William H. Schenke

Prognostic Value of Coronary Vascular Endothelial Dysfunction

Background—Whether patients at increased risk can be identified from a relatively low-risk population by coronary vascular function testing remains unknown. We investigated the relationship between coronary endothelial function and the occurrence of acute unpredictable cardiovascular events (cardiovascular death, myocardial infarction, stroke, and unstable angina) in patients with and without coronary atherosclerosis (CAD). Methods and Results—We measured the change in coronary vascular resistance (&Dgr;CVR) and epicardial diameter with intracoronary acetylcholine (ACh, 15 &mgr;g/min) to test endothelium-dependent function and sodium nitroprusside (20 &mgr;g/min) and adenosine (2.2 mg/min) to test endothelium-independent vascular function in 308 patients undergoing cardiac catheterization (132 with and 176 without CAD). Patients underwent clinical follow-up for a mean of 46±3 months. Acute vascular events occurred in 35 patients. After multivariate analysis that included CAD and conventional risk factors for atherosclerosis, &Dgr;CVR with ACh (P =0.02) and epicardial constriction with ACh (P =0.003), together with increasing age, CAD, and body mass index, were independent predictors of adverse events. Thus, patients in the tertile with the best microvascular responses with ACh and those with epicardial dilation with ACh had improved survival by Kaplan-Meier analyses in the total population, as did those in the subset without CAD. Similar improvement in survival was also observed when all adverse events, including revascularization, were considered. Endothelium-independent responses were not predictive of outcome. Conclusions—Epicardial and microvascular coronary endothelial dysfunction independently predict acute cardiovascular events in patients with and without CAD, providing both functional and prognostic information that complements angiographic and risk factor assessment.

Angina Due to Coronary Microvascular Disease in Hypertensive Patients without Left Ventricular Hypertrophy

When angina occurs in patients with hypertension, it is usually attributed to coronary artery disease or left ventricular hypertrophy. To determine the contribution of coronary microvascular abnormalities to angina in patients with hypertension, we evaluated hypertensive patients without coronary artery disease or left ventricular hypertrophy by measuring the coronary responses to rapid atrial pacing before and after administration of ergonovine. We compared 12 hypertensive patients who had pacing-induced angina with 13 normotensive subjects without such angina. The two groups had similar coronary flow (in the great cardiac vein) at rest; however, pacing increased coronary flow less in hypertensive patients with angina than in normotensive subjects (48 vs. 83 percent; P = 0.05). In the hypertensive patients with angina, pacing after ergonovine increased coronary flow by only 32 percent (as compared with 48 percent before ergonovine; P less than 0.05) and decreased coronary resistance by 15 percent (as compared with 28 percent before ergonovine; P less than 0.05), indicating the presence of ergonovine-induced vasoconstriction. In normotensive subjects, in contrast, cardiac pacing after ergonovine increased coronary flow by 112 percent (P less than 0.001), and its effect on coronary resistance was not different from that of pacing before ergonovine. The hypertensive patients with angina had a significant increase in myocardial oxygen extraction during pacing after ergonovine and less of an increase in myocardial lactate consumption - a response consistent with the presence of myocardial ischemia. Thus, angina in hypertensive patients without epicardial coronary disease may be caused by myocardial ischemia, which appears to be due to an abnormally elevated resistance of the coronary microvasculature.

Acute and Chronic Angiotensin-1 Receptor Antagonism Reverses Endothelial Dysfunction in Atherosclerosis

BACKGROUND The renin-angiotensin system may contribute to atherogenesis through the promotion of endothelial dysfunction. The present study was performed to determine whether angiotensin-1 (AT(1)) receptor inhibition improves endothelial dysfunction. METHODS AND RESULTS In the femoral circulation of 19 patients with atherosclerosis and of 9 control subjects, we studied microvascular responses to reactive hyperemia, angiotensin II, acetylcholine, and sodium nitroprusside before and after the administration of intra-arterial losartan (10 mg). Femoral artery flow velocity was measured with a Doppler flow wire, and the femoral vascular resistance index (FVRI) was calculated as mean arterial pressure divided by flow velocity. Losartan induced a minor (5.9+/-2%, P=0. 02) reduction in FVRI and inhibited angiotensin II-mediated vasoconstriction in both patient groups (P<0.01). After the administration of losartan, acetylcholine-mediated vasodilation was augmented in patients (44+/-5% to 58+/-4% reduction in FVRI with infusion at a rate of 150 microgram/min, P<0.001) but not control subjects. Vasodilation during reactive hyperemia was also greater after AT(1) receptor inhibition (P=0.03) in patients, but the response to sodium nitroprusside remained unchanged. In a separate group of 31 patients with atherosclerosis, we investigated the effect of 8 weeks of oral losartan therapy on brachial artery flow-mediated vasodilation with the use of high-resolution ultrasound. Oral losartan therapy improved flow-mediated brachial artery dilation (1.4+/-0.9% to 3.2+/-0.8%, P=0.03) but had no effect on the nitroglycerin response. Serum nitrogen oxide levels increased from 21.6+/-1.7 to 26.7+/-2.4 micromol/L (P=0.008). CONCLUSIONS The results of the present study indicate that inhibition of the AT(1) receptor in patients with atherosclerosis reverses endothelial dysfunction by improving NO availability and therefore may have long-term therapeutic benefits.

