Improvement of myocardial ischaemia by lipid lowering drugs.
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Cholesterol↗
Biomedical subjects
D Tzivoni
Publications and source records attributed to D Tzivoni.
Efficacy of mibefradil compared with amlodipine in suppressing exercise-induced and daily silent ischemia: results of a multicenter, placebo-controlled trial.
BACKGROUND: Mibefradil is a new benzimidazolyl-substituted tetraline-derivative calcium antagonist. Its vasodilatory activity combined with an ability to lower heart rate without negative inotropic effects as well as its long duration of action make it a promising anti-ischemic agent. METHODS AND RESULTS: Three hundred nine patients with coronary artery disease, stable angina pectoris, and positive exercise tests were randomized to receive mibefradil (50, 100, or 150 mg), amlodipine (10 mg), or placebo. The anti-ischemic effects of mibefradil on exercise test and silent ischemia parameters were assessed. At doses of 100 and 150 mg, mibefradil increased exercise duration (by 55.5 and 51.0 seconds, respectively; P<.001 for both), increased time to onset of angina (by 98.3 and 82.7 seconds, respectively; P<.001), and increased time to 1-mm ST depression (by 81.7 and 94.3 seconds, respectively; P<.001). By comparison, a 10 mg/d dose of amlodipine significantly improved only time to onset of angina (treatment effect: 38.5 seconds, P=.036). Mibefradil 100 mg and 150 mg decreased the number of episodes of silent ischemia (treatment effects: -3.1 and -3.6, respectively; P<.001) and the duration of silent ischemia (treatment effects: -9.2 minutes, P=.048, and -14.6 minutes, P=.002, respectively). The decrease in the number of episodes of silent ischemia was also statistically significant in the group receiving 10 mg of amlodipine (-1.5; P=.036). CONCLUSIONS: Once-daily doses of 100 and 150 mg mibefradil were effective in improving exercise tolerance and reducing ischemic episodes during ambulatory monitoring in patients with coronary artery disease.
Adult↗
Antianginal and anti-ischemic effects of mibefradil in the treatment of patients with chronic stable angina pectoris.
Five placebo-controlled, double-blind, multicenter, parallel-design studies were performed to evaluate the antianginal and anti-ischemic characteristics of the novel T-channel-selective calcium antagonist, mibefradil, in the treatment of patients with chronic stable angina pectoris. Of the 5 studies, 2 were monotherapy dose-finding trials and 3 were conducted in patients receiving background antianginal therapy: either beta blockers (2 studies) or long-acting nitrates (1 study). A total of 865 patients were randomized to 1 of 4 mibefradil dose groups (25, 50, 100, and 150 mg; n = 565) and placebo (n = 300). The antianginal and anti-ischemic effects of mibefradil were assessed across all 5 studies by evaluating exercise tolerance test variables, weekly number of anginal attacks and short-acting nitroglycerin consumption, and in both dose-finding studies, the number and total duration of silent ischemic episodes (48-hour Holter monitoring). A statistically significant increase in exercise duration was achieved in 3 of 5 studies with the 50-mg dose of mibefradil and in 3 of 3 studies with the 100-mg dose of the compound over the effects observed in the placebo groups. A significant delay in time to onset of ischemia during exercise was induced in all studies with the 50- and 100-mg doses of mibefradil. The 25-mg dose of mibefradil was not significantly better than placebo, and the effects of the 150-mg dose of the compound were similar to those observed with the 100-mg dose. Across all studies, a dose-related decrease was observed in the number of weekly anginal attacks and in weekly nitroglycerin consumption. Similarly, a significant dose-related decrease in the number and duration of silent ischemic episodes was observed during Holter monitoring for 48 hours in the 2 dose-finding studies. The antianginal and anti-ischemic effects were associated with a dose-related decrease in heart rate and double product both at rest and at exercise termination. Treatment with the 50- and 100-mg doses of mibefradil was found to be well tolerated and safe compared with placebo, a finding that held true for patients on chronic beta-blocker or long-acting nitrate therapy. Taken together, these studies indicate that mibefradil is an effective and well-tolerated once-daily treatment for chronic stable angina pectoris at doses of 50 and 100 mg, which are the lowest and highest effective doses of the compound, respectively.
