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The effect of meals of differing composition on exercise tolerance in patients with angina pectoris.

In this study we compared different dietary constituents and their effect on the angina threshold. We compared carbohydrate-rich, fat-rich and balanced liquid diets on effort tolerance in 14 patients of mean (range) 61 (41-73) years of age with chronic stable angina. On four different occasions at least 1 week apart, patients had exercise treadmill tests after an overnight fast and then after a rest period of 1 h ingested one of three different approximately isocalorific (about 4000 kJ) liquid drinks of 600 ml consisting mainly of: fat, carbohydrate or a balanced meal with an equal volume of water as control. Meals were given in random order. Analysis of the mean (SD) differences in heart rate between fasting and the post-prandial state for the different meals revealed a significant increase between water and the other meals, fat (+4(6) beats.min-1 P < 0.002), balanced (+9(17) beats.min-1 P < 0.004), and carbohydrate (+10(12) beats.min-1 P < 0.0002). There was no significant difference between the groups as regards systolic or diastolic blood pressure. Cardiac output increased following the meals but decreased after water; however, there was a significant difference between water and balanced meals. Exercise tolerance fell following all the meals but was significantly greater after a balanced (mean (SD) -108(129) s P < 0.01) and carbohydrate meal (-92(52) s P < 0.001). The reduction in exercise duration following a fat meal (-36(53)s) was not significantly different from that following water (-8(43) s) but was significantly smaller than after a carbohydrate meal (P < 0.02). Time to 1 mm of ST depression showed similar changes to that of total exercise duration, being significantly lower after a carbohydrate (mean (SD) -76(77) s P < 0.01) and balanced meal (-76(63) s P < 0.005). Time to 1 mm ST depression, although reduced by a fat meal (-15(84) s) was significantly less than after a carbohydrate meal (P < 0.02). In conclusion, patients with chronic stable angina have impaired effort tolerance and a lower angina threshold after high calorie containing liquid meals. Meals rich in carbohydrate have greater effects than meals where the majority of calories are derived from fat. Patients should be advised to avoid exercise in the first 30 min after eating.

Adult↗

Effect of beta-adrenergic blockade on hyperventilation and exercise tolerance in emphysema.

Ventilation, heart rate, and arterial blood gas tensions were measured at rest and during incremental exercise in 10 patients with emphysema after intravenous placebo or 7 mg metoprolol. Metoprolol reduced heart rate by 14% (P less than 0.001) and ventilation by 11% (P less than 0.01), but there was no significant difference in arterial O2 or CO2 tension (Pao2 and PaCO2, respectively). Metoprolol increased the time to exhaustion on a cycle ergometer (P less than 0.05) but did not improve the 12-min walking distance. A double-blind randomized crossover comparison of 4 wk treatment with atenolol (100 mg/day), metoprolol (100 mg/day), or matched placebo was performed in 12 patients with emphysema. Both beta-adrenoceptor antagonists reduced resting heart rate by 33% (P less than 0.001) and resting minute ventilation by 11% (P less than 0.025). There was no change in resting or exercise Pao2 or Paco2. During steady-state exercise on a cycle ergometer, atenolol and metoprolol reduced ventilation by 14 and 4%, respectively. This was accompanied by 11 and 5% reductions in O2 consumption (P less than 0.05) and 13 and 6% falls in CO2 production (P less than 0.05). There were no significant changes in tests of exercise tolerance, but forced expiratory volume in 1 s and forced vital capacity were reduced during beta 1-adrenergic blockade. beta 1-Blocking drugs reduce hyperventilation in emphysema by reducing pulmonary gas exchange without a change in arterial blood gas tensions. Increased airflow obstruction prevents this reduction being of therapeutic value.

Administration, Oral↗

Improvement in exercise tolerance and immediate beta-adrenergic blockade with intranasal propranolol in patients with angina pectoris.

