Andrew P. Selwyn

Paradoxical Vasoconstriction Induced by Acetylcholine in Atherosclerotic Coronary Arteries

Acetylcholine is believed to dilate normal blood vessels by promoting the release of a vasorelaxant substance from the endothelium (endothelium-derived relaxing factor). By contrast, if the endothelium is removed experimentally, acetylcholine constricts blood vessels. We tested the hypothesis that muscarinic cholinergic vasodilation is impaired in coronary atherosclerosis. Graded concentrations of acetylcholine and, for comparison, the nonendothelial-dependent vasodilator nitroglycerin were infused into the left anterior descending artery of eight patients with advanced coronary stenoses (greater than 50 percent narrowing), four subjects with angiographically normal coronary arteries, and six patients with mild coronary atherosclerosis (less than 20 percent narrowing). Vascular responses were evaluated by quantitative angiography. In several segments each of four normal coronary arteries, acetylcholine caused a dose-dependent dilation from a control diameter of 1.94 +/- 0.16 mm to 2.16 +/- 0.15 mm with the maximal acetylcholine dose (P less than 0.01). In contrast, all eight of the arteries with advanced stenoses showed dose-dependent constriction, from 1.05 +/- 0.05 to 0.32 +/- 0.16 mm at the highest concentration of acetylcholine (P less than 0.01), with temporary occlusion in five. Five of six vessels with minimal disease also constricted in response to acetylcholine. All vessels dilated in response to nitroglycerin, however. We conclude that paradoxical vasoconstriction induced by acetylcholine occurs early as well as late in the course of coronary atherosclerosis. Our preliminary findings suggest that the abnormal vascular response to acetylcholine may represent a defect in endothelial vasodilator function, and may be important in the pathogenesis of coronary vasospasm.

Close Relation of Endothelial Function in the Human Coronary and Peripheral Circulations

OBJECTIVES The relation between endothelium-dependent vasodilator function in the brachial and coronary arteries was determined in the same subjects. BACKGROUND Coronary artery endothelial dysfunction precedes the development of overt atherosclerosis and is important in its pathogenesis. A noninvasive assessment of endothelial function in a peripheral conduit vessel, the brachial artery, was recently described, but the relation between brachial artery function and coronary artery vasodilator function has not been explored. METHODS In 50 patients referred to the catheterization laboratory for the evaluation of coronary artery disease (mean age +/- SD 56 +/- 10 years), the coronary vasomotor response to serial intracoronary infusions of the endothelium-dependent agonist acetylcholine (10(-8) to 10(-6) mol/liter), was studied. Endothelium-dependent vasodilation was also assessed in the brachial artery by measuring the change in brachial artery diameter in response to reactive hyperemia. RESULTS Patients with coronary artery endothelial dysfunction manifested as vasoconstriction in response to acetylcholine had significantly impaired flow-mediated vasodilation in the brachial artery compared with that of patients with normal coronary endothelial function (4.8 +/- 5.5% vs. 10.8 +/- 7.6%, p < 0.01). Patients with coronary artery disease also had an attenuated brachial artery vasodilator response compared with that of patients with angiographically smooth coronary arteries (4.5 +/- 4.6% vs. 9.7 +/- 8.1%, p < 0.02). By multivariate analysis, the strongest predictors of reduced brachial dilator responses to flow were baseline brachial artery diameter (p < 0.001), coronary endothelial dysfunction (p = 0.003), the presence of coronary artery disease (p = 0.007) and cigarette smoking (p = 0.016). The brachial artery vasodilator response to sublingual nitroglycerin was independent of coronary endothelial responses or the presence of coronary artery disease. The positive predictive value of abnormal brachial dilation ( < 3%) in predicting coronary endothelial dysfunction is 95%. CONCLUSIONS This study demonstrated a close relation between coronary artery endothelium-dependent vasomotor responses to acetylcholine and flow-mediated vasodilation in the brachial artery. This noninvasive method may become a useful surrogate in assessing the predisposition to atherosclerosis in patients with cardiac risk factors.

Coronary vasomotor response to acetylcholine relates to risk factors for coronary artery disease.

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.

