Association between polymorphism in the chemokine receptor CX3CR1 and coronary vascular endothelial dysfunction and atherosclerosis.

Fractalkine, a chemokine expressed by inflamed endothelium, induces leukocyte adhesion and migration via the receptor CX3CR1, and the CX3CR1 polymorphism V249I affects receptor expression and function. Here we show that this polymorphism is an independent risk factor for atherosclerotic coronary artery disease (CAD). Genotyping of the CX3CR1-V249I polymorphism was performed in a cohort of 339 white individuals who underwent cardiac catheterization (n=197 with and n=142 without CAD, respectively). In 203 patients, intracoronary acetylcholine 15 microg/min) and sodium nitroprusside (20 microg/min) were administered to test endothelium-dependent and -independent coronary vascular function, respectively. Change in coronary vascular resistance (DeltaCVR) was measured as an index of microvascular dilation. An association was observed between presence of the CX3CR1 I249 allele and reduced prevalence of CAD, independent of established CAD risk factors (odds ratio=0.54 [95% confidence interval, 0.30 to 0.96], P=0.03). Angiographic severity of CAD was also lower in these subjects (P=0.01). Furthermore, endothelium-dependent vasodilation was greater in these individuals compared with individuals homozygous for the CX3CR1-V249 allele (DeltaCVR during acetylcholine = -46+/-3% versus -36+/-3%, respectively, P=0.02), whereas DeltaCVR with sodium nitroprusside was similar in both groups (-55+/-2% versus -53+/-2%, P=0.45). The association between CX3CR1 genotype and endothelial function was independent of established risk factors and presence of CAD by multivariate analysis (P=0.02). Thus, the CX3CR1 I249 allele is associated with decreased risk of CAD and improved endothelium-dependent vasodilation. This suggests that CX3CR1 may be involved in the pathogenesis of CAD.

Role of angiotensin II type 1 receptor in the regulation of cellular adhesion molecules in atherosclerosis.

BACKGROUND: Inflammation is a central feature of coronary artery disease (CAD) that is characterized by increased expression of cellular adhesion molecules with the exception of L-selectin. L-selectin is a leukocyte adhesion molecule that is rapidly shed after leukocyte activation so that it appears to be decreased in CAD. The renin-angiotensin system (RAS) is implicated in atherogenesis and up-regulates these molecules. OBJECTIVES: The aim of this study was to investigate the effect of angiotensin type 1 (AT1) receptor antagonism on serum and leukocyte adhesion molecule expression in patients with CAD. Blood samples were collected from 31 patients before and after 8 weeks of treatment with losartan (44 +/- 2 mg/d, mean +/- SE), an AT1 receptor antagonist. We measured serum intercellular adhesion molecule-1, vascular cell adhesion molecule-1, endothelial-leukocyte adhesion molecule, and C-reactive protein (CRP). By flow cytometry, we also measured the expression of leukocyte CD11a, CD11b, CD11c, CD18, CD31, CD49d, and CD62L (L-selectin) in 13 patients. RESULTS: Treatment with losartan decreased systolic blood pressure (141 +/- 3 vs 135 +/- 4 mm Hg, P =.04) and increased plasma renin activity (1.2 +/- 0.4 vs 2.7 +/- 0.5 ng/mL/h, P =.001). There was a significant increase in L-selectin expression on monocytes (86 +/- 6 vs 118 +/- 10 MESF units, P =.007), lymphocytes (52 +/- 10 vs 79 +/- 8, P =.01), and granulocytes (124 +/- 7 vs 156 +/- 18, P =.056). However, there were no changes in the other leukocyte and serum adhesion molecules or CRP. CONCLUSIONS: These findings suggest that AT1 receptor antagonism selectively modulates L-selectin expression on leukocytes and that endogenous stimulation of AT1 receptors by the RAS contributes to the activation of leukocytes and decreased expression of L-selectin in CAD.

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.

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.

Endocrine and lipid effects of oral L-arginine treatment in healthy postmenopausal women.

