyzed a total of 155 stable and unstable plaques from 13 aortas. In 91.1% of unstable plaques, the lipid content was > 40%, while only 10.9% of stable plaques had lipid pools of this size. The volume of macrophages was 13.7% and 2.9% in unstable and stable plaques, respectively. The volume of smooth muscle cells was 2.8% and 11.8% in unstable and stable plaques, respectively. These data show that factors predisposing a plaque to rupture are: – Lipid accumulation – Increase in lipid-laden macrophages – Disruption in reparative smooth muscle proliferation in the cap

Role of LDL-C in plaque formation and progression Content Points: LDL-C (through Ox LDL-C) is a key mediator in plaque development and subsequent impairment of endothelial and vascular function. Given these findings, reduction of LDL-C becomes an important clinical strategy for decreasing CV events.

Clinical viewpoints on plaques Content Points: Maintaining an intact plaque is vital to prevention of coronary events. Less severely obstructive plaques (< 80% stenosis) are more numerous than severely obstructive plaques.31 Less severely obstructive plaques are also responsible for the majority of coronary events (although it is not clear whether this is due to their greater number or to their composition predisposing them to rupture).