Dan Tzivoni

Noninvasive diagnosis of coronary artery disease: the cardiokymographic stress test.

Stress–induced abnormalities of regional left ventricular wall motion were assessed by cardiokymography (CKG) during the course of maximal treadmill exercise tests in 157 patients, of whom 122 subsequently underwent coronary angiography. Seventy patients had significant angiographic coronary artery disease and 52 were normal. Forty–one of the 70 patients developed >0.1 mV ST–segment depression (ECG sensitivity 59%) and 52 of 70 patients developed abnormal systolic outward motion by CKG (CKG sensitivity 74%). Among the 52 normals, 36 had negative ECG stress tests (ECG specificity 69%) and 49 had normally sustained systolic inward motion by CKG (CKG specificity 94%). The stress CKG was normal in 15 of the 16 false–positive stress ECGs; the stress ECG was correctly normal in two of the three false–positive stress CKG tests. Only one normal patient had concordantly false–positive ECG and CKG tests. The predictive accuracy of concordant ECG and CKG interpretations was, therefore, higher than either test alone.These data suggest that regional wall motion abnormalities, which are sensitive and specific markers of myocardial ischemia, may be detected noninvasively by CKG. We concluded that CKG helps identify falsepositive and false–negative ECG stress tests and improves the diagnostic accuracy of stress testing for detection of coronary artery disease.

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.

Ventricular pacing in atypical ventricular tachycardia

Ventricular pacing was effective in controlling recurrent bouts of atypical ventricular tachycardia (Torsade de Pointes), in four patients. This arrhythmia was induced by quinidine or disopyramide therapy. Isoproterenol, which is the usually recommended therapy, was ineffective in two of the patients and was considered hazardous in two others. We consider ventricular pacing as a safe and reliable method for treatment of AVT, which should be applied if isoproterenol is ineffective or contraindicated.

Analysis of regional ischemic left ventricular dysfunction by quantitative cineangiography.

The ability of left ventricular angiography to detect regional ischemic dysfunction was assessed in 10 closed-chest dogs during the course of acute balloon occlusion of the anterior descending coronary artery. During the 2-minute period of occlusion, serial cineangiography revealed a sequence of wall motion abnormalities over the anteroapical region almost identical to that observed using directly implanted gauges. This sequence consisted of progressive reduction in regional systolic shortening with eventual replacement by systolic expansion. These changes preceded both electrocardiographic ST-segment and hemodynamic alterations, and were readily observed by gross subjective inspection of the cineangiograms, but with an intraobserver variability of 22%. Frame-by-frame motional analysis of the ventricular perimeter relative to its centroid of mass allowed more precise characterization of regional dysfunction. These data are consistent with previous studies demonstrating that regional wall motion abnormalities are both sensitive and specific markers of acute ischemia, and support the use of computerized left ventricular angiography for the quantitative assessment of clinical ischemic dysfunction.

High fidelity ECG in the diagnosis of occult coronary artery disease: a study of patients with normal conventional ECG.

High fidelity (HF) electrocardiography (ECGY) was performed on four groups of patients with a normal resting electrocardiogram (ECG). Two groups (A and B) consisted of normal subjects over or under the age of 40, while the other two groups of patients (C and D) underwent coronary arteriography because of chest pain. HR ECG components within the initial portion of the QRS complex were significantly more common among patients with advanced coronary disease. The difference between the normal groups and the group with documented coronary artery disease (CAD) became more significant when the number of leads showing the HF ECG components was counted. Precordial leads were more sensitive in predicting the presence or absence of CAD than limb leads. HF ECG components in the terminal portion of the QRS complex did not differentiate between normals and patients with coronary artery disease, unless the number of leads showing these HF ECG components was considered. It seems that abnormal HF ECG components can point to minor areas of fibrosis caused by coronary artery disease even if the resting conventional ECG is normal.

Acute and long-term effects on myocardial ischemia of intermittent and continuous transdermal nitrate therapy in stable angina.