As a substrate for nitric oxide synthesis, L-arginine may give the same protection as estrogen, but its other biologic effects may adversely affect atherogenesis. Therefore, possible endocrine and lipid effects of L-arginine were investigated in a double-blind, placebo-controlled, single crossover study. After randomization, oral L-arginine (9 g) or placebo was given daily for 1 month, with crossover to the alternate therapy after a 1-month washout period, to 10 postmenopausal women receiving no estrogen. Compared with placebo, L-arginine increased growth hormone (1.5+/-1.8 mg/L vs. 0.6+/-0.6 mg/L, P = .04) but had no effect on insulin and catecholamines. Total cholesterol, triglyceride, apolipoprotein E, and low-, very-low-, and high-density lipoprotein cholesterol levels were also unaffected. Lipoprotein(a) measured by an immunoturbidimetric method was increased by L-arginine in 9 of 10 women relative to placebo (0.46+/-0.35 g/L vs. 0.38+/-0.30 g/L, P = .053), and the changes in lipoprotein(a) levels significantly correlated with the relative increase in growth hormone (r = 0.85, P = .03). However, lipoprotein(a) measured by an enzyme-linked immunosorbent assay failed to demonstrate significant changes. Lack of an increase by L-arginine in lipoprotein(a) with a verifiable apolipoprotein(a) isoform-independent method, despite an increase in growth hormone, questions the validity of previous observations for growth hormone-induced increases in lipoprotein(a). The observed lack of effect on major endocrine hormones and lipid profile support the safety of oral L-arginine administration.

Effects of oral L-arginine on endothelium-dependent vasodilation and markers of inflammation in healthy postmenopausal women.

OBJECTIVES: We examined whether oral administration of L-arginine, the substrate for nitric oxide (NO) synthesis, increases NO bioactivity in healthy postmenopausal women. BACKGROUND: Nitric oxide may protect arteries against atherosclerosis, as suggested by experimental studies in animals. Estrogen therapy, which has been shown to increase NO bioactivity in the vasculature of healthy postmenopausal women, is not acceptable for long-term use by many women. METHODS: In a randomized, double-blind, crossover study, 10 postmenopausal women without additional risk factors for atherosclerosis received L-arginine 9 g or placebo daily for one month, with treatment periods separated by one month. Nitric oxide levels in serum (as an index of endothelial NO release), brachial artery endothelium-dependent dilator responses to hyperemia by ultrasonography (as an index of vascular NO bioactivity) and markers of inflammation in blood that are inhibited by NO in cell culture experiments were measured at the end of each treatment period. RESULTS: L-arginine levels in plasma were increased in all women during L-arginine treatment compared with placebo (136.8 +/- 63.1 vs. 75.2 +/- 16.2 micromol/liter, p = 0.009). However, there was no change in serum nitrogen oxide levels (42.1 +/- 24.5 vs. 39.1 +/- 16.6 micromol/liter, p = 0.61), nor was there an effect of L-arginine on flow-mediated dilation during hyperemia (3.8 +/- 3.0% vs. 4.9 +/- 4.8%, p = 0.53) compared with placebo. Our study had sufficient power (beta = 0.80) to detect a true absolute treatment difference in flow-mediated brachial artery dilation of 1.7% or larger as statistically significant at alpha = 0.05. There was no effect of L-arginine on serum levels of soluble cell adhesion molecules compared with placebo: E-selectin (50.6 +/- 14.8 vs. 52.1 +/- 17.0 ng/ml, p = 0.45), intercellular adhesion molecule-1 (230 +/- 51 vs. 230 +/- 52 ng/ml, p = 0.97) and vascular cell adhesion molecule-1 (456 +/- 62 vs. 469 +/- 91 ng/ml, p = 0.53). CONCLUSIONS: Oral administration of L-arginine may not augment endothelial NO synthesis and release in postmenopausal women and is thus unlikely to be of general benefit to healthy postmenopausal women in protection from the development of atherosclerosis.

Ischemia during ambulatory monitoring as a prognostic indicator in patients with stable coronary artery disease.

