mV ST Segment Depression Research Articles

Rethinking the false positive exercise stress test in the context of coronary microvascular dysfunction

Abstract Background Exercise stress testing (EST) was the traditional tool to detect myocardial ischaemia, but its use has declined due to its perceived high false positive rate. However, EST was historically validated against the reference standard of obstructive coronary artery disease (CAD). It is now well recognised that myocardial ischaemia can occur in the absence of CAD and this cohort, termed angina with non-obstructive coronary arteries (ANOCA), comprises nearly 50% of all patients presenting with stable angina. Purpose Our study assesses the accuracy of EST in detecting a substrate for myocardial ischaemia, with the reference standard being comprehensive coronary physiology assessment in patients with ANOCA. Methods Patients with typical angina and non-obstructive coronary arteries underwent physiological characterisation of the coronary circulation using a dual sensor-tipped intracoronary guidewire in the left anterior descending artery. The epicardial vessel was assessed by Fractional Flow Reserve (FFR) and the microcirculation by both endothelium-independent function (coronary flow reserve, CFR, using intravenous adenosine) and endothelium-dependent function (acetylcholine flow reserve, AChFR, using intracoronary acetylcholine infusion). Those with FFR≤0.80 were excluded per protocol. Coronary microvascular dysfunction was defined a priori as impaired CFR (<2.5) or impaired AChFR (≤1.5). All patients underwent a treadmill EST, using a standard Bruce protocol, with ischaemic electrocardiographic (ECG) changes defined as the appearance of 0.1mV ST-segment depression 80 milliseconds from the J-point. Patients, physiologists, and researchers were all blinded to the coronary physiology data. All data are presented as mean±SD or median (IQR). Results Ninety-one patients [67% female, 62±9 years, CCS 3 (2 to 3)] were recruited into this study. EST was performed 27 (15 to 139) days after angiography. Twenty-seven patients (30%) developed ischaemic ECG changes during their EST (Ischaemic group), whereas 64 patients (70%) did not (Control group). Both groups were phenotypically similar for demographics, risk factors, exercise time and FFR (Figure 1). 100% of the Ischaemic group and 69% of the control group had CMD. Conversely, 38% of patients with CMD developed ischaemic ECG changes on exercise but none (0%) of those with normal microvascular function did (p=0.001) (Figure 2A). The false positive rates with progressively granular reference standards are depicted in Figure 2B; there were no false positive ESTs using a comprehensive physiological reference standard. Angina reported during EST was less specific for CMD than induced ECG changes (70% vs 100%, p<0.001). Conclusions In patients with ANOCA a positive EST is always indicative of CMD. The potential utility of EST as a rule-in test for CMD makes it an attractive non-invasive widely available test that could be re-integrated into clinical pathways for assessing new onset angina.Patient characteristicsEST versus coronary physiology

Predictive value of lymphocyte to monocyte ratio for cardiac syndrome X.

Cardiac syndrome X (CSX) is typically described with ischemia in stress tests in addition to angina-like chest pain and without stenosis in coronary angiography. We aimed at determining the relationship between LMR and CSX. We retrospectively collected patients with CSX between January 2016 and December 2019. Patients with typical angina-like chest pain, normal 12-lead electrocardiography at rest, a positive response to the exercise test (> 0.1 mV ST-segment depression at 80 ms after the J point in two or more contiguous leads) or ischemia on myocardial perfusion scintigraphy and normal coronary angiography were included in the study as CSX patients. This study consisted of 116 patients with CSX and 153 control groups. The mean age of the patients with CSX was 52.7±9.7 years, and the mean age of the control group was 53.7±10.6 years (p= 0.416). The patients with CSX were more likely to have higher monocyte counts and LMR. According to the Pearson correlation test, the CRP value negatively correlated with the LMR. In multivariate logistic regression analysis, LMR remained a significant predictor of CSX. In ROC analysis, LMR < 4.1 had 64% sensitivity and 50% specificity (ROC area under curve: 0.587, 95% CI: 0.519-0.655, p=0.015) in accurately predicting a CSX diagnosis. We showed that lower LMR levels were associated with the presence of CSX.

O2 Pulse Patterns in Male Master Athletes with Normal and Abnormal Exercise Tests.