The Effect of Cholesterol-Lowering and Antioxidant Therapy on Endothelium-Dependent Coronary Vasomotion

BACKGROUND Patients with coronary artery disease and abnormalities of serum lipids often have endothelial vasodilator dysfunction, which may contribute to ischemic cardiac events. Whether cholesterol-lowering or antioxidant therapy can restore endothelium-dependent coronary vasodilation is unknown. METHODS We randomly assigned 49 patients (mean serum cholesterol level, 209 +/- 33 mg per deciliter [5.40 +/- 0.85 mmol per liter]) to receive one of three treatments: an American Heart Association Step 1 diet (the diet group, 11 patients); lovastatin and cholestyramine (the low-density lipoprotein [LDL]-lowering group, 21 patients); or lovastatin and probucol (the LDL-lowering-antioxidant group, 17 patients). Endothelium-dependent coronary-artery vasomotion in response to an intracoronary infusion of acetylcholine (10(-8) to 10(-6) M) was assessed at base line and after one year of therapy. Vasoconstrictor responses to these doses of acetylcholine are considered to be abnormal. RESULTS Treatment resulted in significant reductions in LDL cholesterol levels of 41 +/- 22 percent in the LDL-lowering-antioxidant group and 38 +/- 20 percent in the LDL-lowering group (P < 0.001 vs. the diet group). The maximal changes in coronary-artery diameter with acetylcholine at base line and at follow-up were -19 and -2 percent, respectively, in the LDL-lowering-antioxidant group, -15 and -6 percent in the LDL-lowering group, and -14 and -19 percent in the diet group (P < 0.01 for the LDL-lowering-antioxidant group vs. the diet group; P = 0.08 for the LDL-lowering group vs. the diet group). (The negative numbers indicate vasoconstriction). Thus, the greatest improvement in the vasoconstrictor response was seen in the LDL-lowering-antioxidant group. CONCLUSIONS The improvement in endothelium-dependent vasomotion with cholesterol-lowering and antioxidant therapy may have important implications for the activity of myocardial ischemia and may explain in part the reduced incidence of adverse coronary events that is known to result from cholesterol-lowering therapy.

Estrogen Improves Endothelium-Dependent, Flow-Mediated Vasodilation in Postmenopausal Women