OBJECTIVE: To assess long-term prognostic significance of transient ischemia in patients with documented coronary artery disease and stable symptoms and to examine the relation between transient ischemia and the site of angiographic disease progression following acute cardiac events. DESIGN: Cohort study with a mean+/-SD follow-up of 51.5+/-23.8 months. SETTING: Ambulatory patients with stable coronary artery disease, assigned to medical therapy. PATIENTS: A total 221 patients (173 men; mean age, 60.8 years) were recruited. Of the 221 patients, 101 (45.7%) had single-vessel, 86 (38.9%) had 2-vessel, and 34 (15.4%) had 3-vessel disease. A total of 135 had a positive exercise test for ischemia, and mean+/-SD resting left ventricular ejection fraction (LVEF) was 49.8%+/-11.4%. Using conventional criteria, patients were prospectively stratified as low risk for continued medical therapy (single-vessel disease, 2-vessel disease with negative exercise test, or LVEF> or =40%; n=189 [85.5%]) or high risk for continued medical therapy (multivessel disease with ischemia and/or left ventricular dysfunction; n=32 [14.5%]). INTERVENTIONS: Ambulatory ST-segment monitoring, treadmill exercise testing, radionuclide ventriculography, and coronary angiography. MAIN OUTCOME MEASURES: Demographic, clinical, ambulatory monitoring, treadmill exercise, and left ventricular function variables as independent predictors of acute (cardiac death, myocardial infarction, or unstable angina) or all (including revascularization) cardiac events in the overall and the low-risk population. RESULTS: None of the clinical or noninvasive measures of ischemia were of prognostic significance in the overall or the low-risk group. The only significant independent predictor of outcome in all patients for all events, including revascularization, was the number of diseased vessels (X2=13.5 [df=1]; P<.001). Exclusion of vessel disease resulted in conventional risk stratification as the most significant predictor of outcome from all events in all patients (X2= 10.3 [df= 1]; P=.001). In the low-risk group, the number of diseased vessels was the only predictor for all events (X2=4.6; P=.03). For acute cardiac events, none of the variables tested were of prognostic significance. Based on the frequency of events in the low-risk patients, a 2-fold increase in the rate of cardiac events in patients with transient ischemia compared with those without transient ischemia during ambulatory monitoring could be excluded with greater than 85% power and alpha of .05. Of 30 patients suffering acute nonfatal cardiac events during follow-up, angiography was performed in 27, revealing significant progression of coronary disease in 24 (88.8%) and the development of new significant lesions at sites remote from previously significant lesions in 20 (74%) cases. These new lesions were equally likely to occur in those with or without transient ischemia at initial assessment. CONCLUSIONS: Acute cardiac events in predominantly low-risk stable angina patients with confirmed coronary disease are unpredictable, and those more likely to suffer such an event cannot be identified by the detection of ambulatory ischemia. Acute nonfatal cardiac events result predominantly from the development of significant new coronary lesions, not initially severe enough to cause ischemia. Patients categorized as high risk for long-term medical therapy have an increased rate of cardiac events (mainly revascularization) when compared with low-risk patients.

Patterns and behavior of transient myocardial ischemia in stable coronary disease are the same in both men and women: a comparative study.

OBJECTIVES: This study sought to compare the circadian variations in transient ischemic activity, mean heart rate and ischemic threshold between women and men with coronary artery disease. BACKGROUND: There is a circadian variation in ischemic activity, onset of myocardial infarction and sudden cardiac death in patients with coronary artery disease, but studies assessing ischemia have incorporated predominantly male subjects. METHODS: Thirty-one women and 45 men underwent at least 48 h of ambulatory ST segment monitoring. RESULTS: There was a similar and significant circadian variation in ischemic activity in both women and men (p < 0.0001 and p < 0.0001, respectively), with a trough at night, a surge in the morning and a peak between 1 and 2 PM, corresponding to a similar circadian variation in mean hourly heart rate (p < 0.0001) that was not different between men and women (p = 0.28, power to detect a shift 99.9%). Mean heart rate at onset of ischemia (ischemic threshold) had similar variability in women and men (p = 0.96), and harmonic regression analysis confirmed a significant circadian variation (p < 0.0001), with a trough at night and a peak during activity hours. Heart rate increased significantly in the 5 min before ischemia throughout the 24 h (p < 0.0001), with no gender differences in the pattern of preonset to onset heart rate changes over time (p = 0.52); the smallest differences were recorded in the middle of the night. The majority of ischemic episodes (80%) had a heart rate increase > 5 beats/min in the 5 min before ischemia, but there were no gender differences. CONCLUSIONS: Women with coronary artery disease have a pattern of ischemic activity and underlying pathophysiologic mechanisms very similar to men. The importance of increase in myocardial oxygen demand in the genesis of ischemia in both men and women is reflected by similar magnitude of heart rate increases before ischemia. The lower ischemic threshold during the nocturnal hours, when blood pressure is also lower, is consistent with a circadian variation in underlying coronary vascular tone.