The clinical relevance of abnormal exercise testing (ET) results (at least 0.1 mV ST segment depression measured during exercise or recovery in three consecutive beats) in athletes without obstructive coronary artery disease (CAD) is not well understood. It is unknown whether this phenomenon reflects a physiological adaptation to sport or a truly ischemic response and a concomitant attenuated stroke volume (SV) response. The aim of this study was to investigate if athletes with abnormal ET results without obstructive CAD showed signs of an attenuated SV response using cardiopulmonary ET parameters. A total of 78 male master athletes with abnormal ET results without obstructive CAD underwent cardiopulmonary ET. ΔO2 pulse/Δwork rate (WR), ΔV˙O2/ΔWR, and Δheart rate (HR)/ΔWR were assessed and compared with data from 78 male master athletes with normal ET results, matched for age, sports characteristics, and exercise capacity. The ΔO2 pulse/ΔWR ratio beyond anaerobic threshold in athletes with abnormal ET results was lower than that in athletes with normal ET results (0.73 ± 0.41 vs 1.12 ± 0.54, respectively, P < 0.001). The ΔV˙O2/ΔWR ratio was also lower in athletes with abnormal ET results (0.9 ± 0.2 vs 1.0 ± 0.3, respectively, P = 0.041). Furthermore, these athletes showed a greater increase in HR in the last 2 min of exercise (ΔHR/ΔWR ratio: 1.19 ± 0.5 vs 0.80 ± 0.6, P < 0.001). Athletes with abnormal ET results without obstructive CAD showed an attenuated O2 pulse slope, decreased ΔV˙O2/ΔWR ratio, and increased ΔHR/ΔWR ratio beyond anaerobic threshold when compared with athletes with a normal ET result. These results support the hypothesis that at least a part of the athletes with an abnormal ET in absence of obstructive CAD have an attenuated SV response at high-intensity exercise.

Design and rationale for the randomised, double-blinded, placebo-controlled Liraglutide to Improve corONary haemodynamics during Exercise streSS (LIONESS) crossover study.

BackgroundGlucagon-like peptide-1 is an incretin hormone essential for normal human glucose homeostasis. Expression of the glucagon-like peptide-1 receptor in the myocardium has fuelled growing interest in the direct and indirect cardiovascular effects of native glucagon-like peptide-1, its degradation product glucagon-like peptide-1(9-36), and the synthetic glucagon-like peptide-1 receptor agonists. Preclinical studies have demonstrated cardioprotective actions of all three compounds in the setting of experimental myocardial infarction and left ventricular systolic dysfunction. This has led to Phase 2 trials of native glucagon-like peptide-1 and incretin-based therapies in humans with and without Type 2 diabetes mellitus. These studies have demonstrated the ability of glucagon-like peptide-1, independent of glycaemic control, to positively modulate the metabolic and haemodynamic parameters of individuals with coronary artery disease and left ventricular systolic dysfunction. We aim to add to this growing body of evidence by studying the effect of chronic glucagon-like peptide-1 receptor activation on exercise-induced ischaemia in patients with chronic stable angina managed conservatively or awaiting revascularisation. The hypothesis being liraglutide, a subcutaneously injectable glucagon-like peptide-1 receptor agonist, is able to improve exercise haemodynamics in patients with obstructive coronary artery disease when compared with saline placebo.Methods and designThe Liraglutide to Improve corONary haemodynamics during Exercise streSS (LIONESS) trial is an investigator-initiated single-centre randomised double-blinded placebo-controlled crossover proof-of-principle physiological study. Primary endpoints are change in rate pressure product at 0.1 mV ST-segment depression and change in degree of ST-segment depression at peak exercise during sequential exercise tolerance testing performed over a 6-week study period in which 26 patients will be randomised to either liraglutide or saline with crossover to the opposing regimen at week 3.DiscussionThe study will be conducted in accordance with the principles of Good Clinical Practice and the Declaration of Helsinki. The local Research Ethics Committee and Medicines and Healthcare Products Regulatory Agency have approved the study.Trial registrationNational Institute of Health Research Clinical Research Network (NIHR CRN) Portfolio ID 11112 and ClinicalTrials.gov Identifier NCT02315001.