Divergent Nitric Oxide Bioavailability in Men and Women With Sickle Cell Disease

Background—Although reduced endothelial nitric oxide (NO) bioavailability has been demonstrated in arteriosclerotic vascular disease, the integrity of this system in sickle cell disease remains uncertain. Methods and Results—We measured forearm blood flow in 21 patients with sickle cell disease (hemoglobin SS genotype) and 18 black control subjects before and after intra-arterial infusions of acetylcholine, nitroprusside, and the NO synthase inhibitor NG-monomethyl-L-arginine (L-NMMA). Endothelium-dependent vasodilation, measured by the percent increase in flow induced by acetylcholine infusion, was significantly greater than in controls (252±37% for patients versus 134±24% for controls;P <0.0001). However, there was a large sex difference in blood flow responses between female and male patients (340±46% versus 173±41%;P =0.035). Similarly, basal NO bioactivity, as measured by the percent decrease in flow induced by L-NMMA, was depressed in male compared with female patients (−17±5% versus −34±4%;P =0.01), as was the response to nitroprusside (86±21% versus 171±22%;P =0.008). L-NMMA reduced the blood flow response to acetylcholine in women, but not in men. Sex differences in vascular cell adhesion molecule-1 were appreciated, with significant correlations between levels of soluble vascular cell adhesion molecule-1 and blood flow responses to L-NMMA and nitroprusside (r =0.53, P =0.004 and r =−0.66, P <0.001, respectively). Conclusions—NO bioavailability and NO responsiveness are greater in women than in men with sickle cell disease and determines adhesion molecule expression. Endothelium-dependent blood flows are largely non-NO mediated in male patients. These results provide a possible mechanism for reported sex differences in sickle cell disease morbidity and mortality and provide a basis for novel pharmacological interventions.

Abnormal cardiac sensitivity in patients with chest pain and normal coronary arteries

The causes of chest pain in patients found to have angiographically normal coronary arteries during cardiac catheterization remain controversial. Cardiac sensitivity to catheter manipulation, pacing at various stimulus intensities and intracoronary injection of contrast medium was examined in several groups of patients who underwent cardiac catheterization. Right heart (especially right ventricular) catheter manipulation and pacing and intracoronary contrast medium provoked chest pain typical of that previously experienced in 29 (81%) of 36 patients with chest pain and angiographically normal coronary arteries and 15 (46%) of 33 symptomatic patients with hypertrophic cardiomyopathy. In contrast, only 2 (6%) of 33 symptomatic patients with coronary artery disease experienced their typical chest pain with these sensitivity tests (p less than 0.001). None of 10 patients with valvular heart disease but without a chest pain syndrome experienced any sensation with these tests. Cutaneous pain threshold testing demonstrated that patients with chest pain and normal coronary arteries had a higher pain threshold to thermal stimulation compared with patients who had coronary artery disease or hypertrophic cardiomyopathy. No relation existed between cardiac sensitivity and cutaneous sensitivity testing. Thus, patients who have chest pain despite angiographically normal coronary arteries may have abnormal cardiac sensitivity to a variety of stimuli. This increased sensitivity may be of causal importance to their chest pain syndrome or may contribute to their perception of ischemia-induced pain. The same phenomenon was also commonly seen in symptomatic patients with hypertrophic cardiomyopathy. Whether this phenomenon represents abnormal activation of pain receptors within the heart or abnormal processing of visceral afferent neural impulses in the peripheral or central nervous system is unknown.

Limited coronary flow reserve after dipyridamole in patients with ergonovine-induced coronary vasoconstriction.

