Recently diagnosed idiopathic dilated cardiomyopathy: incidence of myocarditis and efficacy of prednisone therapy.

Fifty-two patients with recently diagnosed idiopathic dilated cardiomyopathy were studied to determine the incidence of myocarditis; patients were randomly assigned to receive either conventional therapy alone or conventional therapy plus prednisone to assess possible therapeutic efficacy with regard to survival. Inflammatory criteria were present in 23% of the population studied with 13% having overt myocarditis according to the Dallas criteria. The addition of prednisone to conventional therapy did not improve survival in a homogeneous population with new-onset dilated cardiomyopathy. Furthermore, the diagnosis of myocarditis by endomyocardial biopsy did not influence 2-year survival once dilated cardiomyopathy had developed. Biopsy-documented myocarditis resolved in all patients, according to results of 3-month follow-up endomyocardial biopsies, regardless of treatment group. There was a trend for patients with a left ventricular ejection fraction less than 20% to show reduced survival at 2 years compared to the group with a higher ejection fraction (p = 0.07). Right ventricular dysfunction determined at catheterization was present in 20 of 52 patients and was the most significant predictor of survival. Patients with preserved right ventricular function had a 95% 24-month survival rate compared to 47% for patients with right ventricular diastolic dysfunction (right ventricular end-diastolic pressure greater than or equal to 11 mm Hg) (p = 0.005).

The digoxin-amiodarone interaction.

To assess the cause of the digoxin-amiodarone interaction, the systemic availability and renal excretion of digoxin were examined in 10 patients. Patients were studied before and after 1 week and 6 weeks of concurrent amiodarone therapy, and four were also studied after 4-8 months. Mean (+/- SD) peak plasma digoxin concentration rose from 1.55 +/- 0.6 microgram /1 prior to amiodarone therapy to 2.85 +/- 1.3 micrograms/1 after 1 week of combined therapy (p less than 0.01). Mean AUC also rose from 7.2 +/- 2.1 micrograms/1.h to 12.1 +/- 6.4 micrograms/1.h (p less than 0.01) during this period. Mean peak plasma digoxin concentration and AUC remained elevated after 6 weeks and, in the patients studied, at 4-8 months. Mean urinary digoxin clearance remained unchanged. Plasma amiodarone and desethylamiodarone concentrations were consistent with the prescribed doses. This study confirmed previous findings of raised plasma digoxin concentrations following the addition of amiodarone. It has also shown that this interaction is sustained for at least several months. The cause has not been fully elucidated but does not appear to be due to a change in the renal clearance of digoxin.

Clinical pharmacokinetics and therapeutic use of hydralazine in congestive heart failure.

Hydralazine (1-hydrazinophthalazine) has been used extensively in the treatment of hypertension and congestive heart failure and produces arteriolar vasodilation, in part, mediated by prostaglandins. Its associated reflex baroreceptor-mediated responses of tachycardia and increased ejection velocity are attenuated in congestive heart failure. A direct inotropic effect has been attributed to the drug. Pharmacokinetic data indicate hydralazine is absorbed well from the gastrointestinal tract, and has an extensive and complex metabolism depending on acetylator status: slow acetylators undergo primary oxidative metabolism, while rapid acetylators are acetylated. Half-lives, clearances and bioavailability of the drug are not significantly altered in congestive heart failure compared with hypertensive patients. A wide range of dosages in heart failure has been noted (150 to 3000 mg/24h), and may related to a saturation of the first-pass effect. Hydralazine improves haemodynamics in the short term in patients with increased peripheral vascular resistance, and has variable effects on pulmonary capillary wedge and left ventricular filling pressures. Prediction of the short term clinical response is difficult and appears to be independent of pharmacokinetics. A meta analysis did not demonstrate long term efficacy of hydralazine alone in heart failure, but combination therapy with nitrates has been shown to improve survival and exercise performance in patients with mild to moderate heart failure. Side effects are common and are dependent on dose, duration and acetylator status.

Relative efficacy of vasodilator therapy in chronic congestive heart failure. Implications of randomized trials.