Direct comparison between pharmacological stress with adenosine triphosphate disodium and exercise stress myocardial perfusion imagings

To clarify the significance of adenosine triphosphate disodium stress myocardial perfusion imaging (ATP-MPI), we directly compared the findings of ATP-MPI with those of exercise stress myocardial perfusion imaging (Ex-MPI). ATP-MPI, Ex-MPI, and coronary angiography (CAG) were performed within 60 days in 17 coronary artery disease patients with mean age of 62.1+/-7.9 years. CAG revealed single-vessel disease (SVD) in 10 patients and multivessel disease (MVD) in seven patients. The summed stress score (SSS) of ATP-MPI was significantly higher than that of Ex-MPI (10.0 [7.8-14.3] vs. 8.0 [4-18], P<0.05). No difference in the SSS was observed between ATP-MPI and Ex-MPI in patients with SVD (8.0 [6.0-9.0] vs. 8.0 [6.0-10.0], NS), whereas this difference was significant in patients with MVD (15.0 [14.0-22.8] vs.9 [7.3-16.3], P<0.05). There was no difference in the summed rest score between ATP-MPI and Ex-MPI. The univariate logistic analysis showed that "MVD" was the significant factor influencing to the overt discrepancy between ATP-MPI and Ex-MPI (odds ratio: 9.0, 95% confidence interval: 1.07-75.84, P=0.043). The accuracy of ATP-MPI and Ex-MPI in detecting the territory of stenotic coronary vessel or previous myocardial infarction was 98.0% and 92.1% (NS), respectively. In conclusion, ATP-MPI is useful for detecting potential ischemic areas that cannot be detected by Ex-MPI, particularly in patients with MVD.

Role of mean platelet volume in triagging acute coronary syndromes

Acute coronary syndromes, characterized by the rupture of unstable plaque and the subsequent thrombotic process involving platelets, have been increasing in relative frequency. The central role of platelet activation has long been noticed in this pathophysiology; hence, many therapies have been directed against it. In this study, we have aimed to search prospectively the value of mean platelet volume (MPV), which is a simple and accurate measure of the functional status of platelets, in patients hospitalized with diagnosis of acute coronary syndromes (ACS). A total of 216 consecutive patients (156 male, 60 female) hospitalized with the diagnosis of non-ST segment elevation (NSTE) ACS within the first 24 h of their chest pain were enrolled. One hundred and twenty patients, matched according to sex and age, with stable coronary heart disease (CHD) (85 male, 35 female) were enrolled as a control group. Patients were classified into two group: those with unstable angina (USAP, n = 105) and those with non-ST segment elevation myocardial infarction (NSTEMI, n = 111). MPVs were 10.4 +/- 0.6 fL, 10 +/- 0.7 fL, 8.9 +/- 0.7 fL consecutively for NSTEMI, USAP and stable CHD with significant differences. Patients with ischemic attacks in the first day of hospitalization accompanied by >0.05 mV ST segment shift had significantly higher MPV compared to those without such attacks (P = 0.001). Multivariable logistic regression analysis yielded that MPV (P = 0.016), platelet count (P < 0.001), and the presence of >0.05 mV ST segment depression at admission (P = 0.002) were independent predictors of development of NSTEMI in patients presenting with NSTE ACS. In patients presenting with NSTE ACS, higher MPV, though there are overlaps among subgroups, indicates not only more risk of having NSTEMI but also ischemic complications.

Prediction of mortality in patients without angina: use of an exercise score and exercise echocardiography

Background Exercise testing has limited efficacy for identifying coronary artery disease (CAD) in the absence of anginal symptoms. Exercise echocardiography is more accurate than standard exercise testing, but its efficacy in this situation has not been defined. We sought to identify whether the Duke treadmill score or exercise echocardiography (ExE) could be used to identify risk in patients without anginal symptoms . Methods We studied 1859 patients without typical or atypical angina, heart failure, or a history or ECG evidence of infarction or CAD, who were referred for ExE, of whom 1832 (age 51±15 years, 944 men) were followed for up to 10 years. The presence and extent of ischaemia and scar were interpreted by expert reviewers at the time of the original study. Results Exercise provoked significant (>0.1mV) ST segment depression in 215 patients (12%), and wall motion abnormalities in 137 (8%). Seventy-eight patients (4%) died before revascularization, only 17 from known cardiac causes. The independent predictors of death were age (RR 1.1, p<0.0001), smoking, Duke treadmill score (RR 0.9, p<0.0001) and resting LV dysfunction (RR 1.9, p<0.04), but did not include ischaemia at ExE. Echocardiography was not predictive of outcome in subgroups with an intermediate or high risk Duke score, nor in patients with two or more risk factors. Conclusions Patients without anginal symptoms have a low mortality, especially from cardiac causes. If such individuals undergo exercise testing and a resting echocardiogram, exercise echocardiography does not offer additional prognostic information.

Prediction of mortality in patients without angina: use of an exercise score and exercise echocardiography.