Coronary artery disease is the leading cause of death among women in the United States, accounting for 23% of all deaths [1, 2]. The incidence of coronary artery disease in women aged 35 to 44 years is 1 per 1000, increasing to 4 per 1000 in women aged 45 to 54 years [3, 4]. Among women in their fifth decade, the incidence of coronary artery disease is one half that of men. By the sixth decade, however, women and men have the same incidence of coronary disease [2, 5, 6]. This disparity between premenopausal women and men of similar age suggests that endogenous sex hormones such as estrogen may have a significant cardioprotective influence. In postmenopausal women, estrogen replacement therapy independently decreases the risk for cardiovascular events and mortality [6, 7]. Estrogen therapy limited the uptake of cholesterol ester into the arterial wall and attenuated the development of dietary-induced atherosclerosis in monkeys and baboons that had ovariectomy [8-10]. Angiographic studies have consistently found less coronary artery disease in women who receive estrogen replacement therapy [7, 11, 12]. Beneficial effects of estrogen replacement therapy include its ability to reduce low-density lipoprotein (LDL) cholesterol levels and increase high-density lipoprotein (HDL) cholesterol levels [13]. Nonetheless, multiple regression analyses suggest that only 25% to 50% of the reduction in cardiovascular events is attributable to the lipid-lowering effects of estrogen replacement therapy [14], suggesting that other mechanisms contribute to its cardioprotective potential. One such mechanism may involve the effect of estrogen on vascular function. Specifically, estrogen may directly enhance the activity of the endothelium-derived relaxing factor nitric oxide [10, 15-17] and thereby lessen the potential for coronary vasoconstriction and thrombosis [18-21]. When administered to rabbits that had ovariectomy, long-term estrogen replacement improved endothelium-dependent relaxation in vitro [15, 16]. In addition, both short-term and long-term estrogen administration improves in vivo the endothelium-dependent vasodilation in coronary arteries of atherosclerotic cynomolgus monkeys that had ovariectomy [10, 17]. Several recent studies have suggested that short-term estrogen administration improves endothelium-dependent vasodilation of the coronary arteries of postmenopausal women [22, 23]. We hypothesized that long-term estrogen administration would improve vasomotor function in postmenopausal women. Accordingly, we conducted a double-blind, randomized, crossover, placebo-controlled trial to assess the effect of estrogen replacement therapy on endothelium-dependent vasodilation in postmenopausal women. We used high-resolution ultrasonography to serially assess vasomotor function in a peripheral conduit vessel, the brachial artery. Methods Patients The patients enrolled in this study were recruited from a larger cohort that was participating in a clinical research trial investigating the effect of estrogen replacement therapy on lipoprotein metabolism. Thirteen postmenopausal women aged 44 to 69 years (average age, 55 7 years) participated in this study. Women were eligible if menopause had occurred at least 1 year previously. Menopause was confirmed by measuring serum follicle-stimulating hormone levels. No patient had received hormone replacement therapy for at least 2 months before the study began. A history and physical examination were done to exclude persons with clinical evidence of coronary or peripheral atherosclerosis. Initial evaluation included a Papanicolaou smear (if not done in past year), complete blood count, routine chemistry panel, and lipid profile. Inclusion criteria included mild hypercholesterolemia, defined as a serum cholesterol level of 5.17 mmol/L to 6.20 mmol/L and an LDL cholesterol level of 3.36 mmol/L to 4.13 mmol/L. Exclusion criteria included hypertension, diabetes mellitus, tobacco use, obesity (body weight > 135% of ideal weight), history of breast or uterine cancer, thromboembolism, and liver or renal disease. Eligible patients were placed on a low-cholesterol diet (American Heart Association phase I) for 6 weeks before randomization. Patients were randomly assigned to one of three treatment groups: placebo, oral 17 -estradiol (Estrace, Mead Johnson, Evansville, Indiana.) at a dose of 1 mg/d, or oral 17 -estradiol at a dose of 2 mg/d. At the conclusion of each 9-week treatment period, the patients were given progesterone (Provera, Upjohn, Kalamazoo, Michigan) at 10 mg/d for 10 days. Hormone replacement therapy was discontinued for 3 weeks before patients crossed over to the next treatment regimen. All patients received placebo and the two doses of estrogen in random order. Vascular function studies (described below) were done during the eighth or ninth week of each treatment period. Experimental Protocol Studies were done in a temperature-controlled vascular research laboratory. All patients were placed in the supine position. We studied vascular reactivity in a conduit vessel, the brachial artery, as previously described. An imaging study of the brachial artery was done using a high-resolution ultrasound machine (Toshiba, Model SSA-270, Otawara-shir, Tochigi-Ken, Japan) that was equipped with a 7.5 MHz linear-array transducer. Baseline images of the brachial artery were obtained proximal to the antecubital fossa. Imaging of the artery was done longitudinally, allowing clear visualization of the posterior wall intima-lumen interface and the anterior wall media-adventitial interface. We assessed endothelium-dependent vasodilation by measuring the change in the caliber of the brachial artery during reactive hyperemia, a maneuver that increases flow through the conduit segment being studied (flow-mediated vasodilation). To create this stimulus, a cuff placed on the upper arm was inflated to suprasystolic pressure for 5 minutes, thereby occluding flow to the forearm. This results in dilatation of downstream forearm resistance vessels. After cuff deflation, reactive hyperemia occurs, as brachial artery blood flow increases to accommodate the dilated resistance vessels. Imaging of the brachial artery was continually done for the 5-minute period after cuff deflation until basal conditions were re-established. Thereafter, sublingual nitroglycerin (at a dose of 0.4 mg) was administered to assess endothelium-independent vasodilation. The artery was studied for an additional 5 minutes. Blood pressure and heart rate were monitored continuously throughout the procedure. All images were recorded on Super VHS videotape for subsequent analysis. Image analysis was done on a personal computer that was equipped with a video frame grabber. Images recorded on videotape were analyzed by an investigator blinded to treatment assignment. Previous studies have shown that the peak diameter change during reactive hyperemia occurs approximately 1 minute after cuff deflation and 3 minutes after nitroglycerin administration [41]. We used these time points in our study. Images corresponding to the end of the T wave on a simultaneous electrocardiograph were selected and digitized. Image analysis was then done using a proprietary analysis software that searched for the shortest distance between the points on the arterial wall, creating 10 to 20 paired measurements along a 10-mm length. We measured arterial diameter from the intima-lumen interface on the posterior wall to the media-adventitial interface on the anterior wall. We calculated brachial artery diameter by averaging these paired lumen measurements and reported them in millimeters using calibration factors derived from real-time ultrasonography. We used an average of three separate measurements for each condition. In our laboratory, this technique has a variability of only 0.0 0.1 mm [24]. To assure that the blood flow stimulus during reactive hyperemia was similar during each treatment phase, forearm blood flow was measured by venous occlusion strain gauge plethysmography using calibrated mercury-in-silastic strain gauges as previously described [25]. Statistical Analysis The variables compared during the placebo period and during therapy with each dose of estrogen included blood pressure, heart rate, forearm blood flow, basal brachial artery diameter, and the percentage increase in diameter during reactive hyperemia and after patients received sublingual nitroglycerin. Values are expressed as the mean SE. For statistical analysis, we used repeated-measure analysis of variance and the Scheffe-F post hoc test [26]. Significance was accepted at P 0.05. Results Baseline Hemodynamic Measurements The effect of estrogen treatment on blood pressure, heart rate, forearm blood flow and forearm vascular resistance is presented in Table 1. Estrogen therapy did not affect blood pressure or heart rate. Basal forearm blood flow tended to be higher during both estrogen treatment phases (P = 0.08). Basal forearm vascular resistance was similar during all three treatment phases. The peak forearm blood flow during reactive hyperemia was similar during placebo receipt and each estrogen treatment period. However, peak forearm blood flow was greater when patients received the 1-mg dose of estradiol than when they received the 2-mg dose (P = 0.05). Table 1. Effect of Estrogen Replacement on Hemodynamic Measurements Flow-Mediated Endothelium-Dependent Vasodilation We obtained technically adequate ultrasound images during reactive hyperemia for 12 of the 13 patients. The brachial artery diameter, under basal conditions, measured 3.5 mm, 3.4 mm, and 3.3 mm while patients received placebo, estradiol at 1 mg/d, and estradiol at 2 mg/d, respectively (P > 0.2). The percentage increase in brachial artery diameter during reactive hyperemia for each treatment period is shown in Figure 1. The change in brachial artery diameter was greater when patients received estradiol treatment (13.5% and 11.6