A new intranasal spray formulation of propranolol was developed to provide beta-adrenergic blocking medication on an immediate basis to patients with angina pectoris. The effects of this spray or placebo were assessed in 16 patients with effort-induced angina in a blinded, randomized, cross-over design study that compared placebo with intranasal propranolol spray (5 mg/puff) 15 minutes before exercise on a treadmill (Bruce protocol). One week later, each patient, acting as his/her own control, received the alternative treatment and repeated exercise. Mean plasma propranolol level with active therapy was 20 ng/ml. Patients with active spray demonstrated a significant increase in total exercise time than patients taking placebo (530 +/- 197 vs 460 +/- 177 seconds, p = 0.05), an increase in the time to 1 mm ST-segment depression on the electrocardiogram (384 +/- 202 vs 327 +/- 144 seconds, p < 0.05), and an increase in time to onset of angina (452 +/- 149 vs 363 +/- 175 seconds, p = 0.0005). There was a blunting of maximal exercise heart rate with active therapy compared with placebo (120 +/- 13 vs 133 +/- 17 beats/min, p < 0.01), blunting of maximal exercise systolic blood pressure (185 +/- 22 vs 194 +/- 21 mm Hg, p < 0.05), and blunting of peak double product (p < 0.0005), with more modest effects on resting heart rate. Propranolol spray is an effective approach for providing immediate beta blockade and improving exercise tolerance in patients with angina pectoris.

Administration, Intranasal↗

A comparison of the effect of enalapril and metoprolol on renal function, potassium balance, lipid profile, cardiac function, exercise tolerance and quality of life in hypertensive dialysis patients.

26 patients with hypertension while on hemodialysis or continuous ambulatory peritoneal dialysis for end-stage renal diseases were treated first with enalapril and then changed to metoprolol. Both drugs were shown to be similarly effective in controlling blood pressure. There was no difference between the two drugs in their effects on renal function, potassium balance, lipid profile, cardiac function, exercise tolerance, and quality of life. Mild worsening of anemia was observed during treatment with enalapril. No serious side effects were reported. Use of enalapril is safe in the treatment of hypertension in dialysis patients.

Adult↗

Association of Duke prognostic treadmill scores with change in P-wave duration during exercise tolerance tests in patients with interatrial block and coronary heart disease.

Interatrial block (IAB), as denoted by P waves > or =110 ms in duration, is believed to be associated with underlying ischemia, particularly with that of its principal interatrial conduction pathway, the Bachmann bundle. In this study, the association between Duke prognostic treadmill (DPT) scores and change in P-wave duration in IAB was investigated in patients who underwent cardiopulmonary exercise tolerance tests (CPETTs). Twenty-seven patients with IAB and 42 control patients without IAB on electrocardiography at rest who had evidence of myocardial ischemia on coronary angiography after CPETTs were identified consecutively. P-wave measurements were obtained independently at the beginning of every CPETT stage and also when P-wave changes occurred. Increments in P-wave durations were measured to the nearest 20 ms. DPT scores were calculated for the 2 groups. There was no significant difference between the groups in mean values for DPT scores and for exercise capacity. However, change in P-wave duration in patients with IAB was significantly associated with mean DPT score. As the change in P-wave duration increased, the DPT score was significantly less (p = 0.003). DPT scores were more significant with P-wave changes of >20 ms compared with P-wave changes of < or =20 ms (p = 0.00001). In conclusion, in patients with coronary heart disease and IAB at rest, increases in P-wave durations during CPETTs are inversely associated with DPT scores.

Aged↗

Exercise tolerance in asymptomatic elderly men with fluoroscopically detected coronary artery calcification.

STUDY OBJECTIVE: The value of detecting coronary artery calcification (CAC), by cardiac imaging, for the diagnosis of coronary artery disease (CAD) in asymptomatic middle-aged men has been demonstrated. However, the incidence of CAC increases with age. The functional significance of CAC remains unknown in asymptomatic elderly men. The purpose of this study is to explore whether CAC in asymptomatic aging men signifies the presence of cardiovascular dysfunction during exercise. DESIGN: This study was designed to address whether elderly asymptomatic men, selected because they have CAC, have reduced exercise tolerance due to functionally significant CAD. PARTICIPANTS AND SETTING: Thirty-eight asymptomatic male volunteers (ages 50 to 75 years, mean [+/-SD] 64+/-7 years) with a normal resting ECG and at least one coronary risk factor, in a population study. Nineteen subjects had CAC detected by digital subtraction fluoroscopy in at least two major coronary arteries, and 19 subjects had no identifiable CAC. METHODS AND RESULTS: Each subject underwent a symptom-limited incremental exercise test with 12-lead ECG monitoring and respiratory gas analysis. Four indexes of exercise oxygen transport were evaluated: peak oxygen uptake (VO2), lactic acidosis threshold, peak VO2/heart rate ratio, and VO2 relative to a work rate increase. Eleven of 38 subjects (28%) were found to have reduced oxygen transport, which was defined as an abnormal reduction in more than two of the above four indexes of oxygen transport. Five of the 11 subjects with reduced oxygen transport had CAC, and 6 subjects did not (not significant). Only one subject with CAC had exercise ST depression. CONCLUSION: Significant CAC in asymptomatic men over age 50 does not signify exercise limitation due to CAD.