Exercise testing has limited efficacy for identifying coronary artery disease (CAD) in the absence of anginal symptoms. Exercise echocardiography is more accurate than standard exercise testing, but its efficacy in this situation has not been defined. We sought to identify whether the Duke treadmill score or exercise echocardiography (ExE) could be used to identify risk in patients without anginal symptoms. We studied 1859 patients without typical or atypical angina, heart failure, or a history or ECG evidence of infarction or CAD, who were referred for ExE, of whom 1832 (age 51+/-15 years, 944 men) were followed for up to 10 years. The presence and extent of ischaemia and scar were interpreted by expert reviewers at the time of the original study. Exercise provoked significant (>0.1mV) ST segment depression in 215 patients (12%), and wall motion abnormalities in 137 (8%). Seventy-eight patients (4%) died before revascularization, only 17 from known cardiac causes. The independent predictors of death were age (RR 1.1, p<0.0001), smoking, Duke treadmill score (RR 0.9, p<0.0001) and resting LV dysfunction (RR 1.9, p<0.04), but did not include ischaemia at ExE. Echocardiography was not predictive of outcome in subgroups with an intermediate or high risk Duke score, nor in patients with two or more risk factors. Patients without anginal symptoms have a low mortality, especially from cardiac causes. If such individuals undergo exercise testing and a resting echocardiogram, exercise echocardiography does not offer additional prognostic information.

Effects of atorvastatin 80 mg daily early after onset of unstable angina pectoris or non–Q-wave myocardial infarction

This clinical investigation was designed and undertaken to test the hypothesis that the addition of high-dose atorvastatin (80 mg/day) to conventional medical treatment early after either unstable angina pectoris (UAP) or non–Q-wave acute myocardial infarction (AMI) could reduce ischemic recurrences.  All patients consecutively admitted to our institution between January 1999 and July 2001 for UAP or non–Q-wave AMI were prospectively screened for inclusion in the study. In all cases the diagnosis of UAP or non–Q-wave AMI was made in accordance with previously reported criteria. 1 To be enrolled in the trial, patients were required to meet the following criteria: (1) angiographic evidence of severe and diffuse coronary artery disease, that was not amenable to direct revascularization by coronary artery bypass grafting or percutaneous transluminal coronary angioplasty, as determined by a cardiac surgeon and an interventional cardiologist during the index admission; (2) objective evidence of symptomatic reversible myocardial ischemia (0.1 mV ST-segment depression on the electrocardiogram) at a low exercise workload (4 METs) while receiving medical treatment (2 antianginal medications at maximal tolerated doses), as assessed by treadmill ergometry (Bruce’s protocol) before discharge; and (3) left ventricular ejection fraction 35%. Exclusion criteria were the presence of congestive heart failure, the need for continuous use of intravenous antianginal medications, and the presence of any major concurrent illness. The study was planned as an open-label, prospective, randomized, controlled trial with parallel groups. Before enrollment, all patients were receiving maximal conventional combination therapy (nitrates, calcium antagonists, and blockers), including 2 medications at maximal tolerated doses in all cases. All patients provided informed consent to take part in the investigation. At discharge from the hospital, included patients

Exercise-induced ST-segment depression and systolic dysfunction in patients with nonobstructive hypertrophic cardiomyopathy

Background ST-segment depression is common in patients with hypertrophic cardiomyopathy (HCM). However, it is not clear whether exercise-induced ST-segment depression in patients with HCM and patent coronary arteries is associated with changes in left ventricular function. Methods Left ventricular function was continuously evaluated in 53 patients with nonobstructive HCM during supine ergometer exercise with a radionuclide ventricular function monitor equipped with a cadmium telluride detector. On the basis of the ST-segment changes during exercise, the patients were divided into 2 groups: group N had no ST-segment depression, and group D had ≥0.1 mV ST-segment depression. Results Exercise duration, blood pressure, heart rate, and rate-pressure product during exercise did not differ between the 2 groups. End-diastolic volume at rest and at peak exercise did not differ between groups D and N. In contrast, the end-systolic volume in group N decreased during exercise, whereas in group D it increased. As a result, the left ventricular ejection fraction in group D decreased from 70% ± 7% to 59% ± 15% (P <.0001), whereas ejection fraction in group N increased from 65% ± 8% to 71% ± 11% (P =.0002). There was a strong correlation between exercise-induced ST-segment depression and changes in ejection fraction from rest to peak exercise (P <.0001). Conclusions These results suggest that the exercise-induced ST-segment depression seen in patients with nonobstructive HCM is associated with systolic dysfunction during exercise. (Am Heart J 2000;140:52-60.)