Aged↗
Mibefradil in the treatment of chronic stable angina pectoris: comparative studies with other calcium antagonists.
The ability of mibefradil, a new T-channel-selective calcium antagonist, to improve exercise tolerance and silent ischemic parameters in patients with chronic stable angina was compared in 3 separate trials with 2 other commonly used calcium antagonists: diltiazem SR (120 mg/twice daily) and amlodipine (10 mg/day). Compared with amlodipine, mibefradil 100 mg given once daily over a 3-week period resulted in a statistically significantly larger increase from baseline in total exercise tolerance test (ETT) duration (treatment difference of 40.9 sec, p = 0.04), time to onset of angina (treatment difference 61.2 sec, p < 0.001), and time to onset of ischemia (treatment difference of 54.4 sec, p = 0.004). The decrease in weekly anginal episodes was 58% with mibefradil versus 19% with amlodipine, and the reduction in nitroglycerin consumption was 58% with mibefradil versus a 10% increase with amlodipine. The decrease in the number of silent ischemic episodes detected by a 48-hour Holter recording was significantly larger (p = 0.03) with mibefradil 100 mg (88%) compared with amlodipine 10 mg (38%). Similarly, a larger decrease in the duration of silent ischemia was observed with mibefradil (69%) compared with that seen with amlodipine (38%). The preliminary results of a second trial comparing mibefradil with amlodipine were consistent with the first demonstrating that the improvement for all 3 ETT parameters was larger for mibefradil (ETT duration: 55.2 sec; delay in onset angina: 74.2 sec; time to onset of ischemia: 63.6 sec), but in this trial the treatment differences did not reach statistical significance. In the trial comparing mibefradil (100 mg once daily) with diltiazem SR (120 mg twice daily), both compounds had equivalent effects on all ETT parameters tested. Mibefradil produced a 21% increase in exercise duration compared with a 20% increase with diltiazem. Although mibefradil yielded larger increases in the time to onset of angina and the time to onset of 1-mm ST-segment depression (42% and 38%, respectively) than did diltiazem (34% and 25%, respectively), the treatment differences did not reach statistical significance. Both mibefradil and diltiazem SR were associated with at least a 70% reduction from baseline in anginal frequency and nitroglycerin consumption. Mibefradil-treated patients showed greater decreases in heart rate and the rate-pressure product at each stage of the ETT than patients treated with amlodipine or diltiazem SR. All 3 drugs were well tolerated. However, compared with mibefradil, amlodipine and diltiazem SR produced a higher incidence of leg edema. In conclusion, the effectiveness of mibefradil in improving all 3 ETT parameters was greater than that of amlodipine and equivalent to that of diltiazem SR. Moreover, mibefradil provided greater reductions in the heart rate and cardiac workload than did the other 2 drugs.
Adult↗
Treatment of spontaneous coronary artery dissection: report of three cases.
Spontaneous coronary artery dissection is an extremely rare cause of myocardial infarction. It has been reported mainly in young women during or after pregnancy. The prognosis and treatment of coronary dissection are not clear. We report three cases of spontaneous coronary artery dissection in young women. One of them was pregnant and one was 2 weeks after delivery. The dissection involved the left anterior descending artery (LAD) in two cases and the left main coronary artery in one case. There was no evidence of atherosclerosis on angiography or intracoronary ultrasound in any of the patients. Two of the women were treated by stent implantation with excellent results. This is the first known report of successful coronary stenting of spontaneous coronary artery dissection. The pregnant woman was not a candidate for stent implantation and underwent implantation of the left internal mammary to the LAD without cardiopulmonary bypass. She completed her pregnancy uneventfully.