Aged↗

Effects of ranolazine on exercise tolerance and HbA1c in patients with chronic angina and diabetes.

AIMS: The anti-anginal efficacy and safety of ranolazine in diabetic and non-diabetic patients included in the Combination Assessment of Ranolazine In Stable Angina (CARISA) trial (JAMA 2004;291:309) were studied. Glycaemic control was also assessed in CARISA and its long-term open-label extension study. METHODS AND RESULTS: Patients with chronic angina enrolled in CARISA (189 with diabetes, 634 without diabetes) on background atenolol, diltiazem, or amlodipine therapy were randomized to placebo, ranolazine 750 or 1000 mg twice daily for 12 weeks, during which exercise tolerance, angina frequency, nitroglycerin usage, glucose, HbA(1c), and lipids were measured. Patients completing the randomized study could enroll in an ongoing open-label extension study and were evaluated every 3 months. Ranolazine produced similar improvements in exercise parameters, nitroglycerin use, and angina frequency in diabetic and non-diabetic patients. Adverse events were similar between groups. Fasting glucose and lipids remained unaltered in diabetic patients after 12 weeks of therapy. In a post hoc analysis, ranolazine 750 and 1000 mg reduced HbA(1c) vs. placebo by 0.48+/-0.18% (P=0.008) and 0.70+/-0.18% (P=0.0002), respectively; the HbA(1c) levels appeared to remain unchanged over time during long-term therapy. CONCLUSION: Anti-anginal efficacy and safety of ranolazine for angina were similar between diabetic and non-diabetic patients. Ranolazine significantly improved glycaemic control in diabetic patients.

Acetanilides↗

[The effects of trimetazidine on left ventricular function and physical exercise tolerance in patients with ischemic cardiomyopathy].

Trimetazidine is a new metabolic antiischemic agent, which increases the tolerance of cardiomyocytes to ischemia. The aim of the study was to evaluate the effect of additional trimatazidine therapy in patients with ischemic cardiomyopathy (ICMP) in comparison with standard therapy of cardiac insufficiency. According to the results of the study, trimetazidine improves the clinical status, functional class of cardiac insufficiency, left ventricular ejection fraction, in ICMP patients. Trimetazidine increases physical exercise tolerance according to the results of six-minute walking test. Thus, the optimization of myocardial energetic metabolism may be a promising perspective in the treatment of coronary heart disease with systolic dysfunction.

Aged↗

[Effects of ambulatory respiratory rehabilitation on exercise tolerance and quality of life in chronic obstructive lung disease patients].

Respiratory rehabilitation is a multidisciplinary medical approach which allows a total care of patients suffering from COPD. Optimisation of bronchodilator treatment, health education, cessation of smoking, dietetic, relaxation and re-entrainment to effort. We report out experience concerning 88 BPCO (mean age 62.1, FEV1 of 1.4 litres; or 48% of predicted normal); these 88 patients were cared for on an ambulatory basis at our centre for two hours per session, three times per week for seven weeks. The objective results were analysed on exercise tests before and after treatment. For ventilation, there was a significant improvement in the power developed (from 45.5+/-17.1 to 53.4+/-23 watts; p<0.001) without any change in the oxygen consumption (VO2), ventilation (VE) or heart rate (FC) and of oxygen pulse (VO2/FC). For the same level of power (80% of maximum power for the initial exercise test) there was a significant lowering of ventilation (V=33.5+/-9.4 to 30.7+/-7.4 litres per minute, p<0.001), cardiac frequency (FC: from 116.9+/-16 to 111.1+/-13.1 beats per minute, p<0.001) as well as the oxygen pulse (VO2/FC: from 7.9+/-2.7 to 8.3+/-3.7). At the maximum on the exercise test all the parameters studied were significantly better: watts, VO2, VE, cardiac frequency and VO2/FC. A study of the visual analogue scale (EVA), analysing sleep, anxiety, dyspnoea and the physical aspects showed a significant improvement in the four subjective parameters. Respiratory rehabilitation of BPCO practiced as an out patient has shown an improvement in exercise tolerance in every day activities and improvement in dyspnoea and in the quality of life.