A comparison of nicorandil with isosorbide mononitrate in elderly patients with stable coronary heart disease: The SNAPE study

Nicorandil, a potassium channel opener, is an effective antianginal drug, but its therapeutic evaluation is still limited. Objective The efficacy and safety of nicorandil compared with isosorbide mononitrate (ISMN) was evaluated in the treatment of elderly patients (≥65 years) with stable angina pectoris and a positive exercise test result (≥0.1 mV ST-segment depression). Methods and Results In a multicenter, double-blind, double-dummy, controlled trial, 194 patients were randomly assigned to 10 mg nicorandil twice daily or 20 mg ISMN twice daily. For the evaluation of ischemic variables, a symptom-limited bicycle exercise test was performed after 1 week of placebo treatment and after 4 weeks of nicorandil or ISMN treatment. Clinical assessment for safety and side effects occurred at 2-week intervals. One hundred seventy-eight patients were analyzed on an intent-to-treat basis and 145 were terminated from the study per protocol (efficacy analysis). During treatment, within both treatment groups exercise testing revealed a significant postponement of the onset of ischemia (nicorandil, P <.01; ISMN, P =.03) and angina (P ≤.03 for both) and a decrease of maximum ST depression (ISMN, P <.002) compared with baseline. There were no differences between the groups for both intent-to-treat and efficacy analysis, with the exception of the rate-pressure product, which was increased (P =.03) in the nicorandil group. Safety and well-being variables were not different between groups, but the frequency of angina decreased (P =.02) in the ISMN group. Conclusions These data suggest that, although nicorandil seems to be as safe and effective as ISMN for the treatment of stable angina in elderly patients, ISMN may be superior to nicorandil for the symptomatic treatment of daily angina in this patient population.

Effects of Acute l -Arginine Administration in Coronary Atherosclerosis

To the Editor: Lerman et al1 in their interesting study reported that supplementation with l-arginine (the precursor of nitric oxide synthesis) for 6 months in patients without significant coronary artery stenosis reversed coronary small-vessel endothelial dysfunction and improved symptoms. Furthermore, it decreased plasma endothelin concentrations in patients. However, they did not examine the effects of l-arginine on epicardial coronary arteries and stenoses. We have examined2 3 by quantitative angiography the vasomotor effects of intracoronary infusion of normal saline (2 mL/min) for 2 minutes followed by 50 and 150 μmol/min l-arginine and bolus administration of 250 μg of nitroglycerin on 38 nonstenotic epicardial coronary artery segments and 22 stenoses in patients with coronary artery disease and a positive treadmill exercise test result (≥0.1 mV ST-segment depression at between 5 and 7 metabolic equivalents [METS] using the modified Bruce protocol). The diameter of the stenosis …

Effects of doxazosin on exercise-induced angina pectoris, ST-segment depression, and insulin sensitivity in patients with syndrome X

A significant proportion of patients with cardiac syndrome X have impaired coronary vasodilator capacity, which is thought to be caused by an increased sympathetic drive. The α 1-adrenoceptor blocker, doxazosin, increases the coronary vasodilator reserve in patients with syndrome X. To study whether the augmentation is associated with clinical improvement in patients, we conducted a double-blind, placebo controlled, crossover study with doxazosin 1 to 4 mg once daily for 10 weeks in 16 patients with syndrome X (14 women and 2 men; mean ± SD age 56 ± 5 years). Time to angina, exercise duration, time to 0.1 mV ST-segment depression, and maximal ST-segment depression during bicycle exercise testing were compared after treatment with doxazosin 2 mg or placebo for 5 weeks and again after treatment with doxazosin 4 mg or placebo for 10 weeks. Insulin sensitivity was assessed by the minimal model after 10 weeks of doxazosin or placebo treatment. Twelve patients completed the protocol. Doxazosin 4 mg/day decreased systolic blood pressure at rest (109 ± 16 vs 125 ± 18 mm Hg, p <0.05) and increased basal heart rate (85 ± 9 vs 76 ± 11 beats/min, p <0.05), whereas hemodynamics were unaffected during exercise. Time to angina, exercise duration, time to 0.1 mV ST-segment depression, and maximal ST-segment depression were similar during treatment with doxazosin and placebo irrespective of the doxazosin dose. Insulin sensitivity was not different with doxazosin and placebo. In conclusion, α 1 blockade does not significantly improve exercise duration, angina pectoris, and ST-segment depression despite a favorable vasodilator effect in patients with syndrome X. The absent clinical efficacy of doxazosin may challenge the use of the coronary vasodilator capacity as an appropriate method to subclassify patients with syndrome X.