Predictors of exercise benefit after operative relief of left ventricular outflow obstruction by the myotomy-myectomy procedure in hypertrophic cardiomyopathy.

To determine predictors of exercise benefit in patients with hypertrophic cardiomyopathy after operative relief of left ventricular (LV) outflow tract obstruction, 30 patients underwent catheterization and exercise testing before and 6 months after operation, and hemodynamic measurements were obtained. The increase in maximal oxygen consumption (VO2max) during treadmill exercise testing was chosen as an index of exercise benefit. Univariate analysis showed a significant positive correlation of operative change in VO2max with preoperative LV end-diastolic and pulmonary arterial wedge pressures, operative change in exercise duration, and operative reductions in LV end-diastolic and pulmonary arterial wedge pressures and resting LV outflow tract gradient, and a significant negative correlation with preoperative VO2max and percent predicted VO2max. Multivariate analysis by stepwise linear regression of only significant univariate variables selected only preoperative percent predicted VO2max, and operative reduction in LV end-diastolic pressure and resting LV outflow tract gradient as significant predictors of postoperative change in VO2max. Stepwise regression analysis, applied only to preoperative exercise and catheterization hemodynamic variables, selected only preoperative percent predicted VO2max and preoperative LV end-diastolic pressure as predictors of improvement in exercise capacity. Thus, patients with obstructive hypertrophic cardiomyopathy, after failing medical therapy, are most likely to demonstrate improvement in exercise capacity if preoperative exercise testing demonstrates limited exercise capacity and if surgery achieves reduction in elevated resting LV outflow tract gradients and LV filling pressures.

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

BACKGROUND: Exercise-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 RESULTS: Fifty patients with hypertrophic cardiomyopathy underwent exercise 201Tl scintigraphy and, during the same week, measurement of myocardial lactate metabolism and hemodynamics during pacing stress. Thirty-seven patients (74%) had one or more 201Tl abnormalities that completely normalized after 3 hours of rest; 26 had regional myocardial 201Tl 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 201Tl 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 201Tl scans (p less than 0.01). Eleven patients had apparent cavity dilatation as their only 201Tl abnormality; their mean postpacing left ventricular end-diastolic pressure was significantly higher than that of the 13 patients with normal 201Tl studies (33 +/- 5 versus 21 +/- 10 mm Hg, p less than 0.001). There was no correlation between the angiographic presence of systolic septal or epicardial coronary arterial compression and the presence or distribution of 201Tl abnormalities. Patients with ischemic ST segment responses to exercise had an 80% prevalence rate of reversible 201Tl abnormalities and a 70% prevalence rate of pacing-induced ischemia. However, 69% of patients with nonischemic ST segment responses had reversible 201Tl abnormalities, and 55% had pacing-induced ischemia. CONCLUSIONS: Reversible 201Tl 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 201Tl scintigraphy may indicate ischemia-related changes in left ventricular filling, with elevation in diastolic pressures and endocardial compression.

Comparison of exercise testing with studies of coronary flow reserve in patients with microvascular angina.