Aged↗

Four-year efficacy of cardiac resynchronization therapy on exercise tolerance and disease progression: the importance of performing atrioventricular junction ablation in patients with atrial fibrillation.

OBJECTIVES: The goal of this study was to investigate the effects of cardiac resynchronization therapy (CRT) in heart failure patients with permanent atrial fibrillation (AF) and the role of atrioventricular junction (AVJ) ablation. BACKGROUND: Cardiac resynchronization therapy has been proven effective in heart failure patients with sinus rhythm (SR). However, little is known about the effects of CRT in heart failure patients with permanent AF. METHODS: Efficacy of CRT on ventricular function, exercise performance, and reversal of maladaptive remodeling process was prospectively compared in 48 patients with permanent AF in whom ventricular rate was controlled by drugs, thus resulting in apparently adequate delivery of biventricular pacing (>85% of pacing time), and in 114 permanent AF patients, who had undergone AVJ ablation (100% of resynchronization therapy delivery). The clinical and echocardiographic long-term outcomes of both groups were compared with those of 511 SR patients treated with CRT. RESULTS: Both SR and AF groups showed significant and sustained improvements of all assessed parameters (model p < 0.001 for all parameters). However, within the AF group, only patients who underwent ablation showed a significant increase of ejection fraction (p < 0.001), reverse remodeling effect (p < 0.001), and improved exercise tolerance (p < 0.001); no improvements were observed in AF patients who did not undergo ablation. CONCLUSIONS: Heart failure patients with ventricular conduction disturbance and permanent AF treated with CRT showed large and sustained long-term (up to 4 year) improvements of left ventricular function and functional capacity, similar to patients in SR, only if AVJ ablation was performed.

Aged↗

Effect of nifedipine on exercise tolerance in angina pectoris.

Nifedipine is a new antianginal drug, the calcium-antagonistic inhibitory action on excitation-contraction coupling apparently being so pronounced that, in therapeutic dosage, all other pharmacological properties are negligible. Its effect on exercise tolerance in angina was assessed by an exercise study involving 14 patients: single-stage exercise tests were chosen and the advantages of this are given. Our results suggest that the onset of action occurs after about 20 minutes, reaches a peak of activity at approximately one-half to two hours, and some effect may still be present at three hours. There was a significant improvement in exercise times with a mean rise of 50 per cent over placebo.

Adult↗

A rehabilitation program for improving exercise tolerance of patients with chronic lung disease.

A Chronic Chest Disease Rehabilitation Program has been developed in the Toronto General Hospital to improve exercise tolerance in very disabled patients. The most important part of the program is physical conditioning using mainly a motor-driven treadmill. The treadmill exercise is done breathing room air or, in the case of the most disabled patients, an oxygen-enriched gas mixture. Other exercise includes riding a stationary bicycle, going up and down stairs, and turning a wheel by hand. Other aspects of the program are breathing exercises, inhalation therapy using an ultrasonic nebulizer, chest physiotherapy, and patient education. The importance of a team approach with encouragement, enthusiasm and demonstration of steady progress is emphasized.

Breathing Exercises↗

[Effect of treatment with vasodilators on physical exercise tolerance in patients with chronic congestive heart failure].

The studies were performed in 46 patients with chronic congestive heart failure (CCHF), III and IV NYHA classes. During the first two weeks all patients received digoxin (D) and furosemide (F) in optimal doses (stage O). Then, patients were randomly divided into two groups. During the stage A group I (n = 26) received digoxin, furosemide and nifedipine (N), while in the stage B captopril (K) was added to that treatment and it was continued for 4 weeks. During the following two weeks (stage C) patients were treated the same as in stage A. During the same stages group II (n = 20) received D, F and isosorbide dinitrate (S), then, D, F, S and K followed by D, F and S, respectively. After the termination of each stage of the treatment all patients performed physical exercise on bicycle ergometer, until limiting symptoms have occurred. Power (M) and duration (t) of exercise, systolic (ps) and diastolic (Pd) arterial blood pressures, heart rate (HR) at the peak load, and HR x Ps and HR/M indices were determined. It was found that N did not significantly affect the investigated ergometric parameters. Combined treatment with D, F, N and K induced an increase in M, t and HR, and a decrease in. This effect persisted through the stage C. Following the treatment with D, F and S, a significant increase in M and decrease in HR/M were observed. Addition of K to D, F, and S did not induce further improvement in the physical exercise tolerance of these patients.