Adult↗
Assessment of ischemic changes by ambulatory ECG-monitoring: comparison with 12-lead ECG during exercise testing.
The accuracy of commercially available ambulatory electrocardiographic monitoring (AEM) systems for reproducing ischemic changes has been questioned. Since these systems are widely used for evaluation of ST-segment changes, both for prognostic purposes and for assessment of the efficacy of antiischemic drugs, such doubts must be clarified. For this purpose, we recorded electrocardiograms (ECGs) during exercise testing, using split leads, simultaneously with a 12-lead electrocardiograph and with the Marquette AEM recorder. We studied 29 patients with proven coronary artery disease and positive exercise tests and 19 individuals with low likelihood of coronary artery disease and negative stress tests. All 29 patients who had ST-segment depression during exercise as recorded on the 12-lead ECG had ST-segment depression in at least one of the three AEM leads (resembling the V5, V3, and aVF leads of the 12-lead system). The maximal degree of ST-segment depression with AEM was similar to 12-lead ECG (2.3 mm and 2.1 mm, respectively). The best lead for ischemia detection with AEM was the V5 type, which detected ischemic changes in 26 of the 29 patients, while the 12-lead V5 detected ischemia in 24 patients. The inferior AEM lead detected ischemia in only 4 patients, while the aVF lead of the 12-lead ECG detected ischemia in 23 patients. Of the 19 patients with negative exercise tests only 1 patient had a 1-mm ST-segment depression on AEM. Thus, of the 48 patients studied, similar responses were observed in 47. The results of indicate that the Marquette AEM system is as accurate as the 12-lead ECG in detecting ischemic changes and in assessing their severity.
Aged↗
Attenuation of severity of myocardial ischemia during repeated daily ischemic episodes.
OBJECTIVES: The purpose of this study was to assess whether the severity of myocardial ischemia would be attenuated by repeated daily ischemic episodes, recorded by ambulatory electrocardiographic monitoring (AEM). BACKGROUND: Repetitive ischemic episodes induced by brief coronary occlusions in animal experiments and in humans during balloon coronary angioplasty produce preconditioning. We wanted to assess whether this phenomenon also exists during daily ischemic episodes. METHODS: Twenty-one patients with known coronary artery disease and ischemia on exercise testing and AEM were requested to walk a distance known to have previously caused myocardial ischemia on three consecutive occasions. Walking time was approximately 15 min and was followed by 5 min of rest. RESULTS: Mean maximal heart rate during the three walks was similar; however, the mean maximal ST segment depression decreased significantly from 2.21 mm during the first walk to 1.61 mm and 1.43 mm, respectively, on the second and third walks (p = 0.001). Ischemia duration was also significantly reduced on the second and third walks by 56% from 514 to 228 and 254 s, respectively (p = 0.012). The heart rate at onset of ischemia (ischemic threshold) increased from 99 beats/min on the first walk to 101 beats/min on the second walk and to 106 beats/min on the third walk (p = 0.058). CONCLUSIONS: This study demonstrated attenuation of myocardial ischemia with an associated increase in ischemic threshold in patients with repeated and adjacent ischemic episodes. This form of myocardial protection is likely to be encountered in patients during ordinary activity and may represent the clinical counterpart of myocardial preconditioning.
Coronary Disease↗
Distinguishing between the warm-up phenomenon and training during repeated exercise testing.
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Adaptation, Physiological↗
Comparison between metoprolol orally osmotic once daily and metoprolol two or three times daily in suppressing exercise-induced and daily myocardial ischemia.
