Charles B. Treasure

In animals, acetylcholine dilates normal arteries and produces vasoconstriction in the presence of hypercholesterolemia, hypertension, or atherosclerosis, reflecting endothelial cell dysfunction. In patients with angiographically smooth coronary arteries, acetylcholine has been reported to produce both vasodilation and constriction. To test the hypothesis that the acetylcholine response relates to risk factors for coronary artery disease, acetylcholine 10(-8) to 10(-6) M was infused into the left anterior descending or circumflex coronary artery, and diameter changes were assessed with quantitative angiography in 34 patients with angiographically smooth coronary arteries. The acetylcholine response ranged from +37% (dilation) to -53% (constriction) at the peak acetylcholine dose. All coronary arteries dilated in response to nitroglycerin (26 +/- 17%), suggesting an abnormality of endothelial function in the patients with a constrictor response to acetylcholine. By multiple stepwise regression analysis, serum cholesterol (p less than 0.01), male gender (p less than 0.001), family history (p less than 0.05), age (p less than 0.05), cholesterol level (p less than 0.01), and total number of risk factors (p less than 0.0001) were independently associated with the acetylcholine response. Thus, coronary risk factors are associated with loss of endothelium-dependent vasodilation. The development of vasoconstriction is likely to be an abnormality of endothelial function that precedes atherosclerosis or an early marker of atherosclerosis not detectable by angiography.

Dilator reserve of the coronary microvasculature is diminished in patients with dilated cardiomyopathy. Although increased extravascular compressive forces, tachycardia, and increased myocardial mass can explain some impairment, recent evidence suggests the possibility of intrinsic microvascular disease. We tested the hypothesis that impairment of endothelium-dependent dilation of the microvasculature could be a contributing mechanism. We infused the endothelium-dependent dilator acetylcholine (Ach) (10(-8) to 10(-6) M) and the smooth muscle vasodilator adenosine (AD) (10(-6) to 10(-4) M) into the left anterior descending coronary artery in eight patients with dilated cardiomyopathy (mean ejection fraction, 28%) and seven controls (atypical chest pain). Small vessel resistance was assessed by measuring coronary blood flow (CBF) at constant arterial pressure with a Doppler velocity catheter (corrected for cross-sectional area by angiography). With Ach, control patients increased CBF 232 +/- 40% (mean +/- SEM), whereas CBF did not significantly change in cardiomyopathy patients (41 +/- 24%) (p less than 0.0001, control vs. cardiomyopathy). With AD, control patients increased CBF 422 +/- 56% and cardiomyopathy patients increased CBF 268 +/- 43% (p = 0.13). An index of the proportion of coronary flow reserve attributable to endothelium-dependent vasodilation was obtained by standardizing each patient's Ach dose response to his maximal AD flow response. In seven control patients receiving both Ach and AD, 56 +/- 9% of the maximal AD flow response was attained with the endothelium-dependent vasodilator Ach, whereas in seven cardiomyopathy patients receiving both Ach and AD, only 23 +/- 14% of the maximal AD response was attained (p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Studies in animals have suggested that increases in blood flow result in dilation of large arteries by an endothelium-dependent mechanism. Atherosclerosis can impair endothelium-dependent vasodilation to vasoactive agents. The purpose of this study was to determine whether or not large coronary arteries in humans exhibit dilation with increases in blood flow and to test the hypothesis that this response is impaired in the presence of atherosclerosis. Graded concentrations of adenosine were infused into the distal left anterior descending (LAD) coronary artery to test the dilator response of the proximal LAD to increases in blood flow. The proximal LAD was thereby exposed to changes in blood flow, but not directly to adenosine. Ten patients with angiographically smooth proximal LAD segments (group 1) and seven patients with irregularities in the proximal LAD consistent with mild atherosclerosis (group 2) were studied. Infusions of adenosine throughout the range of 0.022 to 2.2 mg/min into the LAD produced a dose-dependent increase in estimated coronary blood flow and a mean increase of 305 +/- 27% at 2.2 mg/min adenosine. At 2.2 mg/min adenosine, a striking difference (p less than 0.001) occurred between the significant flow-mediated dilation of the proximal LAD observed in group 1 (+13.2 +/- 1.3% from 2.63 +/- 0.16 mm, p less than 0.001), and the lack of dilation in group 2 (+1.8 +/- 1.5% from 3.20 +/- 0.17 mm, p = NS), despite a greater increase in coronary blood flow in group 2 (+387 +/- 29%) than in group 1 (+230 +/- 36%).(ABSTRACT TRUNCATED AT 250 WORDS)

