The continuum of risk: vascular pathophysiology, function, and structure.

What factors place people at risk for developing cardiovascular disease as they grow from youth to adulthood? How do both physiological and epidemiological investigations contribute to the development of the evidence that can support or refute current hypotheses regarding the development of atherosclerosis? How can the interplay of differing study designs improve our understanding of atherosclerosis? See p 2918 Atherosclerosis is a systemic disease that is the leading cause of death in the developed world and leads to carotid artery, coronary artery, and peripheral arterial atherosclerotic syndromes. Inasmuch as atherosclerotic diseases affect as many as 64 million adults in the United States, considerable health care resources have been deployed to provide care for those affected.1 Past research findings have contributed to considerable advances in survival for individuals who have overt heart disease, stroke, and peripheral arterial disease, yet the continued aging of the population implies that the prevalence of each atherosclerotic disorder will increase in the decades ahead. In this context, investigations that provide insights into disease mechanisms and that define how vulnerability to atherosclerosis is established are now particularly valuable. The pathophysiology of atherosclerosis is known to be dependent on multiple hereditary and environmental factors. It is presumed that these genetic and acquired factors contribute in a complex manner to a progressive pathophysiological process that causes a normal artery to develop progressive endothelial dysfunction. Loss of normal endothelial function is hypothesized to be a fundamental step in the atherosclerotic disease process. In this conceptual model, the iterative exposure of endothelium to risk factors leads sequentially to endothelial dysfunction, followed by intimal-medial thickening, overt manifestations of atherosclerosis, development of arterial stenoses, and ultimately to plaque rupture and endovascular thrombosis. This sequence of events has become central to current theories of atherosclerosis. Yet how do we know that this sequence …