Peter L. Friedman

Effect of d-sotalol on mortality in patients with left ventricular dysfunction after recent and remote myocardial infarction

BACKGROUND Left ventricular dysfunction after myocardial infarction is associated with an increased risk of death. Other studies have suggested that a potassium-channel blocker might reduce this risk with minimal adverse effects. We investigated whether d-sotalol, a pure potassium-channel blocker with no clinically significant beta-blocking activity, could reduce all-cause mortality in these high-risk patients. METHODS Patients with a left ventricular ejection fraction of 40% or less and either a recent (6-42 days) myocardial infarction or symptomatic heart failure with a remote (> 42 days) myocardial infarction were randomly assigned d-sotalol (100 mg increased to 200 mg twice daily, if tolerated) or matching placebo twice daily. FINDINGS After 3121 of the planned 6400 patients had been recruited, the trial was stopped. Among 1549 patients assigned d-sotalol, there were 78 deaths (5.0%) compared with 48 deaths (3.1%) among the 1572 patients assigned placebo (relative risk 1.65 [95% CI 1.15-2.36], p = 0.006). Presumed arrhythmic deaths (relative risk 1.77 [1.15-2.74], p = 0.008) accounted for the increased mortality. The effect was greater in patients with a left ventricular ejection fraction of 31-40% than in those with lower ( <or= 30%) ejection fractions (relative risk 4.0 vs 1.2, p = 0.007). INTERPRETATION Among the 1549 patients evaluated, administration of d-sotalol was associated with increased mortality, which was presumed primarily to be due to arrhythmias. The prophylactic use of a specific potassium-channel blocker does not reduce mortality, and may be associated with increased mortality in high-risk patients after myocardial infarction.

Exploring Postinfarction Reentrant Ventricular Tachycardia With Entrainment Mapping

Ventricular tachycardia late after myocardial infarction is usually due to reentry in the infarct region. These reentry circuits can be large, complex and difficult to define, impeding study in the electrophysiology laboratory and making catheter ablation difficult. Pacing through the electrodes of the mapping catheter provides a new approach to mapping. When pacing stimuli capture the effects on the tachycardia depend on the location of the pacing site relative to the reentry circuit. The effects observed allow identification of various portions of the reentry circuit, without the need for locating the entire circuit. Isthmuses where relatively small lesions produced by radiofrequency catheter ablation can interrupt reentry can often be identified. A classification that divides reentry circuits into one or more functional components helps to conceptualize the reentry circuit and predicts the likelihood that heating with radiofrequency current will terminate tachycardia. These methods are helping to define human reentry circuits.

Propafenone versus sotalol for suppression of recurrent symptomatic atrial fibrillation

Because conventional antiarrhythmic therapy is often ineffective in maintaining sinus rhythm or is associated with adverse side effects in patients with atrial fibrillation (AF), there is a clinical need to test newer agents. One hundred patients with AF who had unsuccessful therapy with 1.9 +/- 1.0 type IA antiarrhythmic agents were randomized to receive either propafenone (n = 50) or sotalol (n = 50). Patients were stratified into 4 groups based on AF pattern (chronic vs paroxysmal) and left atrial size (large [> or = 4.5 cm] vs small [< 4.5]). The proportion of patients remaining in sinus rhythm on each agent was calculated for each group by the Kaplan-Meier method. For patients randomized to propafenone, 46 +/- 8%, 41 +/- 8% and 30 +/- 8% remained in sinus rhythm at 3, 6 and 12 months, respectively, after cardioversion. A similar proportion of patients treated with sotalol remained in sinus rhythm at follow-up (49 +/- 7%, 46 +/- 8% and 37 +/- 8% at 3, 6 and 12 months, respectively; p = NS). The proportion of patients remaining in sinus rhythm on propafenone and sotalol was not dependent on arrhythmia pattern or left atrial dimension. Except for constipation that occurred more frequently in patients treated with propafenone, adverse side effects were equally distributed between the 2 therapies. Two patients receiving sotalol died during follow-up. Propafenone and sotalol, 2 new antiarrhythmic agents, were found to be equally effective in maintaining sinus rhythm in 100 patients with recurrent AF. Response rates were not affected by arrhythmia pattern, left atrial size or unsuccessful prior drug therapy.(ABSTRACT TRUNCATED AT 250 WORDS)

Feasibility of cardiac cryoablation using a transvenous steerable electrode catheter

