Rupture of the thinning fibrous cap promotes thrombus formation resulting in clinical ischemic ASCVE. Unresolved inflammation results in formation of vulnerable plaques characterized by enhanced macrophage apoptosis and defective efferocytosis of apoptotic cells resulting in necrotic cell death leading to increased smooth muscle cell death, decreased extracellular matrix production, and collagen degradation by macrophage proteases.
Smooth muscle cells produce the extracellular matrix providing a stable fibrous barrier between plaque prothrombotic factors and platelets. Macrophage inflammatory chemoattractants stimulate infiltration and proliferation of smooth muscle cells. HDL, apoA-I, and endogenous apoE prevent inflammation and oxidative stress and promote cholesterol efflux to reduce lesion formation. Macrophage inflammation results in enhanced oxidative stress and cytokine/chemokine secretion, causing more LDL/remnant oxidation, endothelial cell activation, monocyte recruitment, and foam cell formation. Internalization of the apoB containing lipoproteins by macrophages promotes foam cell formation, which is the hallmark of the fatty streak phase of atherosclerosis. Arterial injury causes endothelial dysfunction promoting modification of apoB containing lipoproteins and infiltration of monocytes into the subendothelial space. Indeed, infiltration and retention of apoB containing lipoproteins in the artery wall is a critical initiating event that sparks an inflammatory response and promotes the development of atherosclerosis. Population studies have demonstrated that elevated levels of LDL cholesterol and apolipoprotein B (apoB) 100, the main structural protein of LDL, are directly associated with risk for atherosclerotic cardiovascular events (ASCVE).
Early observations that cholesterol is a key component of arterial plaques gave rise to the cholesterol hypothesis for the pathogenesis of atherosclerosis. Atherosclerosis is the underlying cause of heart attack and stroke.
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