Herman O. Klein

The influence of verapamil on serum digoxin concentration.

The-effect of verapamil on the pharmacokinetics of digoxin was studied in 49 patients with chronic atrial fibrillation. A dose of 240 mg/day of verapamil was given to the patients who were receiving a stable dose of digoxin. Serum digoxin levels rose from 0.76 ± 0.54 ng/ml (mean ± SD) to 1.31 ± 0.54 ng/ml during verapamil treatment (p < 0.0005). This effect was dose-dependent, as shown in seven subjects who received 160 mg and then, 240 mg of verapamil: There was a stepwise rise in serum digoxin concentration from a control value of 0.60 ± 0.11 ng/ml to 0.84 ± 0.18 ng/ml and 1.24 ± 0.40 ng/ml, respectively (p < 0.01 for both steps). The effect of verapamil developed gradually within the first few days in seven subjects in whom serum digoxin concentration reached, within 7 days, 90% of the increase observed 14 days after onset of verapamil. Renal digoxin clearance decreased significantly (26.1 ± 9.7 vs 55.1 ± 12.3 ml/min, p < 0.005) in six patients in whom serum digoxin concentration increased. It did not change in one patient in whom serum digoxin concentration was not influenced by verapamil. Creatinine clearance did not change in any of these seven. The same effects on digoxin clearance were observed in three normal subjects. Among the 49 patients, verapamil resulted in the development of signs and symptoms that suggested digitalis toxicity in seven. Verapamil significantly increases serum digoxin concentration. The process is dose-dependent and gradual, and it is at least partially explained by reduced renal excretion without reduction in glomerular filtration. The dose of digoxin may need readjustment in patients who are concomitantly receiving verapamil.

The early recognition of right ventricular infarction: diagnostic accuracy of the electrocardiographic V4R lead.

The sensitivity and specificity of ST-segment elevation in the right precordial lead V4R as an early indicator of right ventricular infarction were examined in a consecutive series of 110 patients admitted for acute inferior myocardial infarction. The sensitivity was 82.7%, the specificity 76.9% and the positive predictive value 70% in 58 patients with right ventricular infarction documented by autopsy or a combination of radionuclide ventriculography and one or more of the following tests: echocardiography, technetium- 99m pyrophosphate scintigraphy and hemodynamic monitoring. The negative predictive value was 87.7%. Because of its simplicity and its high sensitivity and specificity, recording of V4R should be an intrinsic part of the early evaluation and electrocardiographic examination of acute inferior wall infarction.

Inefficacy of Digitalis in the Control of Heart Rate in Patients With Chronic Atrial Fibrillation: Beneficial Effect of an Added Beta Adrenergic Blocking Agent

The role of digoxin and the new beta adrenergic blocking agent, timolol, in controlling heart rate at rest and during exercise was investigated in 28 patients with chronic atrial fibrillation. Digoxin failed to prevent excessively rapid heart rates during mild to moderate exercise. Increasing digoxin blood levels from a mean of 0.6 to 1.8 ng/ml had no effect on heart rate either at rest or during exercise. The addition of timolol, 20 to 30 mg/day, resulted in a satisfactory and significant attenuation of the rapid heart rates both at rest and during exercise. Heart rates at rest were 91 and 98 beats/min in the patients with low and high digoxin dosage and rose to 135 and 139 beats/min, respectively, during exercise. Timolol reduced the heart rate to 67 at rest and to 92 beats/min during exercise. The effect of beta adrenergic blockade at rest was less pronounced in patients whose initial heart rates were below 90 beats/min. Digoxin alone may not suffice to control excessive heart rate in patients with chronic atrial fibrillation. The additional beta adrenergic blockade actually normalizes the heart rate response in these patients.

Verapamil improves exercise capacity in chronic atrial fibrillation: Double-blind crossover study

Oral verapamil has previously been shown to reduce heart rate at rest and during mild exercise in chronic atrial fibrillation. Its efficacy in improving cardiovascular performance at higher levels of exercise and its safety were investigated in a prospective, randomized, placebo controlled double-blind study preceded by an open label titration phase in 20 digitalized patients with chronic atrial fibrillation. Maximal exercise capacity was improved (from 522 +/- 257 to 806 +/- 348 work units, p less than 0.0005) when tested by a standardized multistage ergometry exercise test. Heart rate was also reduced at rest, at the end of 3 minutes of 300 KPM exercise, and at the point of maximal exercise. Blood pressure and double product were also reduced. Its efficacy and safety may make verapamil the treatment of choice in chronic atrial fibrillation.

Verapamil and digoxin: Their respective effects on atrial fibrillation and their interaction

Abstract Although digitalis has long been used in the management of patients with atrial fibrillation (AF), it does not block the excessive increase in ventricular rate which occurs in such patients during mild exercise; in contrast, this inappropriate response is effectively blocked by verapamil. During regular sinus rhythm, the atrioventricular (A-V) node works well as a delaying structure (the P-R interval), and the ventricular rate is a function of the sinus rate only; however, in AF, the A-V node has to adopt the role of a filter for numerous wave fronts of activity, a function it fulfills poorly, especially during the enhanced sympathetic responses and decreased vagal tone that accompany exercise. In patients with AF, during exercise, these autonomic alterations override the vagal effects of digitalis on the A-V node, but verapamil remains effective by virtue of its direct action on the slow channel ionic fluxes within the A-V nodal cells. The beneficial effect of verapamil on ventricular rate is accompanied by a significant improvement in maximal exercise capacity in patients with AF receiving long-term oral verapamil therapy; thus, it appears superior to digoxin in the treatment of chronic AF. Verapamil significantly increases serum digoxin concentration by reducing renal and nonrenal digoxin clearance and, possibly, by reducing its volume of distribution. Serum digoxin concentrations also are increased by nifedipine. The clinical implications of these interactions are unclear; at present it is recommended that the dose of digoxin be reduced when therapy with a calcium antagonist is given concomitantly.