Mibefradil, a T-Type Channel-Selective Calcium Antagonist: Clinical Trials in Chronic Stable Angina Pectoris

Pharmacotherapy with nitrates, β-blockers, and calcium antagonists is the cornerstone of management of patients with chronic stable angina pectoris. While these agents are all effective, their use may be limited by pharmacologic tolerance, side effects, and drug interactions. Mibefradil is a recently developed calcium antagonist with a unique chemical structure, pharmacologic profile, and mode of action. Unlike all previously available calcium antagonists, mibefradil acts primarily by selective blockade of T-type calcium channels, rather than L-type channels, at clinically relevant concentrations. It has been evaluated as a treatment for angina in placebo-controlled and active-controlled clinical trials. Treatment with 50 mg mibefradil resulted in a significant improvement in exercise tolerance test duration in three of the five placebo-controlled trials, and a significant improvement in time to onset of angina in two of the five trials. Time to onset of ischemia as evaluated by 0.1 mV ST-segment depression was increased in all five placebo-controlled trials. Treatment with 100 mg mibefradil resulted in significant improvement in all three exercise tolerance test parameters in all studies. Mibefradil further improved exercise tolerance test duration and other efficacy parameters when administered concomitantly to patients on background β-blocker or nitrate therapy. In addition, treatment with mibefradil was associated with a dose-dependent decrease in heart rate, double product, frequency of anginal attacks, nitroglycerin consumption, and both frequency and duration of silent ischemic episodes. In comparative trials, 100 mg mibefradil once daily was superior in efficacy to 10 mg amlodipine once daily and was at least equivalent to diltiazem in both efficacy and tolerability. Mibefradil was safe and well tolerated in all studies.

Amlodipine in Patients with Stable Angina Pectoris Treated with Beta-blockers: Double-blind Comparison with Placebo

In order to assess additional anti-ischaemic effects of amlodipine (AML) on coronary artery disease (CAD) treated with beta-blockers, 32 patients with CAD, verified on angiograms, and stable angina were randomized to receive 5 mg/day of AML or placebo, increasing to 10 mg/day after 2 weeks. Baseline recording of 24-h ambulatory ECG and blood pressure, echocardiography and bicycle exercise test was repeated after treatment for 2 weeks and for 6 weeks. Reduction of ambulatory ischaemia was not significantly greater with AML than with placebo. In exercise tests the time to 0.1 mV ST segment depression and the total exercise time remained unaltered. Blood pressure was reduced by 10 mg AML. The total variability and the very low frequency component of heart rate were reduced after both doses. The clinical significance of the possible unfavourable change in autonomic modulation of the heart in CAD patients is not known.

Protective effect of nisoldipine on dipyridamole-induced myocardial ischemia: correlation with exercise electrocardiography.

Nisoldipine, a dihydropyridine calcium channel blocker with strong coronary dilatative action, is commonly used in the treatment of myocardial ischaemia; its beneficial effect on effort angina has been demonstrated by several previous reports. Infusion of dipyridamole in doses sufficient to provoke myocardial ischaemia in patients with significant coronary artery disease is used safely in imaging studies for diagnostic purposes. To evaluate the potential effect of nisoldipine on dipyridamole-induced ischaemia and to compare the results with the effect of nisoldipine on exercise-induced ischaemia. Twelve patients (10 men and two women, mean age 62 +/- 8 years) with significant coronary artery disease (at least 70% lumen reduction in at least one major coronary vessel) were selected for inclusion in the study. In accordance with the inclusion criteria, the patients exhibited an ischaemic diagnostic response to a multistage exercise electrocardiography stress test (> 0.15 mV ST segment depression compared with the resting electrocardiographic tracing) and to a dipyridamole-echocardiography test (transient left ventricular dyssynergy of contraction during infusion of dipyridamole up to 0.84 mg/kg over 10 min), after 3 days' cessation of antianginal treatment. After treatment with oral nisoldipine (10 mg twice daily) was introduced, the patients repeated the two tests, within 18 days of the first evaluation. The dipyridamole-echocardiography test was positive for ischaemia in 12 patients who were not receiving nisoldipine and in eight patients who were receiving the drug (100% and 67% respectively, P < 0.05). In the eight patients who gave positive dipyridamole-echocardiography tests both with and without treatment, dipyridamole time (time to onset of dyssynergy during the test) increased from 7.9 +/- 2.9 min to 10.2 +/- 3.1 min (P < 0.01). In these patients, no significant changes were observed, at ischaemia, in the severity and extent of induced dyssynergy, evaluated as wall motion score index (each of 16 left ventricular segments scored from 1 = normal to 4 = dyskinetic) after treatment (score variations from baseline to ischaemia: 0.20 +/- 0.11 without nisoldipine and 0.16 +/- 0.06 with nisoldipine; NS). Variations in dipyridamole time (arbitrarily considered to be 15 min in the negative dipyridamole-echocardiography test) were significantly correlated with variations in exercise time (duration of exercise to exhaustion or diagnostic positive response on the electrocardiogram): r = 0.75 (P < 0.01). No significant differences were recorded in rate-pressure product (beats/min x mmHg x 100) at peak ischaemia between patients who were or were not receiving nisoldipine, during either the exercise electrocardiography stress test (233 +/- 36 with nisoldipine and 244 +/- 39 without nisoldipine; NS) or the dipyridamole-echocardiography test (147 +/- 21 with nisoldipine and 133 +/- 30 without nisoldipine; NS). Nisoldipine treatment can protect from dipyridamole-induced ischaemia, being associated with a longer stress time, and completely preventing the development of ischaemia in some patients. The therapy-induced changes in ischaemic threshold during the dipyridamole-echocardiography test correlate with variations in exercise tolerance.