Adult↗

Role of exercise tolerance test (ETT) and gated single photon emission computed tomography-myocardial perfusion imaging (SPECT-MPI) in predicting severity of ischemia in patients with chest pain.

This was an observational study carried out in the department of cardiology. Bangabandhu Shikh Mujib Medical University (BSMMU), Dhaka in collaboration with Institute of Nuclear Medicine (INM), Shabag, Dhaka during the period October 2002-March 2003. A total of 54 patients presenting with Canadian Cardiovascular Society (CCS) class I-II severity of chest pain with mean +/-SD age 49.88 +/- 8.44 yrs and having male to female ratio 5.75:1 were included in the study. The main objective of the study was to predict severity of myocardial ischemia by Exercise Tolerance Test (ETT) determined by Duke Treadmill Score (DTS) and by perfusion pattern observed following Single-Photon Emission Computed Tomography myocardial perfusion imaging (SPECT-MPI). All patients underwent ETT and then SPECT-MPI scan using Tc-99m-tetrofosmin in one-day stress and rest protocol. Coronary angiogram (CAG) was done with in six months of the perfusion study. After performing ETT, patients were categorized by DTS and myocardial perfusion studies were also stratified according to severity of perfusion defect. The formula used to calculate the score was: Exercise time- (5 x ST segment deviation)-(4 X Treadmill angina index). The angiographic findings (significant >50% stenosis) and perfusion defects in MPI were compared with the severity of DTS. There were 31 patients who had CAG proven (>50% luminal diameter narrowing) CAD and 23 patients free of CAD. After ETT patients were categorized by Duke Treadmill Score into high DTS 12 (22.22%) patients, intermediate DTS 20 (37.03%) patients low DTS 22 (40.74%) patients. In high DTS group 91.66% patients had perfusion defect, whereas in intermediate and low risk group it was 60% and 40.9% respectively. In high DTS group 91.66% of patients had angiographicaly proven CAD, 58.33% of them had triple vessel disease (TVD) while in intermediate and low risk groups angiographically proven CAD were 65% and 22.72% of whom TVD only in 15% & 0% respectively. The results of ETT using DTS score were satisfactorily correlated with SPECT-MPI scanning in high DTS subsets of patients only. It is therefore, suggested that patient of high risk DTS do not need for myocardial perfusion imaging study and should undergo CAG for further evaluation. But the intermediate and low risk groups were needed myocardial perfusion imaging study to guide for further evaluation.

Adult↗

Late intervention after anterior myocardial infarction: effects on left ventricular size, function, quality of life, and exercise tolerance: results of the Open Artery Trial (TOAT Study).

OBJECTIVE: We sought to conduct a randomized trial comparing late revascularization with conservative therapy in symptom-free patients after acute myocardial infarction (AMI). BACKGROUND: In the absence of ischemia, the benefits of reperfusion late after AMI remain controversial. However, the possibility exists that an open infarct related artery benefits healing post AMI. METHODS: Of 223 patients enrolled with Q-wave anterior AMI, 66 with isolated persistent occlusion of the left anterior descending coronary artery (LAD) were randomized to the following treatments: 1) medical therapy (closed artery group; n = 34) or 2) late intervention and stent to the LAD + medical therapy (open artery group; n = 32). The study was powered to compare left ventricular (LV) end-systolic volume between the two groups 12 months post AMI. RESULTS: Late intervention 26 +/- 18 days post AMI resulted in significantly greater LV end-systolic and end-diastolic volumes at 12 months than medical therapy alone (106.6 +/- 37.5 ml vs. 79.7 +/- 34.4 ml, p < 0.01 and 162.0 +/- 51.4 ml vs. 130.1 +/- 46.1 ml, p < 0.01, respectively). Exercise duration and peak workload significantly increased in both groups from 6 weeks to 12 months post AMI, although absolute values were greater in the open artery group. Quality of life scores tended to deteriorate during this time interval in the closed artery patients but remained unchanged in the open artery patients. Coronary angiography at 1 year documented a low incidence of intergroup cross-over (spontaneous recanalization in 19% and closure in 11%). CONCLUSIONS: In the present study, recanalization of occluded infarct-related arteries in symptom-free patients approximately 1 month post AMI had an adverse effect on remodeling but tended to increase exercise tolerance and improve quality of life.