Abnormal small coronary artery function may cause limited coronary flow responses to stress, resulting in anginal symptoms and ischemia in some patients with chest pain despite angiographically normal coronary arteries. To assess the exercise hemodynamic correlates of coronary flow abnormalities measured in the cardiac catheterization laboratory, 105 patients with microvascular angina (defined as an increase in coronary vascular resistance during pacing stress after ergonovine administration in the absence of significant epicardial constriction and associated with provocation of the patient's typical chest pain) and 27 patients without any coronary flow abnormality (normal) were analyzed. Of the 105 patients with microvascular angina, 75 had normal electrocardiographic responses to treadmill exercise testing, 22 had ischemic responses, and eight had bundle branch block during exercise. All 27 normal patients had normal electrocardiographic responses to exercise. Patients with ischemic electrocardiographic responses (0 +/- 7%, p less than 0.01), and those with bundle branch block (-2 +/- 6%, p less than 0.01) had abnormal left ventricular ejection fraction responses to exercise compared with the normal group, who demonstrated an 8 +/- 6% increase in left ventricular ejection fraction by radionuclide angiography during exercise, and microvascular angina patients with a normal electrocardiographic response to exercise, who demonstrated a 5 +/- 7% increase in ejection fraction. Although the microvascular response to ergonovine was no different among the three microvascular angina exercise groups, the administration of dipyridamole caused less coronary vasodilation in those patients with apparently ischemic or bundle branch block responses to exercise compared with those with normal electrocardiograms during exercise.(ABSTRACT TRUNCATED AT 250 WORDS)

Airway hyperresponsiveness in patients with microvascular angina. Evidence for a diffuse disorder of smooth muscle responsiveness.

Anginal chest pain in patients with angiographically normal coronary arteries may be caused by a limited coronary flow response to stress because of abnormal function of the coronary microcirculation (microvascular angina). Studies of forearm arterial function suggested that patients with microvascular angina may have a diffuse disorder of smooth muscle tone. Because dyspnea is common in these patients and seems disproportionate to the severity of myocardial ischemia, we studied air flow (forced expiratory volume in 1 second, or FEV1) in the basal state and after methacholine inhalation to determine whether bronchial smooth muscle is affected in this syndrome. Five of 36 patients with microvascular angina had a basal FEV1 of less than 70% of that predicted and did not receive methacholine. Of the remaining 31 patients, 14 (45%) had a more-than-20% reduction in FEV1 after methacholine inhalation (as much as 25 mg/ml), a response significantly greater than that of nine patients with heart disease (0%, p less than 0.025) and 24 normal volunteers of similar age and gender distribution (13%, p less than 0.025). Furthermore, the product of the methacholine dose inhaled and the magnitude of decline in FEV1 from baseline (methacholine response score) was significantly lower in patients with microvascular angina than in normal volunteers (16 +/- 8.6 versus 22.2 +/- 3.7, p = 0.026). We conclude that airway hyperresponsiveness is frequently demonstrable in patients with microvascular angina; these findings are consistent with our hypothesis that this syndrome may represent a more generalized abnormality of vascular and nonvascular smooth muscle function.

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.

Beneficial and detrimental effects of lidoflazine in microvascular angina.

Lidoflazine, a piperazine derivative calcium antagonist, was investigated as therapy in 22 patients with microvascular angina (chest pain, angiographically normal coronary arteries and left ventricle, microvascular constrictor response to pacing after ergonovine administration and limited coronary flow response to dipyridamole). Eighteen of 22 patients reported symptom benefit while taking lidoflazine 360 mg daily. Compared to baseline exercise treadmill testing, lidoflazine resulted in significant improvement in exercise duration (812 +/- 337 vs 628 +/- 357 seconds, p less than 0.01) and time to onset of chest pain (530 +/- 343 vs 348 +/- 246 seconds, p less than 0.01). The 5 patients with ischemic ST-segment changes during baseline testing demonstrated an almost 4-minute delay in ST-segment depression (3 patients) or no ST-segment depression (2 patients) while taking lidoflazine. Repeat invasive study of coronary flow in 11 patients taking lidoflazine demonstrated significantly greater coronary vasodilation at rest, during pacing, during pacing after ergonovine and after dipyridamole administration (all p less than 0.03), compared to the initial drug-free study. During the randomized, placebo-controlled phase of the study with 7-week treatment periods, 9 of 11 patients who completed this phase of the study preferred lidoflazine and all demonstrated improved exercise capacity with lidoflazine compared to placebo. However, 3 patients developed malignant ventricular arrhythmias, and 1 died while taking lidoflazine, resulting in termination of the study. Limited coronary vasodilator response in microvascular angina has a reversible vasoconstrictor component and may be due to elevated systolic calcium levels. Despite the hemodynamic, symptom and exercise benefit, lidoflazine may be unsafe for clinical use because of its propensity to cause potentially fatal ventricular arrhythmias.