Patients with anginal chest pain despite angiographically normal coronary arteries and left ventricles may have abnormalities of coronary flow reserve. Twenty-five patients were found to have limited flow reserve during rapid atrial pacing after administration of 0.15 to 0.30 mg iv ergonovine, associated with precipitation of chest pain and hemodynamic and metabolic evidence of myocardial ischemia. No significant narrowing occurred in epicardial coronary artery luminal diameter. An additional 15 patients had no chest pain during pacing; because they developed significantly higher great cardiac vein flow and lower coronary resistance they were considered to have normal vasodilator reserve. After administration of dipyridamole (0.5 to 0.75 mg/kg iv), the lowest absolute levels to which coronary resistance fell (0.79 +/- 0.23 vs 0.47 +/- 0.12 mm Hg X min/ml; p less than .001) and the maximal absolute levels to which great cardiac vein flow rose (134 +/- 34 vs 202 +/- 45 ml/min; p less than .001) were impaired in the 25 patients with ergonovine-induced flow limitation compared with the 15 patients without flow limitation after ergonovine. In addition, 18 of the 25 patients with limited flow reserve after dipyridamole experienced chest pain despite an increase in coronary flow. In these patients, dipyridamole-induced increased flow across small prearteriolar coronary arteries, which were narrowed because of abnormal tonus or sensitivity to vasoconstrictor stimuli, could have resulted in a transmural redistribution of blood flow away from the subendocardium, precipitating subendocardial ischemia. These studies suggest that patients with anginal chest pain despite normal epicardial coronary arteries may have exaggerated coronary responses to vasoconstrictor stimuli, which can result in myocardial ischemia during stress, as well as attenuated responses to coronary vasodilator stimuli.

Myocardial metabolic, hemodynamic, and electrocardiographic significance of reversible thallium-201 abnormalities in hypertrophic cardiomyopathy.

BackgroundExercise-induced abnormalities during thallium-201 scintigraphy that normalize at rest frequently occur in patients with hypertrophic cardiomyopathy. However, it is not known whether these abnormalities are indicative of myocardial ischemia. Methods and ResultsFifty patients with hypertrophic cardiomyopathy underwent exercise 20UT1 scintigraphy and, during the same week, measurement of myocardial lactate metabolism and hemodynamics during pacing stress. Thirty-seven patients (74%) had one or more 201TI abnormalities that completely normalized after 3 hours of rest; 26 had regional myocardial 201T1 defects, and 26 had apparent left ventricular cavity dilatation with exercise, with 15 having coexistence of these abnormal findings. Of the 37 patients with reversible 201T1 abnormalities, 27 (73%) had metabolic evidence of myocardial ischemia during rapid atrial pacing (myocardial lactate extraction of 0 mmol/l or less) compared with four of 13 patients (31%) with normal 201T1 scans (p < 0.01). Eleven patients had apparent cavity dilatation as their only 201T1 abnormality; their mean postpacing left ventricular end-diastolic pressure was significantly higher than that of the 13 patients with normal 2OtTl studies (33±5 versus 21±10 mm Hg, p < 0.001). There was no correlation between the angiographic presence of systolic septal or epicardial coronary arterial compression and the presence or distribution of 201TI abnormalities. Patients with ischemic ST segment responses to exercise had an 80% prevalence rate of reversible 20MT1 abnormalities and a 70% prevalence rate of pacing-induced ischemia. However, 69% of patients with nonischemic ST segment responses had reversible 20MT1 abnormalities, and 55% had pacing-inducedischemia. ConclusionsReversible 2OtTl abnormalities during exercise stress are markers of myocardial ischemia in hypertrophic cardiomyopathy and most likely identify relatively underperfused myocardium. In contrast, ST segment changes with exercise and systolic compression of coronary arteries on angiography are unreliable markers of inducible myocardial ischemia in hypertrophic cardiomyopathy. Apparent cavity dilatation during 20tTI scintigraphy may indicate ischemia-related changes in left ventricular filling, with elevation in diastolic pressures and endocardial compression.

Oral l-Arginine in Patients With Coronary Artery Disease on Medical Management

BACKGROUND Vascular nitric oxide (NO) bioavailability is reduced in patients with coronary artery disease (CAD). We investigated whether oral L-arginine, the substrate for NO synthesis, improves homeostatic functions of the vascular endothelium in patients maintained on appropriate medical therapy and thus might be useful as adjunctive therapy. METHODS AND RESULTS Thirty CAD patients (29 men; age, 67+/-8 years) on appropriate medical management were randomly assigned to L-arginine (9 g) or placebo daily for 1 month, with crossover to the alternate therapy after 1 month off therapy, in a double-blind study. Nitrogen oxides in serum (as an index of endothelial NO release), flow-mediated brachial artery dilation (as an index of vascular NO bioactivity), and serum cell adhesion molecules (as an index of NO-regulated markers of inflammation) were measured at the end of each treatment period. L-Arginine significantly increased arginine levels in plasma (130+/-53 versus 70+/-17 micromol/L, P<0.001) compared with placebo. However, there was no effect of L-arginine on nitrogen oxides (19.3+/-7.9 versus 18. 6+/-6.7 micromol/L, P=0.546), on flow-mediated dilation of the brachial artery (11.9+/-6.3% versus 11.4+/-7.9%, P=0.742), or on the cell adhesion molecules E-selectin (47.8+/-15.2 versus 47.2+/-14.4 ng/mL, P=0.601), intercellular adhesion molecule-1 (250+/-57 versus 249+/-57 ng/mL, P=0.862), and vascular cell adhesion molecule-1 (567+/-124 versus 574+/-135 ng/mL, P=0.473). CONCLUSIONS Oral L-arginine therapy does not improve NO bioavailability in CAD patients on appropriate medical management and thus may not benefit this group of patients.

