Contribution of delayed ventricular repolarization to the anti-arrhythmic efficacy of sotalol.

Eighteen patients with sustained ventricular tachycardia underwent serial electrophysiological studies to establish the therapeutic efficacy of sotalol as compared to other available anti-arrhythmic agents. One or more acutely effective drug was found in 14 of the 18 patients (78%). Sotalol was tested in all 18 patients and was effective in 12 of them (67%). For assessment of the prophylactic efficacy of other anti-arrhythmic agents, an average of 3.5 additional studies per patient were performed resulting in successful prevention of ventricular tachycardia in a total of 10 of 63 (16%) additional trials. Nine patients were placed on chronic oral therapy with sotalol. In these nine patients long-term prophylaxis against ventricular tachycardia was documented over a mean follow-up period of 9.6 months (range 2-18 months). The study suggests that sotalol can provide effective prophylaxis against ventricular tachycardia in a significant proportion of patients refractory to other available drugs and that this prophylactic efficacy is predominantly due to its Class III anti-arrhythmic properties. Experimental studies were performed in eight conscious dogs 3-7 days following proximal LAD ligation. Epicardial recordings were obtained using implanted composite electrodes. Sotalol prevented sustained VT by a predominant increase in refractoriness of the infarcted zone. In vitro, sotalol caused a significant prolongation of the action potential of epicardial and endocardial fibres within both the infarcted and noninfarcted myocardium. Refractoriness of epicardial ventricular fibres was significantly more prolonged in ischemically damaged cells as compared to normal fibres.

Differential effects of sotalol and metoprolol on induction of paroxysmal supraventricular tachycardia.

Seventeen patients with recurrent paroxysmal supraventricular tachycardia (SVT) underwent serial electrophysiologic studies to compare the effects of i.v. sotalol (1.5 mg/kg) and i.v. metoprolol (0.15 mg/kg). The plasma concentrations of sotalol (2.1 +/- 1.1 microgram/ml) and metoprolol (67 +/- 15 ng/ml) were within the therapeutic range. Before drug administration, sustained SVT could be reproducibly induced in all patients. Sotalol prevented induction of sustained SVT in 10 of 17 patients (59%) and metoprolol in 4 (28%) (p less than 0.05). In 6 of 8 patients with atrioventricular (AV) nodal reentrance, the site of action of sotalol was the anterograde or the retrograde limb, reflecting an increase in refractoriness in both pathways of the circus movement. In 4 of 9 patients with AV reentrance, the site of action of sotalol was exclusively the AV nodal pathway; conduction through the extranodal accessory tract appeared to be unchanged, but its anterograde effective refractory period was prolonged (from 285 +/- 25 to 322 +/- 28 ms, p less than 0.001; mean +/- standard deviation). In the 7 patients in whom sotalol did not prevent sustained SVT, the tachycardia cycle length increased from 347 +/- 42 to 392 +/- 45 ms (p less than 0.01). Compared with sotalol, metoprolol had qualitatively similar but quantitatively less potent effects on the AV nodal pathways; however, different from sotalol, metoprolol had no effect on extranodal accessory tracts. The study suggests that at therapeutic plasma concentrations, sotalol would be effective in preventing clinical SVT in a significant proportion of patients refractory to metoprolol; because sotalol not only has beta-blocking properties but also results in acute prolongation of the action potential duration, this combination of class II and III activity may contribute to its superior prophylactic efficacy compared with pure beta blockade.

Electrophysiologic testing in assessment of therapy with sotalol for sustained ventricular tachycardia.

Eighteen patients with sustained ventricular tachycardia underwent electrophysiologic studies to establish the therapeutic efficacy of sotalol. In each patient ventricular tachycardia could be reproducibly initiated by programmed stimulation during control studies. Sotalol prevented induction of sustained ventricular tachycardia in 12 of the 18 patients (67%). Prolongation of the QTC interval and of ventricular refractoriness was regularly observed after sotalol but did not reliably predict prophylactic efficacy. Severe adverse effects, including congestive heart failure and sinus node dysfunction, were noted early during sotalol therapy in three patients. Nine patients were placed on long-term oral treatment with sotalol and four patients on another effective agent. In these 13 patients, complete (12 patients) or partial (one patient) long-term prophylaxis against ventricular tachycardia was documented over a mean follow-up period of 16 months (range 8 to 24). The study suggests that sotalol can provide effective prophylaxis against sustained ventricular tachycardia; this prophylactic efficacy is not typical for pure beta-adrenergic antagonism but may at least partly result from experimentally observed prolongation of the ventricular action potential duration.

Electrophysiological effects of glucose-insulin-potassium on sinus node function in patients with and without sinus node dysfunction.

The electrophysiological effects of glucose (100 g)-insulin (20 U)-potassium (10 mmol X litre-1) infusion (GIK) on three parameters of sinus node function were studied in 14 control subjects (mean age 53 +/- 14 yr) and 11 patients (mean age 50 +/- 17 yr) with sinus node dysfunction (SND). In a first series of experiments the response to GIK was examined in nine control and 11 SND patients. Following GIK, the mean spontaneous cycle length decreased by 17% (671 to 560 ms; P less than 0.01) in the control group and by 33% (1066 to 715 ms; P less than 0.001) in the SND patients; this difference between both groups was statistically significant (P less than 0.01). In the control group mean corrected sinus node recovery time (CRST) and calculated sinoatrial conduction time (SACT; n = 6) were not significantly altered after GIK. In SND patients GIK decreased the mean value of CSRT by 40% (693 to 416 ms; P less than 0.05) and of calculated SACT (n = 6) by 27% (130 to 95 ms; P less than 0.05); prolonged secondary pauses following termination of rapid atrial pacing in SND patients were also shortened. In a second series of experiments, mannitol (100 g, iv) was administered in five control patients but had no significant effect on the electrophysiological parameters tested. Plasma levels of glucose were significantly increased, by 500% (P less than 0.01), after GIK; plasma potassium and sodium concentrations decreased by 7 and 5% (P less than 0.05). The results indicate that GIK had a beneficial effect on sinus node dysfunction.