We examined existing evidence concerning the relative efficacy of various vasodilator agents in chronic congestive heart failure. Only randomized placebo-controlled trials with clinical end points and treatment durations of four weeks or more were selected from an exhaustive search of the English-language medical literature. Twenty-eight trials involving 1976 patients were found. Treatment durations of the trials varied from one month to two years. Patients with symptomatic heart failure despite digitalis and diuretic therapy were studied; most were middle-aged men and approximately half had coronary artery disease. Results of the trials were appraised by three independent observers, and mortality and functional status outcomes were pooled in a meta-analysis. All vasodilator agents except hydralazine hydrochloride were associated with improvements in functional status. Angiotensin converting-enzyme inhibitors were the only agents associated with both decreased mortality (odds ratio, 0.51; 95% confidence interval, 0.34 to 0.75) and improved functional status (odds ratio, 4.53; 95% confidence interval, 3.46 to 5.92). The optimal timing for initiation of these agents was not established.

Cardiovascular reserve in idiopathic dilated cardiomyopathy as determined by exercise response during cardiac catheterization.

Simultaneous right- and left-sided cardiac high-fidelity hemodynamic measurements were obtained at rest and supine exercise during cardiac catheterization in 27 patients (mean age 32 +/- 10 years) with idiopathic dilated cardiomyopathy to investigate the hemodynamic exercise response and possible mechanisms for the wide variation in exercise tolerance observed clinically. There were no significant differences in other rest hemodynamic variables between group 1, patients with a normal exercise factor (more than 600, n = 10), and group 2, patients with an abnormal exercise factor (less than 600, n = 17). A greater increase in stoke volume index (12 +/- 6 vs 2 +/- 8 ml/beats/m2, mean +/- standard deviation) and a greater decrease in systemic vascular resistance with exercise occurred in group 1 than in group 2 (-614 +/- 304 vs -406 +/- 291 dynes cm-5). Elevation of right ventricular end-diastolic pressure with exercise was significantly greater in group 2 than in group 1 (7 +/- 5 vs 1 +/- 4 mm Hg, respectively, p less than 0.05). A maintained cardiac reserve in patients with idiopathic dilated cardiomyopathy appears to be largely dependent on 2 primary factors: preservation of normal right ventricular function during exercise; and preservation of systemic vasodilator capability sufficient to produce a significant degree of afterload reduction during exercise.

Variability of ventricular arrhythmias in hypertrophic cardiomyopathy and implications for treatment.

Asymptomatic ventricular arrhythmias are common in patients with hypertrophic cardiomyopathy (HC) and are associated with sudden death. The variability of ventricular extrasystoles and optimal duration of electrocardiographic (ECG) monitoring necessary to exclude ventricular tachycardia (VT) were assessed in 16 patients with HC in whom VT was detected during the first 48 hours of ECG monitoring. One hundred eight episodes of VT (range 0 to 10, mean 1.5 per day) were recorded (52% incidence) during 48 to 168 hours of ECG monitoring (median 72) without cardiac medication within a 1-year period. The likelihood of excluding VT on K days of ECG monitoring was determined. The probability of failing to detect VT in our selected group was 48% for 24 hours of ECG monitoring, 23% for 48 hours and 11% for 72 hours. Daily ventricular extrasystole rates were 2 to 17,693 (median 187). Analysis of variance, applied to 10 patients with enough ventricular extrasystoles for analysis, indicated that a 61% reduction of ventricular extrasystoles in consecutive 24-hour periods was necessary to attribute an effect to the intervention rather than to spontaneous variability with 95% confidence. A sine wave curve fitted to the ventricular extrasystole counts revealed a circadian rhythm with a night frequency peak in 5 patients and an afternoon peak in 5. Thus, 48- to 72-hour ECG monitoring represents a pragmatic compromise in assessing drug intervention once VT is detected;longer periods (5 to 6 days) of ECG monitoring are required to exclude VT at initial evaluation, although the prognostic significance of VT detected after the first 72 hours is uncertain.(ABSTRACT TRUNCATED AT 250 WORDS)

The electrophysiological substrate of atrial fibrillation.

The electrophysiological substrate that predisposes the human atrium to sustain atrial fibrillation is incompletely understood. However, abnormalities of atrial size, refractory period and conduction are important precursors to this arrhythmia. The propensity of various disease states, cardioactive drugs and the autonomic nervous system to potentiate atrial fibrillation may be explained by changes in these electrophysiological properties.