Contribution of Nitric Oxide to Reactive Hyperemia Impact of Endothelial Dysfunction

Our objectives were to (1) test the hypothesis that nitric oxide (NO) contributes to peak reactive hyperemia (RH) in the human peripheral vasculature, (2) examine the impact of atherosclerosis and its risk factors on RH, and (3) investigate whether L-arginine will improve RH in patients with endothelial dysfunction. The endothelium contributes to shear stress-mediated vasomotion by releasing a variety of dilating factors, including NO, but the contribution of NO to peak RH in patients with and without endothelial dysfunction is unknown. Endothelium-dependent and endothelium-independent function was assessed with intrafemoral arterial acetylcholine (ACh) and sodium nitroprusside. RH was produced by occlusion of blood flow to the leg for 3 minutes. The study was repeated after NG-monomethyl-L-arginine (L-NMMA) in 44 subjects and L-arginine in 9 patients with atherosclerosis. There were 15 normal control subjects without risk factors for atherosclerosis and 29 patients with risk factors or angiographic atherosclerosis. Microvascular vasodilation in response to ACh, but not to sodium nitroprusside, was lower in the patients with risk factors or atherosclerosis compared with normal control subjects, P=0.048, and the inhibition of ACh-induced microvascular dilation by L-NMMA was also greater in normal control subjects (P=0.045). Similarly, RH, including the peak response, was inhibited by L-NMMA in normal control subjects (P=0.0011) but not in patients with risk factors or atherosclerosis, suggesting that the contribution of NO to both ACh-induced dilation and RH was diminished in patients with risk factors or atherosclerosis. L-Arginine did not affect vasodilation in response to ACh, sodium nitroprusside, or RH. We concluded that (1) NO contributes to all phases of RH in the normal human peripheral vasculature, (2) patients with atherosclerosis or its risks have abnormal NO bioactivity in response to pharmacological and physiological stimulation, and (3) L-arginine does not improve RH in atherosclerosis. Reduced physiological vasodilation in atherosclerosis may contribute to or exacerbate hypertension and ischemia.

Differences in coronary flow and myocardial metabolism at rest and during pacing between patients with obstructive and patients with nonobstructive hypertrophic cardiomyopathy

Fifty patients with hypertrophic cardiomyopathy underwent invasive study of coronary and myocardial hemodynamics in the basal state and during the stress of pacing. The 23 patients with basal obstruction (average left ventricular outflow gradient, 77 +/- 33 mm Hg; left ventricular systolic pressure, 196 +/- 33 mm Hg, mean +/- 1 SD) had significantly lower coronary resistance (0.85 +/- 0.18 versus 1.32 +/- 0.44 mm Hg X min/ml, p less than 0.001) and higher basal coronary flow (106 +/- 20 versus 80 +/- 25 ml/min, p less than 0.001) in the anterior left ventricle, associated with higher regional myocardial oxygen consumption (12.4 +/- 3.6 versus 8.9 +/- 3.3 ml oxygen/min, p less than 0.001) compared with the 27 patients without obstruction (mean left ventricular systolic pressure 134 +/- 18 mm Hg, p less than 0.001). Myocardial oxygen consumption and coronary blood flow were also significantly higher at paced heart rates of 100 and 130 beats/min (the anginal threshold for 41 of the 50 patients) in patients with obstruction compared with those without. In patients with obstruction, transmural coronary flow reserve was exhausted at a heart rate of 130 beats/min; higher heart rates resulted in more severe metabolic evidence of ischemia with all patients experiencing chest pain, associated with an actual increase in coronary resistance. Patients without obstruction also demonstrated evidence of ischemia at heart rates of 130 and 150 beats/min, with 25 of 27 patients experiencing chest pain. In this group, myocardial ischemia occurred at significantly lower coronary flow, higher coronary resistance and lower myocardial oxygen consumption, suggesting more severely impaired flow delivery in this group compared with those with obstruction. Abnormalities in myocardial oxygen extraction and marked elevation in filling pressures during stress were noted in both groups. Thus, obstruction to left ventricular outflow is associated with high left ventricular systolic pressure and oxygen consumption and therefore has important pathogenetic importance to the precipitation of ischemia in patients with hypertrophic cardiomyopathy. Patients without obstruction may have greater impairment in coronary flow delivery during stress.