Coronary flow reserve, esophageal motility, and chest pain in patients with angiographically normal coronary arteries.

PURPOSE AND METHODS: To ascertain the relative prevalence of abnormalities of coronary flow reserve and esophageal function in patients with chest pain despite angiographically normal coronary arteries, 87 patients underwent invasive study of coronary flow reserve and, during the same week, esophageal testing. RESULTS: Sixty-three of the 87 patients (72%) demonstrated abnormalities of coronary flow reserve, as evidenced by an increase in coronary resistance during the stress of rapid atrial pacing after administration of ergonovine 0.15 mg intravenously (1.33 +/- 0.36 mm Hg.minute/mL), compared with pacing at the same heart rate before ergonovine administration (1.10 +/- 0.33 mm Hg.minute/mL). This higher coronary vascular resistance occurred in the absence of significant epicardial coronary artery luminal narrowing. Fifty-seven of these 63 patients (90%) with a coronary vasoconstrictor response to ergonovine described their typical chest pain during pacing stress, compared with only six of 24 patients (25%) who demonstrated no coronary flow abnormality (p less than 0.001). After administration of dipyridamole 0.5 to 0.75 mg/kg intravenously to 65 patients, the 48 patients with ergonovine-induced vasoconstriction had a significantly higher minimum coronary resistance, compared with the 17 patients without a coronary vasoconstrictor response to ergonovine (0.65 +/- 0.21 versus 0.47 +/- 0.13 mm Hg.minute/mL, p less than 0.03). Twenty of 87 patients (23%) had abnormal esophageal motility [nutcracker esophagus (11), nonspecific motility disorder (seven), and diffuse esophageal spasm (two)], including 16 of the 63 patients (25%) with abnormal coronary flow reserve. Twenty-four (28%) patients experienced their typical chest pain during motility testing, but only five of these patients met criteria for abnormal esophageal motility. Nine of 75 patients tested (12%) had their typical chest pain during Bernstein testing, and 18 of 38 patients (47%) tested had their typical chest pain provoked by intraesophageal balloon distention. CONCLUSIONS: Seventy-one of 87 patients (82%) with anginal-like chest pain and normal epicardial vessels in our series had a disorder of either coronary flow reserve, esophageal motility, and/or reproduction of typical chest pain during acid infusion. Of interest, chest pain was commonly encountered during cardiac and esophageal testing (85% of patients), regardless of the ability to demonstrate an abnormality of coronary flow reserve or abnormal esophageal function. This suggests that pain experienced by these patients may be a consequence of myocardial ischemia, esophageal dysfunction, abnormal visceral nociception, or a combination of any or all of these entities.

Effect of surgical reduction of left ventricular outflow obstruction on hemodynamics, coronary flow, and myocardial metabolism in hypertrophic cardiomyopathy.