Metoprolol is a widely used anti-ischemic drug with a relatively short half-life. To improve patient' compliance and to provide 24-hour coverage, its once daily ORally OSmotic (OROS) formulation was developed. In this multicenter double-blind study, the anti-ischemic effects of metoprolol OROS given once daily at doses of 190 and 285 mg were compared to the regular metoprolol formulation of 100 mg 2 or 3 times daily. Sixty-five patients with stable coronary artery disease, positive exercise tests, and ischemic episodes during daily activity as recorded by ambulatory electrocardiographic monitoring (AEM) were included. In the OROS group, 23 patients completed all 3 treatment periods. In these patients, the number of myocardial ischemic episodes decreased from 239 on placebo to 128 during the 190 mg/day dose (p < 0.0001) and to 86 during the 285 mg/day treatment period (p < 0.0001). In the metoprolol group, there were 204 episodes at baseline and 142 and 140 during the 100 mg 2 or 3 times daily treatment periods (p < 0.0001 for both). During exercise testing, time to 1-mm ST depression increased significantly in the OROS group from 6.3 minutes at baseline to 7.1 and 9.6 minutes during 190- and 285-mg treatment periods. In the metoprolol group, it increased from 5.8 to 7.2 and 8.2 minutes, respectively. Both formulations of metoprolol were well tolerated. The OROS formulation was highly effective in suppressing daily and exercise-induced ischemia and exerted its effect throughout the 24-hour period.
Administration, Oral↗
Improvement in ischemic parameters during repeated exercise testing: a possible model for myocardial preconditioning.
Repeated short episodes of coronary occlusion in experimental animals, and in humans during balloon angioplasty, cause myocardial preconditioning. This study examines whether myocardial ischemia induced by repeated exercise testing can reduce the extent of ischemia induced by subsequent exercise tests. Twenty-six patients with positive stress tests underwent 3 treadmill exercise tests at 30-minute intervals. Two additional tests were performed on each of the previous 2 days in order to eliminate and/or reduce the training effect. All 3 exercise tests were of similar work load. In spite of that, total ischemic time was markedly shortened from 633 to 399 seconds (p <0.0001) as well as the recovery time from 259 to 126 seconds (p <0.0001) between the first and the second tests. There was no further improvement on the third test. Time to 1-mm ST depression was prolonged from 487 to 593 seconds (p = 0.004) and double product at 1-mm ST depression was increased in the second test from 20,322 to 22,325 mm Hg/second (p = 0.008), implying a higher ischemic threshold. An improvement of > or = 10% in < or = 1 ischemic parameter was observed in 25 of the 26 patients and in > or = 2 of the ischemic parameters in 76% of the patients. Improvement in ischemic parameters develops during repeated exercise induced ischemia in most patients. We suggest that this phenomenon, which was previously known as "warm up," is the clinical counterpart of myocardial preconditioning which develops not only during ischemia caused by reduction in coronary flow, but also during demand-induced ischemia.
Coronary Angiography↗
Detection and significance of myocardial ischemia in women versus men within six months of acute myocardial infarction or unstable angina. The Multicenter Myocardial Ischemia Research Group.
Ischemia detection after an acute coronary event predicts subsequent cardiac events. However, gender-related aspects in the prevalence and prognostic significance of ischemia detection after an acute coronary event have not been reported. Noninvasive tests, which included resting 12-lead electrocardiogram (ECG), 24-hour ambulatory ECG, exercise ECG, and thallium-201 stress scintigraphy were performed in 936 stable patients (224 women and 712 men) 1 to 6 months (average 2.7) after an acute coronary event (i.e., myocardial infarction or unstable angina). Primary end points during an average follow-up of 23 months included cardiac death, nonfatal myocardial infarction, and unstable angina, while restricted end points included the first 2. Ischemia detection was significantly less frequent among women than among men on 24-hour ambulatory ECG, exercise ECG, and thallium-201 stress scintigraphy. Primary end points occurred in 19.2% of women and in 19% of men, and restricted end points occurred in 5.8% of women versus 8%. of men (p = NS). Cox analyses revealed that gender and its interaction with each of the ischemia tests did not contribute to the prediction of the primary or restricted end points. We conclude that in stable patients 1 to 6 months after an acute coronary event, ischemia detection by noninvasive tests was significantly less prevalent in women than in men. However, subsequent cardiac event rates in women were similar to those observed in men, and there was no gender-ischemic detection interaction regarding subsequent events.