The aim of this study was to compare the efficacy and safety of continuous and intermittent transdermal nitrate therapy using ambulatory electrocardiographic (Holter) monitoring. Eighty-five patients with stable angina pectoris and positive exercise test results participated during their concomitant antiischemic medication in a randomized open trial lasting 12 weeks. After a 3-week run-in period with continuous therapy (10 mg/24 hours), patients were randomized to either continuous- or intermittent-therapy groups. In the intermittent-therapy group the patients removed their patch at night (the mean patch-off period was 10 hours). Forty-eight-hour Holter monitoring was performed in each patient after randomization, and again after 2 and 12 weeks. Eighteen patients withdrew, 9 in each group. A total of 11,194 hours of electrocardiography were recorded and 607 ischemic episodes were detected, of which 79% were asymptomatic and 95% appeared during daytime. The number of ischemic episodes per 48 hours with intermittent therapy was 3.1 +/- 0.7 (mean +/- SEM) after randomization, 1.8 +/- 0.4 at 2 weeks and 2.0 +/- 0.6 at 12 weeks. With continuous therapy the respective numbers were 3.8 +/- 1.1, 3.5 +/- 0.9 and 4.2 +/- 1.2. The differences were not statistically significant because a large number of patients (30%) had no ischemic episodes on Holter recording. However, when examining 47 patients with episodes during the study, the number of episodes was significantly reduced in the intermittent-therapy group (p less than 0.05 at 12 weeks). The changes in asymptomatic and symptomatic episodes were concordant. No changes and differences between the treatment groups were seen in nighttime episodes.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

Comparison Between Silent and Symptomatic Ischemia During Exercise Testing in Patients with Coronary Artery Disease

Among 544 patients with proven coronary disease (299 with pathologic coronary arteriograrris and 241 postmyocardial infarction) all of whom had an abnormal treadmill test (ST depression of 1.0–4.0 mm), 253 patients (46.9%) had no angina (silents), whereas 287 (53.1%) had chest pain (symptomatics). Age, sex, previous myocardial infarction, medical therapy, frequency of single vessel and multivessel diseases and the average number of diseased coronary arteries, as well as the heart, rate, blood pressure, and double product at the beginning of the treadmill test and the maximal ST depression, were similar in the silents and the symptomatics. However, in those with silent ischemia, 1 mm ST depression appeared later and at a higher heart rate; they had longer exercise duration, reached higher peak double product, and the postexercise recovery time was shorter than in symptomatic patients. This distinction between “silents” and “symptomatics” was even more pronounced in the analysis of 288 of the patients with an ST depression of only 1.0–1.9 mm (“mildly abnormal” treadmill test). On the other hand, in the 252 patients with ≥2.0 mm ST depression (“strongly abnormal” treadmillt test) this difference disappeared, and all the treadmill variables of the “silents” and the “symptomatics” were found to be similar. It seems, therefore, that if all patients with abnormal treadmill tests are grouped together, irrespective of the degree of ST depression or if only patients with mildly abnormal exercise tests are studied, patients with silent ST depression during exercise testing have milder ischermic parameters during the test than symptomatics. However, according to the similar ischemic parameters observed in the silent and the symptomatic “strongly abnormal” treadmill tests, in such patients the silent and the symptomatic tests express a similar degree of ischemia.

Cardioversion-induced fulminant ischaemic hepatitis.

Ischaemic hepatitis, although infrequent, should be considered as a cause of fulminant hepatitis in patients with congestive heart failure. Ischaemic hepatitis is characterized by a marked rise in transaminases occurring within 24-48 h of circulatory failure. Cardioversion of atrial fibrillation to sinus rhythm is associated with an increase in cardiac output in most patients; however, a transient reduction in cardiac output may occur in more than one-third of patients, and may therefore induce ischaemic hepatitis. This is the first report of fulminant ischaemic hepatitis as a complication of cardioversion of atrial fibrillation.

A second zone of compensation during atrial premature stimulation: Evidence for decremental conduction in the sinoatrial junction

125 consecutive patients with premature atrial stimulation were studied. Three demonstrated sinus node return cycles that were fully compensatory following premature atrial stimuli delivered early in diastole. This second zone of compensation was unaccompanied by significant alterations in the post-return cycle lengths or in P-wave morphology of the return cycle. To account for the occurrence of a complete compensatory pause following very early premature atrial depolarizations, we consider the possibility that retrograde conduction of the early atrial premature depolarization (APD) in the sinoatrial junction was delayed for a sufficient length of time to allow the sinus node to depolarize spontaneously on schedule. Collision between the APD and sinus beat would then occur despite the marked prematurity of the APD. Thus, the early APD had encountered the relative refractory period of the sinoatrial junction, suggesting that decremental conduction takes place within the sinoatrial region in man. These findings imply that there is the potential for reentry in the region of the human sinoatrial junction.