To assess the impact of operative reduction of left ventricular outflow obstruction in hypertrophic cardiomyopathy, measurements of great cardiac vein flow, oxygen and lactate content, left ventricular pressures, and cardiac index were measured at rest and during pacing stress in 20 consecutive patients (13, myotomy-myectomy; six, mitral valve replacement; one, both myotomy-myectomy and mitral valve replacement) who underwent both preoperative and postoperative studies. All had angiographically normal epicardial coronary arteries. Operation resulted in reduction in outflow gradient (64 +/- 38 to 4 +/- 7 mm Hg, p less than 0.001) and in left ventricular systolic pressure (186 +/- 32 to 128 +/- 22 mm Hg, p less than 0.001) and was associated with reduction in great cardiac vein flow (101 +/- 26 to 78 +/- 16 ml/min, p less than 0.001) and oxygen consumption in the anterior left ventricle and septum (11.9 +/- 4.1 to 8.4 +/- 1.9 ml O2/min, p less than 0.001) in the basal state. During rapid atrial pacing, 13 of 20 patients experienced chest pain postoperatively, whereas all 20 developed chest pain during preoperative pacing, with an improvement in pacing anginal threshold (or heart rate 150 if no chest pain was experienced) of 16 +/- 18 beats/min (p less than 0.001). The peak great cardiac vein flow (161 +/- 41 to 131 +/- 45 ml/min, p less than 0.025) and myocardial oxygen consumption (19.4 +/- 6.1 to 14.3 +/- 5.5 ml O2/min, p less than 0.005) during pacing, which correlated directly with the severity of the basal left ventricular gradient (p = 0.011 and p = 0.002, respectively), were also reduced by surgery. Lactate metabolism during pacing changed from net production before surgery to net consumption after operation (-17 +/- 47.6 to 4.4 +/- 29.8 mumol/min, p less than 0.01), with six of 20 patients producing lactate after surgery compared with 13 of 20 before surgery (p = 0.06). The six patients with the highest peak great cardiac vein flow (greater than 175 ml/min) during preoperative pacing had greater symptom and metabolic benefit during pacing after surgery compared with the 14 patients with lower peak coronary flow. Postpacing left ventricular end-diastolic pressure (30 +/- 7 to 23 +/- 7 mm Hg, p less than 0.001) and pulmonary artery wedge pressure (24 +/- 6 to 20 +/- 5, p less than 0.001) were reduced after surgery.(ABSTRACT TRUNCATED AT 400 WORDS)

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.

Dynamic limitation of coronary vasodilator reserve in patients with dilated cardiomyopathy and chest pain.

Twenty-six patients with dilated cardiomyopathy and angiographically normal coronary arteries, 12 of whom gave a history of anginal chest pain, underwent noninvasive and invasive hemodynamic study. During treadmill exercise testing, patients with a history of angina demonstrated worse effort tolerance (7.4 +/- 4.9 versus 13.6 +/- 5.1 minutes, p less than 0.005) and a lower end-exercise systolic blood pressure-heart rate product (17.9 +/- 3.4 versus 23.6 +/- 4.9 mm Hg.beats/min x 10(3), p less than 0.005) compared with patients without a history of angina. During rapid atrial pacing after ergonovine, 0.15 mg intravenously, 11 of the 12 patients with a history of angina experienced their typical chest pain, in contrast to only 1 of 12 patients without a history of angina. The angina group, compared with the nonangina group, had significantly lower great cardiac vein flow (118 +/- 24 versus 160 +/- 43 ml/min, p less than 0.01), and higher coronary resistance (0.87 +/- 0.21 versus 0.66 +/- 0.25 mm Hg.min/ml, p less than 0.05), significant widening of the arterial--great cardiac vein oxygen difference and a significant fall in cardiac index during pacing. Further, ergonovine resulted in higher coronary resistance during pacing in the angina group compared with pacing alone (+0.16 +/- 0.16 mm Hg min/ml, p less than 0.01), in the absence of significant reduction in epicardial coronary artery luminal diameter. After dipyridamole, 0.5 to 0.75 mg/kg intravenously, to 21 patients, the 7 patients with a history of angina had significantly lower flow (149 +/- 37 versus 218 +/- 73 ml/min, p less than 0.05) and higher coronary resistance (0.59 +/- 0.09 versus 0.43 +/- 0.17 mm Hg.min/ml, p less than 0.05) than did the nonangina group. It is concluded that patients with dilated cardiomyopathy and chest pain unrelated to epicardial coronary artery disease exhibit impaired vasodilator responses to both metabolic and pharmacologic stimuli, and an increased sensitivity to the vasoconstrictor effects of ergonovine. Whether these findings are of etiologic or long-term prognostic significance is unknown.