We investigated the feasibility of using cryogenic technology in an electrode catheter for percutaneous ablation of cardiac tissue. Despite its high success rate, radiofrequency catheter ablation has important limitations especially with regards to the treatment of ventricular arrhythmias associated with a chronic scar. Arrhythmia surgery experience has shown that freezing with a hand held probe can permanently ablate the arrhythmogenic substrate of ventricular tachycardia associated with an old scar. Moreover, cryosurgery also allows for reversible “ice mapping,” in which the area likely responsible for the arrhythmia can be evaluated by suppressing its electrophysiologic properties prior to the creation of an irreversible state. A new steerable cryoablation catheter using Halocarbon 502 as a refrigerant was utilized in six dogs. Serial cryoapplications were performed in the right and left ventricles. In two dogs, we attempted reversible ice mapping of the AV node. Pathological evaluation of the lesions was done acutely in all the animals. Forty-two cryoapplications were delivered at a mean temperature of −45 ± 9.8°C. No lesion was found at pathological evaluation for 16 cryoapplications which did not achieve a temperature of less (colder) than −30°C. The remaining applications resulted in 26 lesions which were hemorrhagic and sharply demarcated from normal myocardium. Histological evaluation revealed contraction band necrosis. Reversible ice mapping of the AV node was successfully achieved in two animals. Cryoablation is feasible using an electrode catheter with multiple electrodes. This technology has the potential to allow for reversible ice mapping to confirm a successful ablation target before definitive ablation.

Coronary Vasoconstrictor Effect of Indomethacin in Patients with Coronary-Artery Disease

Prostaglandins may be important regulators of coronary blood flow. To investigate this possibility, we studied the effect of blockade of prostaglandin synthesis by indomethacin in nine patients with coronary-artery disease. Coronary-sinus blood flow (determined with the thermodilution technique) was recorded, together with mean arterial blood pressure and the myocardial arteriovenous oxygen difference from simultaneously obtained arterial and coronary-sinus blood samples, before and 20 minutes after an intravenous dose of indomethacin (0.5 mg per kilogram of body weight). There were significant increases (P less than 0.05) in mean arterial pressure (from 99 +/- 4 to 118 +/- 5 mm Hg [+/- S.E.M.]), coronary vascular resistance (+73 per cent), and myocardial arteriovenous oxygen difference (from 107 +/- 5 to 138 +/- 4 ml per liter) after indomethacin, but coronary blood flow fell significantly, from 181 +/- 29 to 111 +/- 14 ml per minute (P less than 0.05). Thus, despite an increase in myocardial oxygen demand, coronary blood flow fell and coronary vascular resistance increased. This coronary vasoconstrictor effect may have been due to blockade of vasodilatory prostaglandin synthesis or to a direct drug effect. Whatever the mechanism, indomethacin should be used with caution in patients with severe coronary-artery disease.

Therapy of refractory symptomatic atrial fibrillation and atrial flutter: a staged care approach with new antiarrhythmic drugs

One hundred nine patients with recurrent episodes of symptomatic atrial fibrillation or flutter, or both, who had failed one to five previous antiarrhythmic drug trials were treated with propafenone and, subsequently, sotalol if atrial fibrillation recurred. The clinical profile of the study group was as follows: age 63 +/- 13 years, left atrial anteroposterior dimension 4.4 +/- 0.9 cm and left ventricular ejection fraction 57 +/- 14%. Paroxysmal atrial fibrillation occurred in 56 patients (51%) and chronic atrial fibrillation occurred in 53 patients (49%). After loading and dose titration phases were completed, the maintenance doses of drugs were 450 to 900 mg/day for propafenone and 160 to 960 mg/day for sotalol. Life table estimates of the duration of freedom from atrial fibrillation were constructed for each drug trial. The percent of patients free of recurrent symptomatic arrhythmia at 6 months was 39% for propafenone and 50% for sotalol. The cumulative proportion of patients successfully treated with propafenone or sotalol, or both, by 6 months was 55% and remained relatively constant beyond that point. The incidence of intolerable side effects necessitating discontinuation of therapy ranged from 7% to 8%. Thus, despite previous unsuccessful drug trials, a substantial proportion of patients with recurrent symptomatic atrial fibrillation refractory to conventional therapy can be treated successfully and safely with newer antiarrhythmic drugs. Treatment failures tend to occur early in the course of follow-up, permitting easy identification of candidates for alternative therapeutic approaches.

Efficacy and safety of timolol for prevention of supraventricular tachyarrhythmias after coronary artery bypass surgery.