Myocardial ischaemia during daily life in patients with stable angina: its relation to symptoms and heart rate changes

In thirty patients with stable angina and positive exercise tests, ambulatory ST segment monitoring was used to record episodes of transient myocardial ischaemia during daily life. All patients had four consecutive days of monitoring and in 20 patients long-term variability was assessed by repeated 48 hour monitoring and exercise testing over 18 months. There were 1934 episodes of rectilinear or downsloping ST-depression (911, 1 mm; 638, 2 mm; 385, greater than 3 mm) in 446 days of recording, of which only 470 (24%) were accompanied by angina. Positron tomography showed evidence of regional myocardial ischaemia during both symptomatic and asymptomatic ST depression. On average, heart rate at the onset of both symptomatic and asymptomatic ST episodes was significantly lower than the rate at the onset of ST depression during exercise testing (98 +/- 20.5 vs 124 +/- 17 beats/minute). Heart rate rose by more than 10 beats in the minute preceding ST depression in only 23% of episodes. Over 18 months, 8 (40%) patients exhibited marked variability in the number of daily ST episodes. Variability of ST depression was consistently underestimated by symptoms and not reflected by exercise testing. Thus, patients with stable angina showed frequent, variable, and often asymptomatic electrocardiographic evidence of ischaemia. Heart rate increase was not common before myocardial ischaemia, suggesting that, in such patients, transient impairment in coronary supply may be at least as important as excessive increase in demand in the genesis of ischaemia during daily life.

The effect of atherosclerosis on the vasomotor response of coronary arteries to mental stress.

BACKGROUND Mental stress can cause angina in patients with coronary artery disease, but its effects on coronary vasomotion and blood flow are poorly understood. Because atherosclerosis affects the reactivity of coronary arteries to various stimuli, such as exercise, we postulated that atherosclerosis might also influence the vasomotor response of coronary arteries to mental stress. METHODS We studied 26 patients who performed mental arithmetic under stressful conditions during cardiac catheterization. (An additional four patients who did not perform the mental arithmetic served as controls.) Coronary segments were classified on the basis of angiographic findings as smooth, irregular, or stenosed. In 15 of the patients without focal stenoses in the left anterior descending artery, acetylcholine (10(-8) to 10(-6) mol per liter) was infused into the artery to test endothelium-dependent vasodilation. Changes in coronary blood flow were measured with an intracoronary Doppler catheter in these 15 patients. RESULTS The response of the coronary arteries to mental stress varied from 38 percent constriction to 29 percent dilation, whereas the change in coronary blood flow varied from a decrease of 48 percent to an increase of 42 percent. The direction and magnitude of the change in the coronary diameter were not predicted by the changes in the heart rate, blood pressure, or plasma norepinephrine level. Segments with stenoses (n = 7) were constricted by a mean (+/- SE) of 24 +/- 4 percent, and irregular segments (n = 20) by 9 +/- 3 percent, whereas smooth segments (n = 25) did not change significantly (dilation, 3 +/- 3 percent; P less than 0.0002). Coronary blood flow increased by 10 +/- 10 percent in smooth vessels, whereas the flow in irregular vessels decreased by 27 +/- 5 percent. The degree of constriction or dilation during mental stress correlated with the response to the infusions of acetylcholine (P less than 0.0003, r = 0.58). CONCLUSIONS Atherosclerosis disturbs the normal vasomotor response (no change or dilation) of large coronary arteries to mental stress; in patients with atherosclerosis paradoxical constriction occurs during mental stress, particularly at points of stenosis. This vasomotor response correlates with the extent of atherosclerosis in the artery and with the endothelium-dependent response to an infusion of acetylcholine. These data suggest that in atherosclerosis unopposed constriction caused by a local failure of endothelium-dependent dilation causes the coronary arteries to respond abnormally to mental stress.

