Regression of atherosclerosis. A role for calcium antagonists.

The key processes responsible for plaque in atherosclerosis are cholesterol accumulation, caused by increased net uptake of atherogenic lipoproteins; cell proliferation and recruitment, caused by mitogenic and chemotactic activity; extracellular matrix expansion and collagen accumulation, caused by increased intimal cell synthesis; and high rates of cell death, caused by increased metabolic needs of tissue in an unfavorable milieu. Cell death is associated with neovascularization, dense fibrosis, and calcification, with the subsequent plaque complications of hemorrhage and thrombosis. An additional functional feature of atherosclerosis, even in prestenotic stages, is severe vasomotor abnormalities, caused in part by endothelial dysfunction. Reversal of atherosclerosis involves interrupting these processes. Calcium antagonists may block specific stages of atherogenesis. Anticalcifying agents (diphosphonates, thiophenes, and metallic ions) inhibit accumulation of connective tissue. Calcium channel blockers reduce endothelial injury and intimal permeability, block proliferation of intimal cells, inhibit lipid accumulation by a number of mechanisms, and reduce exaggerated vasoconstrictor responses. Thus, calcium antagonists may promote regression of lesions beyond what can be achieved by reducing risk factors alone.