Coronary stenosis dilatation induced by L-arginine

L-arginine, a substrate in the production of endotheliumderived nitric oxide (NO), may stimulate the release of NO. L-arginine improves the coronary blood flow response to acetylcholine in patients with normal coronary arteries and hypercholesterolaemia. However, it is unknown whether local administration of L-arginine dilates coronary stenoses in patients with stable angina. This study assessed the effects of L-arginine and D-arginine at the stenotic site in patients with coronary artery disease and stable angina. 15 patients with chronic stable angina, coronary artery disease, and a positive treadmill exercise test ( 0·1 mV ST segment depression) at between 5 and 7 METS with the modified Bruce protocol, were studied in the cardiac catheterisation laboratory of the Hippokration Hospital, Athens University. The protocol was approved by the research ethics committee of the Hippokration Hospital and each patient gave written informed consent. Antianginal medication was stopped 24 h before the study. The patients were allowed to use sublingual glyceryl trinitrate as necessary, but no study was done within 3 h of its administration. None of the study patients had taken glyceryl trinitrate on the day of the study. Following the diagnostic coronary angiogram, an optimum radiographic projection was selected and kept constant for subsequent angiograms. In ten patients (seven male, three female, mean age 58 [SD 8] years) intracoronary infusion of 0·9% saline (2 mL/min) for 2 min was followed by intracoronary infusion of 150 μmol/min of L-arginine for 8 min. In five patients (four male, one female, mean age 61 [10] years) the same protocol was used, substituting 150 μmol/min of D-arginine for L-arginine. The chosen dose and the infusion time of L-arginine administration was consistent with a study showing a response after L-arginine administration in the brachial artery. The arterial segments in each frame were analysed at the Hammersmith Hospital in random order with quantitative computerised analysis, with an automated edge contour detection analysis system. The percentage change in luminal diameter from baseline was calculated at the end of the 8 min infusions and the values for L-arginine and D-arginine and normal saline were compared with Student’s t-test. The infusions of L-arginine and D-arginine did not affect systolic blood pressure (mean [SE]) (L-arginine: mean 152 [7·1] vs 150 [7·2] mm Hg, p=0·82 D-arginine: 154 [11·2] vs 157 [11·6] mm Hg, before and after infusions, respectively, p=0·27). L-arginine administration was associated with significant dilatation of stenoses (11·7 [2·3]%: p=0·004 vs D-arginine, p=0·001 vs normal saline) (figure), but there was no significant change with D-arginine (2·0 [0·04]%) (figure). No patients were receiving longacting nitrates, and the previous antianginal treatment did not affect the response to L-arginine ( -blockers: 11·1 [6·0]%; calcium antagonists 10·5 [4·7]%; -blockers and calcium antagonists 12·5 [3·4]%). Arginine, a semiessential aminoacid serves as the substrate for the enzyme NO synthase, which converts arginine to citrulline and NO, reducing vascular tone. A recent study in experimental models suggested possible beneficial effects of L-arginine administration. Long-term oral therapy with L-arginine reduced endothelial dysfunction and inhibited the development of atherosclerosis, but the mechanisms by which it exerts its vasodilator effect are not completely understood. Possible explanations include an effect on endothelial synthesis and release of NO, and direct or indirect physiological actions on the vascular smooth muscle to augment its responsiveness to NO. In our study a significant dilation was found in coronary stenotic segments after L-arginine administration in patients with coronary artery disease and stable angina. These data suggest that the 25