The acute hemodynamic effects of intravenous verapamil in coronary artery disease. Assessment by equilibrium-gated radionuclide ventriculography.

The acute hemodynamic effects of an i.v. bolus of verapamil, 0.1 mg/kg or 0.06–0.075 mg/kg, were examined by serial radionuclide studies in 46 patients with coronary artery disease. In 20 patients with ejection fractions (EFs) > 35% (group 1A), verapamil, 0.1 mg/kg given over 1–1½ minutes, had a biphasic effect: first, a transient decrease in EF accompanied by increased left ventricular (LV) volumes and cardiac output equivalents; then, an overshoot of EF to values above control, accompanied by a decrease in peripheral vascular resistance and a drastic decrease in LV volumes, while cardiac output equivalent remained slightly elevated. In eight patients with EFs < 35% (group 1B), only the first effect on EF was noted. In 10 patients with EFs > 35% (group 2), verapamil, 0.06–0.075 mg/kg, exerted qualitatively similar but milder effects on hemodynamic function. Finally, verapamil, 0.1 mg/kg given more slowly, over 2–2½ minutes, produced no significant changes in EF or LV volumes in another eight patients (group 3). The acute effects of verapamil are thus both time-related and dose-dependent. They are also related to the baseline functional reserve of the left ventricle. This study documents that verapamil exerts a depressant effect on LV function. However, the transient nature of this depression and the quick recovery to normal or above-normal values indicate that verapamil, in the doses used in this study, is safe to use intravenously in patients with coronary artery disease.

Effects of the dipyridamole test on left ventricular function in coronary artery disease

The dipyridamole stress test is used with thallium-201 to detect areas of inhomogeneity of blood flow that point to coronary artery disease (CAD). It is unclear whether dipyridamole produces inhomogeneous perfusion only or whether it actually decreases net flow in the obstructed vessels and produces true ischemia. It is also unclear what effect dipyridamole has on global and segmental left ventricular function. Therefore, ejection fraction, segmental wall motion and ventricular volume equivalents were measured before and after dipyridamole in 113 patients and 32 normal subjects. Ejection fraction responded in an abnormal fashion in 98 patients (87%), decreasing from 49 +/- 11% to 43 +/- 13% (p less than 0.0001), whereas it increased in 29 normal subjects (90%) from 57 +/- 6% to 64 +/- 10% (p less than 0.0001). Wall motion worsened distinctly in 75 patients (66%), and pressure/volume ratio deteriorated in 72%. The effect of dipyridamole lasted between 10 and 25 minutes, but was promptly reversed by aminophylline. These findings indicate that dipyridamole generally induces true ischemia in CAD. Furthermore, the degree of dysfunction is related to the angiographically assessed severity of CAD. The shortness of breath (seen in 10% of patients) may be partially explained by the findings, and it seems advisable to give aminophylline to every patient in order to promptly correct left ventricular dysfunction.

Digitalis and verapamil in atrial fibrillation and flutter: is verapamil now the preferred agent?

Almost 80 years ago, Mackenzie first noted the beneficial effects of digitalis in patients with atrial fibrillation (AF) and considered the slowing of the heart rate as the most important effect of digitalis (Mackenzie 1911). After this first historical account, digitalis became the cornerstone of therapy of acute and chronic atrial fibrillation (Bellet 1971) and remained so for 50 years. In the late 1960s, the calcium antagonist verapamil was shown by Bender and colleagues (Bender 1967, Bender et al. 1966)to be effective in slowing the ventricular rate in atrial fibrillation. In the 20 years that have lapsed since then, verapamil has come to share the honours with digitalis as the drug of choice in the control of atrial fibrillation and has practically replaced it in some cases. This article outlines the reasons for this evolution in the approach to the treatment of atrial fibrillation.

Contribution of echocardiography and immediate surgery to the management of severe aortic regurgitation from active infective endocarditis

The timing of surgery in patients with severe aortic regurgitation and left ventricular (LV) failure, particularly when associated with active infective endocarditis (IE), is of the utmost importance. From July 1982 to May 1984, 34 patients, aged 15 to 60 years, with severe aortic regurgitation underwent immediate (within 24 hours of diagnosis) aortic valve surgery. All patients were in New York Heart Association class IV for LV failure. Eighteen patients had right-sided heart failure. Decision for immediate surgery was based on the echocardiographic demonstration of diastolic closure of the mitral valve or of vegetations on the aortic valve. Premature closure of the mitral valve was demonstrated echocardiographically in 17 patients, 13 of whom had diastolic crossover of LV and left atrial pressure tracings recorded at surgery. IE of the aortic valve was confirmed at surgery in 29 patients, 27 of whom had vegetations on echocardiography. Seven patients required replacement of both aortic and mitral valves. Antibiotic therapy for IE was started immediately after blood cultures were taken and continued for 4 to 6 weeks postoperatively. The mortality rate within 30 days of surgery was 6% for the group as a whole and 7% for those with IE. Mean follow-up period for the 32 survivors was 10.6 months. There were 2 late deaths. No patient had periprosthetic regurgitation or persistence of endocarditis. Procrastination in referral for surgery of these extremely ill patients is not justified and is likely to be associated with higher risks of morbidity and mortality.

Cessation of Paroxysmal Supraventricular Tachycardias by Parasympathomimetic Interventions

Abstract The mode of cessation of 39 episodes of supraventricular tachycardias during reflex vagal stimulation was studied in 11 patients. In each instance slowing of supraventricular tachycardia w...