Angina, Unstable↗
Effects of transdermal nicotine patches on ambulatory ECG monitoring findings: a double-blind study in healthy smokers.
The cardiovascular effects and safety of transdermal nicotine patches were assessed in 50 healthy smokers using repeated 48 hour ambulatory electrocardiographic monitoring as a part of a smoking cessation program. Following baseline measurements, subjects were randomized to active (n = 25) or placebo (n = 25) treatment groups for a period of 2 weeks. Twenty-two patients in each group completed the trial. During the treatment period, subjects also received behavioral supportive therapy. Heart rate and blood pressure were significantly reduced relative to baseline both groups. In the active treatment group, mean values at baseline and after 2 weeks of double-blind treatments were as follows: heart rates, 74.0 and 71.3 beats/min, respectively; systolic blood pressure, 108.9 and 106.9 mmHg; and diastolic blood pressure, 69.7 and 68.2 mmHg, respectively. Values for the placebo group were as follows: heart rate, 73.2 and 69.6 beats/min; systolic blood pressure, 110.6 and 105.3 mmHg; diastolic blood pressure, 71.4 and 70.5 mmHg. The confidence intervals of the mean for the differences between the groups are as follows: heart rate, -4.0 +8.2; systolic blood pressure, -6.7, +10.1; diastolic blood pressure, -7.9, +3.9. There were no changes in the frequency of atrial or ventricular arrhythmia as documented by repeated 48 hour ambulatory ECG recordings from baseline period before stopping smoking compared with the treatment period in the active as well as in the placebo groups. No ischemic events were detected in any of the volunteers during either the baseline or treatment periods. As a measure of smoking abstinence, we assessed the level of carbon monoxide in expired air; in the active group, the mean levels fell from 14.2 to 4.4 ppm after smoking cessation and in the placebo group from 13.2 to 4.2 ppm. The mean urine cotinine level fell from 8.18 mmol/l at baseline to 5.74 mmol/l after 2 weeks of treatment in the active group and from 8.78 to 3.93 mmol/l in the placebo group. The number of cigarettes smoked per week in both treatment groups was significantly reduced: from 175.2 to 8.4 for the active group and from 136 to 8.6 for the placebo group. Eleven out of 22 subjects in each group quit smoking completely. Smoking withdrawal symptoms during the first week of treatment were more severe in the placebo group than in those on active treatment. There were no significant side effects in either the placebo or the active treatment groups. These results indicate that nicotine delivered by transdermal system is free of cardiac adverse effects in healthy volunteers.
Administration, Cutaneous↗
Dobutamine-induced ST segment elevation and ventricular fibrillation with nonsignificant coronary artery disease.
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Arrhythmias, Cardiac↗
Circadian variations in total ischaemic burden and ischaemic threshold.
Myocardial ischaemia in daily life varies according to a circadian rhythm and is induced by many factors, including both increased myocardial oxygen demand and changes in coronary tone. In most patients, ischaemia is induced by a combination of different contributing factors, although the relative contribution of each mechanism varies from patient to patient. Moreover, in the same individual, various episodes may be due to different mechanisms. The relative contributions of increased myocardial oxygen demand and decreased ischaemic threshold to the development of ischaemia in daily life can be assessed by continuous ambulatory ECG monitoring which may help to optimize medical anti-ischaemic therapy.
Circadian Rhythm↗
Severe hypotension induced by combination of dobutamine and dipyridamole.