Nifedipine gastrointestinal therapeutic system versus atenolol in stable angina pectoris

The gastrointestinal therapeutic system formulation of nifedipine enables a once-daily dosing resulting in predictable, relatively constant plasma concentrations. To evaluate the efficacy and safety of this formulation and to compare this with the β-blocker atenolol, we conducted a double-blind, randomised, multi-centre study in 129 male patients with documented exercise induced angina pectoris. After 4 weeks' treatment, nifedipine (60 mg), improved time to onset of 0.1 mV ST-segment depression from 536 s by 72 ± 117 s, time to onset of pain from 619 s by 56 ± 120 s, and total exercise time from 685 s by 40 ± 88 s. Atenolol 100 mg, had a comparable effect, time to onset of 0.1 mV ST-segment depression improved from 496 s by 53 ± 129 s, time to onset of pain from 572 s by 57 ± 118 s, and total exercise time from 653 s by 33 ± 99 s. Between group analysis revealed no statistically significant differences for these exercise parameters. Atenolol, but not nifedipine, significantly reduced heart rate and systolic blood pressure at rest and during exercise ( P < 0.001 between groups), indicating different modes of action of the drugs. With regard to safety, both drugs were generally well tolerated. There were significantly ( P = 0.01) more vasodilation related side effects with nifedipine. These data demonstrate that gastrointestinal therapeutic system formulation of nifedipine and atenolol as once-daily monotherapy are equally effective and safe, but with different effects on exercise parameters.

Comparison of efficacy of nisoldipine, metoprolol, and isosorbide dinitrate in patients with stable exertional angina: a randomized, cross-over, placebo-controlled study

We evaluated the acute antianginal effect of oral nisoldipine (10 mg), metoprolol (40 mg), and long-acting isosorbide dinitrate (20 mg) in 15 patients with stable exertional angina. The patients performed symptom-limited treadmill exercise at 2 h after the administration of placebo (Placebo stages 1 and 2) and each of the active drugs. After Placebo stage 1, the patients were randomized for cross-over evaluation of the acute effect of a single oral dose of placebo (Placebo stage 2), nisoldipine, metoprolol, or long-acting isosorbide dinitrate. All 15 patients developed angina during all of exercise tests and their exercise tests were terminated at the onset of angina. The time until development of 0.1 mV ST segment depression was increased by all three drugs compared to placebo, and it was significantly longer with metoprolol than with isosorbide dinitrate. Similarly, the time to ceasing exercise because of angina was also prolonged by all three drugs. The exercise time was longer with nisoldipine and metoprolol compared to isosorbide dinitrate, but there was no significant difference between nisoldipine and metoprolol. In conclusion, metoprolol and nisoldipine more effectively prolonged exercise compared to long-acting isosorbide dinitrate in patients with stable exertional angina.

Efficacy of Anipamil, a Phenylalkylamine Calcium Antagonist, in Treatment of Angina Pectoris

To evaluate the efficacy of anipamil, a phenylalkylamine calcium antagonist, in treatment of stable angina pectoris, we performed a randomized, double blind placebo-controlled, cross-over study. Inclusion criteria were (a) stable angina pectoris for at least 2 months, (b) an exercise test with > or = 0.1-mV horizontal or downsloping ST-segment depression limited by angina, and (c) at least 10 attacks of angina pectoris in a single-blind 3-week run-in period. Nineteen patients were randomized to enter the study. In 3-week periods, they received either anipamil 80 mg once daily (o.d.), anipamil 160 mg o.d., or placebo. At the end of each period, an exercise test was performed. The number of angina pectoris attacks was significantly reduced during treatment with anipamil 80 mg (p < 0.05) and anipamil 160 mg (p < 0.001) as compared with placebo. Glycerol nitrate consumption was significantly reduced during treatment with anipamil 80 mg (p < 0.01) and 160 mg (p < 0.001) as compared with placebo. During exercise testing, the load (W) at start of angina was significantly increased during treatment with anipamil 80 mg (p < 0.01) and 160 mg (p < 0.05) as compared with placebo. Heart rate (HR) at 0.1 mV ST-segment depression was increased during treatment with anipamil 80 mg (p < 0.001). Few adverse events were reported.