Commentary Vascular Endothelium, Hemodynamic Forces, and Atherogenesis

Intimal lipid accumulation, hyperplasia, and scarring are stigmata of atherosclerotic vascular disease, whose major complications—myocardial and cerebral ischemia and infarction—continue to be major health problems in developed nations. This insidiously progressive disease typically spans decades, but can reach a clinical horizon in a matter of minutes due to critical changes in a given atherosclerotic plaque that result in localized but lifethreatening thrombosis. Epidemiological studies have established that hypercholesterolemia is an important risk factor in this disease process, and lipid-lowering drugs have been proven to have clinical efficacy. Experimental animals that are fed lipid-rich diets to elevate their plasma cholesterol levels also can develop atherosclerotic-like lesions, as do animals with naturally occurring or genetically engineered mutations that result in altered cholesterol metabolism. However, regardless of a given patient’s risk factor profile, species of animal model, or type of natural or engineered genetic alteration, the early, lipid-rich lesions of atherosclerosis show a markedly nonrandom pattern of distribution within the arterial vasculature. Atherosclerotic lesions typically develop in the vicinity of branch points and areas of major curvature. These arterial geometries are associated with blood flow disturbances such as nonuniform laminar flow with boundary layer separation, complex secondary flows with flow reversal and dynamic stagnation points, and resultant temporal and spatial gradients in wall shear stresses. In contrast to these atherosclerosis-prone areas, unbranched, tubular arterial geometries, which are associated with a more uniformly laminar flow profile, characteristically are relatively atherosclerosis-resistant, at least in the early phases of the disease. This strikingly localized pattern of lesion formation, even in the face of systemic risk factors such as elevated plasma cholesterol, has intrigued experimental pathologists and fluid mechanical engineers alike for decades, and has motivated the search for a mechanistic link between hemodynamic forces and atherogenesis. In this issue of The American Journal of Pathology, Zand and coworkers describe a novel experimental model system for creating flow disturbances in the aorta of the rat that have significant effects on the pattern of intimal lipid deposition induced by chronic dietary hypercholesterolemia. Surgical insertion of a hemispherical glass plug into the aortic lumen, through the ostium of a severed renal artery, created a significant stenosis (greater than 50% cross-sectional area reduction) without causing any compression of the adjacent aortic wall, as typically occurs in other models involving an externally applied ligature or metal clip. This model thus accomplishes two useful things: it reliably creates an altered vascular geometry designed to induce well characterized intraluminal flow perturbations while it minimizes the confounding issue of concomitant (and often less well characterized) changes in intramural stresses and strains. Detailed quantitative studies of the flow field perturbations created by the hemispherical plug were performed in parallel, using a scaled-up in vitro biophysical model. Histopathological analysis of the experimental aortas showed a clear-cut association of intimal lipid deposition with certain types of flow perturbation. Crescentic areas of intimal lipid accumulation and subendothelial thickening were localized both proximal and especially distal to the plug, in the regions of predicted low wall shear stress, flow separation, stagnation, and recirculation. In contrast, there were essentially no lipid deposits visible in the intimal area opposite the plug, ie, in a region of increased wall shear stress. These observations, in particular the asymmetric expansion of intimal changes in the direction of flow, also may have implications for the growth of