Pharmacologic testing with dobutamine or dipyridamole in conjunction with echocardiography has become an accepted method for diagnosis of coronary artery disease (CAD). The sensitivity of dobutamine echo ranges from 68 to 86%, and of dipyridamole from 53 to 69% for diagnosis of CAD. Our purpose was to investigate whether the addition of dipyridamole to dobutamine, which may improve the test sensitivity, is safe. Ten patients with low probability of CAD underwent dobutamine echo; 5 were control patients and 5 patients had low dose dipyridamole added at the maximal dose of dobutamine. Four of the latter patients had severe hypotension, while no hypotension was observed in control patients. Our findings suggest that this combination of dobutamine and dipyridamole can be hazardous and should not be used in patients with suspected CAD.
Adult↗
The role of coronary tone and increased demand in daily ischemia.
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Coronary Vessels↗
Analysis of HLA and disease susceptibility: chromosome 6 genes and sex influence long-QT phenotype.
The long-QT (LQT) syndrome is a genetically complex disorder that is characterized by syncope and fatal ventricular arrhythmias. LQT syndrome, as defined by a prolonged electrocardiographic QT interval, has a higher incidence in females than in males and does not exhibit Mendelian transmission patterns in all families. Among those families that are nearly consistent with Mendelian transmission, linkage between a locus for LQT syndrome and the H-ras-1 locus on the short arm of chromosome 11 has been reported in some families but not in others. Earlier analyses suggesting that LQT syndrome might be caused by a gene in the HLA region of chromosome 6 were not confirmed by standard linkage analyses. Here, we present an analysis of HLA haplotype sharing among affected pedigree members, showing an excess of haplotype sharing in a previously published Japanese pedigree and possibly also in 15 families of European descent. The haplotypes shared by affected individuals derive from both affected and unaffected parents. In an analysis of independent (unrelated) HLA haplotypes, we also found a nonrandom distribution of HLA-DR genes in LQT syndrome patients compared with controls, suggesting an association between the LQT phenotype and specific HLA-DR genes. Our data indicate that DR2 has a protective effect and, particularly in males, that DR7 may increase susceptibility to the LQT syndrome. Thus, LQT syndrome may be influenced by genes on chromosomes 11 and 6, possibly with a sex-specific effect. These results provide a model for an effect of HLA-region genes inherited from either parent on the expression of an illness that may be determined principally by alleles at loci not linked to HLA.
Chromosomes, Human, Pair 6↗
Ischemic threshold during two exercise testing protocols and during ambulatory electrocardiographic monitoring.
OBJECTIVES: The aim of this study was to examine the dependence of the ischemic threshold during exercise testing on the exercise protocol employed and to determine the relation between the ischemic thresholds observed during exercise and during daily activity. BACKGROUND: The ischemic threshold (heart rate at 1-mm ST segment depression) during daily activity has been reported to be lower than that observed during exercise testing. Recent reports have hypothesized that this difference is probably dependent on the exercise protocol employed. METHODS: Twenty-two patients with known coronary artery disease, not receiving antianginal medications, were evaluated by repeated exercise testing according to the Bruce and the modified Davidson protocols and by 48-h ambulatory electrocardiographic monitoring. RESULTS: Although the heart rate at 1-mm ST segment depression was somewhat lower with the Davidson than with the Bruce protocol (112 +/- 14 vs. 115 +/- 14 beats/min), the rate-pressure product at 1-mm ST segment depression was similar during the two protocols (16,900 +/- 4,000 vs. 17,700 +/- 3,600). The mean heart rate (100 + 12 beats/min) at 1-mm ST segment depression during ambulatory ischemic episodes (n = 137) was significantly lower than that observed during both exercise protocols (p < 0.001 for both comparisons). CONCLUSIONS: Exercise-induced ischemia occurs at a relatively fixed threshold that is mainly dependent on myocardial oxygen demand and is independent of the exercise protocol employed. Ischemia on ambulatory monitoring, however, occurs at a much more variable threshold that is commonly lower than that observed during exercise and is therefore dependent on other factors in addition to increased demand.
Aged↗