Dilation of normal and constriction of atherosclerotic coronary arteries caused by the cold pressor test

Increased vascular constriction has been observed at the site of atherosclerotic lesions, suggesting an association between atherosclerosis and altered vascular tone. While atherosclerosis may increase sensitivity to exogenous vasoconstrictors, little is known about the response of normal and atherosclerotic coronary arteries to an exogenous stimulus that excites the sympathetic nervous system. Therefore, we studied the response to cold pressor test (CPT) using quantitative angiography and Doppler flow velocity measurements in eight patients with angiographically normal coronary arteries (group I), nine patients with mild coronary atherosclerosis (less than 50% diameter narrowing) (group II), and 13 patients with advanced coronary stenoses (greater than 50% diameter narrowing) (group III). In 31 segments of angiographically smooth arteries in group I, the CPT produced vasodilation from a control mean diameter of 2.68 +/- 0.09 (mean +/- SE) to 2.99 +/- 0.09 mm at peak CPT (p less than 0.001), a 12 +/- 1% increase in diameter. In group II, 27 irregular segments constricted to peak CPT from a mean control diameter of 1.82 +/- 0.12 to 1.66 +/- 0.12 mm (p less than .001), a 9 +/- 1% decrease, while 10 smooth segments dilated from a mean control diameter of 1.98 +/- 0.11 mm to 2.34 +/- 0.15 mm (p less than .01), a 19 +/- 2% increase in diameter. Likewise, in group III, the 17 stenotic segments constricted from 1.16 +/- 0.09 to 0.89 +/- 0.09 mm (p less than .001), a 24 +/- 6% decrease; the irregular segments also constricted from 2.44 +/- 0.11 to 2.22 +/- 0.12 mm (p = .002), a 10 +/- 2% decrease. In contrast, two smooth segments dilated from 2.98 to 3.23 mm (mean), an 8% increase in diameter. Coronary blood flow increased 65 +/- 4% (mean) during CPT in group I, it increased 15 +/- 6% in group II, and it decreased 39 +/- 8% in group III. The vasodilator response in four normal patients was partly inhibited by the administration of intracoronary propranolol (17 +/- 3% increase during control, 10 +/- 2% increase after propranolol, 41% less dilation; p = .002). We conclude that the response of normal coronary arteries to the CPT test is dilation, in part related to beta-adrenoreceptor stimulation and possibly flow-mediated endothelial dilation or alpha 2-adrenergic activity. The paradoxical vasoconstrictor response induced by atherosclerosis may represent altered catecholamine sensitivity and/or a defect in endothelial vasodilator function. The presence of atherosclerosis impairs vasodilator responses and thus may contribute to the pathogenesis of myocardial ischemia.

Circadian variation of transient myocardial ischemia in patients with coronary artery disease.

To examine whether a significant circadian variation of transient myocardial ischemia exists and to better understand the character of such variation, 32 patients with chronic stable symptoms of coronary artery disease underwent one or more days of ambulatory monitoring of ischemic ST segment changes during daily life. A total of 251 episodes of ischemic ST segment depression occurred in 24 (75%) of the 32 patients with a median duration of 5 min (range 1 to 253). A significant circadian increase in ischemic activity was found with 39% of episodes and 46% of total ischemic time occurring between 6 A.M. and 12 P.M. (p less than .05 and p = .02, respectively). In 21 patients with ST segment depression during the 6 hr after waking and the 6 hr before sleep, 68% of episodes occurred in the morning compared with 32% in the evening. There were no significant differences in heart rate at onset, heart rate at 1 min before onset, and activity score associated with ST segment depression. The proportion of minutes showing ST segment depression when the heart rate was above the lowest rate associated with ST segment depression was significantly greater in the morning compared with the evening (26% vs 15%; p = .03). Thus the early morning increase in ST segment depression does not appear to be explained by differences in extrinsic activity and/or stress measured by physical activity score and heart rate response. More importantly, this phenomenon is often ignored by the usual patterns of drug administration for angina.(ABSTRACT TRUNCATED AT 250 WORDS)

Endothelium-dependent dilation of the coronary microvasculature is impaired in dilated cardiomyopathy.

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 patients 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)