BACKGROUND: Patients with hypertension and myocardial hypertrophy may have signs and symptoms of myocardial ischemia in the absence of obstructive coronary disease. Prior investigations have demonstrated impaired coronary flow reserve and have led to speculation that microvascular dysfunction might contribute to ischemia in these patients. Experimental studies have shown that the endothelium, an important regulator of microvascular tone, can be damaged by hypertension and is dysfunctional in cardiomyopathy. We hypothesized that endothelium-dependent vasodilation is impaired in the coronary microvasculature of patients with hypertension and ventricular hypertrophy. METHODS AND RESULTS: We studied coronary microvascular responses in 10 patients with left ventricular hypertrophy secondary to essential hypertension (HTN) (mean arterial pressure at catheterization, 151/94 mm Hg; mean posterior wall thickness, 1.4 +/- 0.1 cm) and nine normal control subjects with no history of hypertension (mean arterial pressure at catheterization, 128/75 mm Hg; mean posterior wall thickness, 1.0 +/- 0.02 cm) using the intracoronary Doppler catheter and quantitative angiography to assess changes in coronary blood flow (CBF). All patients had normal left ventricular systolic function. To assess microvascular endothelial function, we infused the endothelium-dependent vasodilator acetylcholine (10(-8)-10(-6) M) and the endothelium-independent vasodilator adenosine (10(-6)-10(-4) M) into the left anterior descending coronary artery. In response to acetylcholine, CBF increased only 32 +/- 25% in HTN patients, whereas CBF increased 192 +/- 39% in normal control subjects (p = 0.003). CBF increased 465 +/- 93% in HTN patients and 439 +/- 41% in normal control subjects in response to adenosine (p = NS). The proportion of coronary flow reserve attributable to endothelium-dependent dilation (obtained from peak acetylcholine/peak adenosine flow response) was 48 +/- 9% in normal control subjects but only 7 +/- 8% in HTN patients (p = 0.008). CONCLUSIONS: Endothelium-dependent vasodilation is markedly impaired in the coronary microvessels of patients with hypertension and ventricular hypertrophy. Loss of this vasodilator mechanism may contribute to disordered coronary flow regulation and the ischemic manifestations of hypertensive heart disease.

BACKGROUND: Studies in patients undergoing cardiac catheterization have demonstrated that normal coronary arteries dilate and atherosclerotic arteries constrict in response to exercise and the cold pressor test, but the mechanisms are unknown. These vasomotor responses are mirrored by the vasomotor response to the endothelium-dependent agent acetylcholine. Exercise and the cold pressor test are associated with adrenergic stimulation and increased circulating catecholamines. The present study tested the hypothesis that coronary arteries with intact endothelial function are relatively resistant to the constrictor effects of catecholamines, whereas arteries with loss of endothelial function have increased sensitivity to catecholamine-induced constriction. METHODS AND RESULTS: The vasomotor function of the coronary endothelium was assessed by serial acetylcholine infusions (final concentration, 10(-8) to 10(-6) M) in 30 segments in 15 patients with minimal or no evidence of coronary atherosclerosis. The acetylcholine responses were related to the vasomotor response to intracoronary phenylephrine infusion (final concentration, 10(-9) to 10(-6) M) in the same segments. In the group of 18 segments that constricted to acetylcholine, there was a constrictor response to phenylephrine at an approximately 100-fold lower concentration than the group of 12 segments that did not constrict to acetylcholine. CONCLUSIONS: These results suggest that the endothelial dysfunction that characterizes early and late atherosclerosis is associated with a marked increase in sensitivity to the constrictor effects of catecholamines. This finding may explain the constrictor responses of atherosclerotic coronary arteries to exercise and the cold pressor test. In stenotic coronary arteries this mechanism may play a role in the production of myocardial ischemia.