Endothelium-mediated coronary blood flow modulation in humans. Effects of age, atherosclerosis, hypercholesterolemia, and hypertension.

Abstract

The effects ofage, atherosclerosis, hypertension, and hypercholesterolemia on vascular function of the coronary circulation were studied by subselective intracoronary infusions of acetylcholine, which releases endothelium-derived relaxing factor, and papaverine, which directly relaxes vascular smooth muscle, in normal patients (n = 18; no risk factors for coronary artery disease), in patients with evidence of early atherosclerosis but normal cholesterol levels and normal blood pressure (n = 12), in patients with hypertension without left ventricular hypertrophy (n = 12), and in patients with hypercholesterolemia (n = 20). Papaverine-induced maximal increases in coronary blood flow were significantly greater in normals, but no differences were noted between the groups of patients with early atherosclerosis, with hypertension, and with hypercholesterolemia. The capacity of the coronary system to increase blood flow in response to acetylcholine was similar in normal and normocholesterolemic patients with epicardial atherosclerosis and/or hypertension but was significantly impaired in patients with hypercholesterolemia, irrespective of evidence of epicardial atherosclerotic lesions. Age (r = -0.62, P < 0.0001) and total serum cholesterol levels (r = -0.70; P < 0.0001 ) were the only significant independent predictors of a blunted coronary blood flow response to acetylcholine. Thus, hypercholesterolemia and advanced age selectively impair endothelium-mediated relaxation of the coronary microvasculature in response to acetylcholine, whereas endothelial dysfunction is restricted to epicardial arteries in age-matched normocholesterolemic patients with evidence of coronary atherosclerosis and/or hypertension. (J. Clin. Invest. 1993. 92:652-662.) Key words: endo-

Age-Dependent Impairment of Reendothelialization After Arterial Injury

“…To date, aging is the only clinical phenotype found to be associated with impaired reendothelialization. Although other cardiovascular risk factors, including hypercholesterolemia and smoking, have been associated with endothelial dysfunction, 6,10 previous studies have shown no detrimental effect of these phenotypes on endothelial regeneration after arterial injury. 11,12 The precise mechanisms involved in the regulation of reendothelialization are poorly understood.…”

“…In fact, an inverse relationship has classically been observed between endothelial integrity and neointimal formation after arterial injury. 4 Although age-dependent endothelial dysfunction has been well documented in different vascular beds, 5,6 the effect of aging on arterial healing and reendothelialization after injury is currently unknown. In the present study, we tested the hypothesis that aging impairs reendothelialization.…”

Endothelial dysfunction and hypertension in aging

“…Attenuation of endothelium-dependent vasodilation has been observed in elderly subjects and animal models. 48,49 Several possible mechanisms by which advancing age impairs endothelial function are postulated (Figure 2). An imbalance between NO and ROS, so-called 'oxidative stress,' should be a key regulator of age-induced endothelial dysfunction.…”

In Vivo Gene Transfer of Nitric Oxide Synthase Enhances Vasomotor Function in Carotid Arteries From Normal and Cholesterol-Fed Rabbits

“…Reduced NO bioavailability occurs early in the atherosclerotic process in animal models; for example, hypercholesterolemia impairs endothelium-dependent relaxation in rabbits, 24 pigs, 25 and primates. 26 Similarly, a number of studies in humans document decreased vasomotor responsiveness in preatherosclerotic conditions such as hypercholesterolemia, 27 hypertension, 28 and cigarette smoking. 29 The mechanism for the NO deficit has not been firmly established in any model of atherogenesis.…”