Forty-one patients undergoing coronary artery bypass grafting were randomly assigned to receive prophylactic timolol or placebo, given in a double-blind fashion. beta-Adrenoceptor-blocking therapy was stopped at least one half-life before surgery. Three to 7 hr after surgery (304 +/- 56 min), 0.5 mg of timolol or placebo was given intravenously twice daily in a double-blind manner. When oral medications were resumed postoperatively, 10 mg of timolol twice daily or placebo was continued orally. Continuous electrocardiograms were recorded for 24 hr before and for 7 days after surgery with a standard cassette recorder. No patient received digoxin. Both groups were comparable for frequency of preoperative supraventricular arrhythmias, left ventricular ejection fraction, duration of cardiopulmonary bypass, aortic cross-clamp time, number of bypass grafts, and total duration of monitoring. Analysis of arrhythmias was done by hand counts, and supraventricular arrhythmias were divided into supraventricular tachycardia and atrial fibrillation and/or flutter. Timolol decreased the frequency of supraventricular tachycardia (581 episodes placebo vs 84 timolol; p less than .05) and of atrial fibrillation and/or flutter (291 episodes placebo vs five timolol; p less than .05). Timolol decreased the number of patients with severe (heart rate greater than 200 beats/min, duration greater than 50 beats) episodes of supraventricular tachycardia (four placebo vs 0 timolol; p less than .05) and also decreased the number of episodes of severe (heart rate greater than 200 beats/min, duration greater than 5 min) atrial fibrillation and/or flutter (16 placebo vs one timolol; p less than .005). There were differences in the durations of supraventricular arrhythmias.(ABSTRACT TRUNCATED AT 250 WORDS)

Detection of transient myocardial ischemia by computer analysis of standard and signal-averaged high-frequency electrocardiograms in patients undergoing percutaneous transluminal coronary angioplasty.

Electrocardiographic manifestations of transient myocardial ischemia were studied, in 11 patients undergoing angioplasty (PTCA) of a left anterior descending coronary artery stenosis, by the visual inspection of the standard surface electrocardiogram (S-ECG) and the intracoronary ECG (IC-ECG) as well as computer-assisted analysis of the S-ECG. Cross-correlation analysis (CCA) performed by computer was used to compare beat-to-beat variability in ST-T morphology of the S-ECG during different stages of PTCA. CCA was also applied to the signal-averaged high-frequency QRS (SA-HFQ). All patients developed angina during balloon inflation, accompanied by transient marked ST-T changes in IC-ECG in 10 of 11 patients (90%). Visual inspection of S-ECG revealed transient ST-T changes in only 6 of 11 (54%). In contrast, CCA of the S-ECG revealed transient ST-T changes in 9 of 11 (82%). Analysis of SA-HFQ revealed that balloon inflation was associated with a marked reduction in the calculated root-mean-square (RMS) voltage for such signals (2.31 +/- 1.04 microV) as compared with RMS values before (3.27 +/- 1.12 microV, p less than .05) PTCA or after conclusion of PTCA (3.79 +/- 1.39 microV, p less than .01). Balloon inflation was also accompanied by changes in waveform morphology of the SA-HFQ, including the development of new or more prominent time zones of reduced amplitude in 10 of 11 individuals (90%). Such zones may represent slow conduction in regions of the heart rendered ischemic during PTCA. CCA of the S-ECG and of SA-HFQ appears to detect evidence of transient ischemia with greater sensitivity than simple visual inspection of S-ECG, and may therefore prove to be of use in the evaluation of patients with chest pain of uncertain origin.

Analysis of implantable cardioverter defibrillator therapy in the Antiarrhythmics Versus Implantable Defibrillators (AVID) Trial

Introduction: The implantable cardioverter defibrillator (ICD) is commonly used to treat patients with documented sustained ventricular tachycardia (VT) or ventricular fibrillation (VF). Arrhythmia recurrence rates in these patients are high, but which patients will receive a therapy and the forms of arrhythmia recurrence (VT or VF) are poorly understood.

Mapping and Radiofrequency Catheter Ablation of the Three Types of Sustained Monomorphic Ventricular Tachycardia in Nonischemic Heart Disease

Ventricular Tachycardia Ablation, Introduction. Sustained monomorphic ventricular tachycardia (VT) associated with nonischemic cardiomyopathy (CMP) is uncommon. Optimal approaches to catheter mapping and ablation are not well characterized, but they are likely to depend on the VT mechanism. The purpose of this study was to evaluate the mechanisms of sustained monomorphic VT encountered in nonischemic CMP and to assess the feasibility, safety, and efficacy of catheter radiofrequency ablation for treatment.