Coronary Angiography↗

[Exercise tolerance in patients after successful percutaneous transluminal coronary angioplasty].

In 32 patients with successful percutaneous transluminal coronary angioplasty (PTCA), we performed treadmill exercise tests (TMET) before and about one month after PTCA to assess the correlation between the improvement in coronary artery lesions and exercise tolerance. Either the Bruce protocol (B: n = 12) or the modified Bruce protocol (MB: n = 20) was used; with the latter being applied to patients whose cardiac function seemed depressed. In 15 patients, oxygen consumption (VO2) was measured by analyzing the expired gases, 13 patients underwent exercise thallium-201 myocardial perfusion scintigraphy before and after PTCA, whose results were compared with those of TMET. In both B and MB protocols, the treadmill walking time was significantly prolonged after PTCA, compared to that before PTCA (B: 7.4 +/- 1.3 vs 9.5 +/- 1.9, MB: 11.4 +/- 3.5 vs 12.7 +/- 3.5 min). Heart rates (HR) and rate pressure products (RPP) were significantly increased after PTCA in both protocols (HR B: 139 +/- 18 vs 154 +/- 17, MB: 121 +/- 20 vs 137 +/- 19 bpm, RPP B: 26,500 +/- 5,600 vs 30,300 +/- 6,700, MB: 19,400 +/- 6,200 vs 22,700 +/- 6,600 mmHg.bpm), however, systolic blood pressure did not change significantly after PTCA in either protocol. While there was a significant improvement in VO2 after PTCA (21.6 +/- 6.3 vs 25.7 +/- 4.2 ml/kg/min), the O2-pulse remained unchanged. Thallium-201 myocardial scintigraphy revealed improvement of myocardial perfusion in 8 of the 13 cases examined.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

Effects of metformin on microvascular function and exercise tolerance in women with angina and normal coronary arteries: a randomized, double-blind, placebo-controlled study.

OBJECTIVES: This study sought to determine whether metformin improves vascular function or myocardial ischemia in nondiabetic subjects. BACKGROUND: Metformin prevents diabetes and may reduce coronary events in patients with diabetes, but effects on microvascular function and angina are not clear. METHODS: We conducted an 8-week double-blind, randomized, placebo-controlled study of metformin 500 mg twice a day in 33 nondiabetic women with a prior history of normal coronary angiography but two consecutive positive (ST-segment depression > or =1 mm) exercise tolerance tests. All parameters were measured at baseline and at 8 weeks, together with an in vivo assessment of forearm (skin) microvascular function using laser Doppler imaging combined with iontophoresis. RESULTS: In comparison with placebo (n = 17), metformin recipients (n = 16) showed significant reductions in weight and in homeostatic model assessment for insulin resistance (p < 0.05, intention to treat). Endothelium-dependent microvascular responses improved significantly with metformin (2-way repeated analysis of variance, p = 0.0003), but responses with placebo were unchanged (p = 0.50). A comparison of change in acetylcholine responses between metformin and placebo recipients was significant, whether analyzed by a 2-way analysis of variance (p < 0.0001) or change in area under curves (mean change +392 perfusion units, 95% confidence interval [CI] 20 to 764). Endothelium-independent responses were not altered. Maximal ST-segment depression (-0.84 mm, 95% CI -1.49 to -0.20, p = 0.013), Duke score (6.1 U, 95% CI 1.8 to 10.5, p = 0.008), and chest pain incidence (-0.11 episodes/day, 95% CI -0.22 to 0.00, p = 0.056) improved in metformin relative to placebo recipients. CONCLUSIONS: Metformin may improve vascular function and decrease myocardial ischemia in nondiabetic women with chest pain and angiographically normal coronary arteries. Larger controlled trials of longer duration are warranted.

Adult↗