Efficacy and Proarrhythmia with the Use of d,l-sotalol for Sustained Ventricular Tachyarrhythmias

Abstract

This study prospectively evaluated the clinical efficacy, the incidence of torsades de pointes, and the presumable risk factors for torsades de pointes in patients treated with d,l-sotalol for sustained ventricular tachyarrhythmias. Eighty-one consecutive patients (54 with coronary artery disease, and 20 with dilated cardiomyopathy) with inducible sustained ventricular tachycardia or ventricular fibrillation received oral d,l-sotalol to prevent induction of the ventricular tachyarrhythmia. During oral loading with d,l-sotalol, continuous electrocardiographic (ECG) monitoring was performed. Those patients in whom d,l-sotalol prevented induction of ventricular tachycardia or ventricular fibrillation were discharged with the drug and followed up on an outpatient basis for 21 +/- 18 months. Induction of the ventricular tachyarrhythmia was prevented by oral d,l-sotalol in 35 (43%) patients; the ventricular tachyarrhythmia remained inducible in 40 (49%) patients; and two (2.5%) patients did not tolerate even 40 mg of d,l-sotalol once daily. Four (5%) patients had from torsades de pointes during the initial oral treatment with d,l-sotalol. Neither ECG [sinus-cycle length (SCL), QT or QTc interval, or U wave] nor clinical parameters identified patients at risk for torsades de pointes. However, the oral dose of d,l-sotalol was significantly lower in patients with torsades de pointes (200 +/- 46 vs. 328 +/- 53 mg/day; p = 0.0017). Risk factors associated with the development of torsades de pointes were the appearance of an U wave (p = 0.049), female gender (p = 0.015), and significant dose-corrected changes of SCL, QT interval, and QTc interval (p < 0.05). During follow-up, seven (20%) patients had a nonfatal ventricular tachycardia recurrence, and two (6%) patients died suddenly. One female patient with stable cardiac disease had recurrent torsades de pointes after 2 years of successful treatment with d,l-sotalol. Torsades de pointes occurred early during treatment even with low doses of oral d,l-sotalol. Pronounced changes in the surface ECG (cycle length, QT, and QTc) in relation to the dose of oral d,l-sotalol might identify a subgroup of patients with an increased risk for torsades de pointes. Other ECG parameters before the application of d,l-sotalol did not identify patients at increased risk for torsades de pointes. Recurrence rates of ventricular tachyarrhythmias are high despite complete suppression of the arrhythmia during programmed stimulation. Therefore programmed electrical stimulation in the case of d,l-sotalol seems to be of limited prognostic value.

Sex, Age, and Regional Differences in L-Type Calcium Current Are Important Determinants of Arrhythmia Phenotype in Rabbit Hearts With Drug-Induced Long QT Type 2

“…In papillary muscles of female rabbits, ovariectomy increased and estrogen replacement (7 days) decreased isometric force. Estrogen reduced 3 H-nitrendipine binding in plasma membrane preparations compared with ovariectomy and control groups, yet peak L-type calcium currents (I Ca,L ) was not significantly different for the 3 treatment groups. 19 In contrast, Pham et al reported higher I Ca,L density on the epicardium of adult female rabbit hearts compared with males and no sex differences on the endocardium such that female hearts, but the authors did not examine apex-base differences in I Ca,L .…”

“…1,2 A number of studies have shown an increase of TdP in women versus men following an exposure to agents known to block the K ϩ channel HERG and inhibit the rapid component of the delayed rectifying current, I Kr . 1,[3][4][5] The increase in vulnerability to sudden death in women has been reported for cardiac 1,5 and noncardiac drugs. 6 These sex differences result most likely from the regulation of ionic channel expression by sex steroids.…”

“…22,23 (2) Sex differences in arrhythmia phenotype are similar in rabbits and men. 11 (3) Numerous studies have used rabbit models of drug-induced LQT to investigate the factors that precipitate TdP. 24 -26 (4) Rabbits are "reflex ovulators" with estrogen levels that remain elevated until mating, 27 which avoids estrogen oscillations that occur in most mammals during the estrus cycle and thereby minimizes estrogen-dependent genomic variations of ion channel expression.…”

Sotalol unmasks susceptibility to drug-induced long QT syndrome and torsades de pointes

“…In a retrospective study of 1288 patients receiving sotalol for control of ventricular (85%) and supraventricular (15%) arrhythmias, QTc interval following initiation of sotalol therapy was significantly longer in those patients who later developed serious proarrhythmias as compared to patients with no proarrhythmic events [5]. TdP generally occurs early during treatment even with low doses of oral sotalol and pronounced electrocardiographic changes (cycle length and QTc) in relation to the dose of sotalol may recognize a subgroup of patients with an increased risk for TdP [6].…”

Deciphering Arrhythmia Mechanisms: Tools of the Trade

“…Numerous studies have shown an increase of TdP in women versus men following an exposure to agents that block K + channel HERG and inhibit I Kr 56,59,66,84 . The increase in vulnerability to sudden death in women has been reported for cardiac drugs 66,59 as well as numerous non-cardiac drugs 38 and are the result of regulation of ionic channel by sex steroids 39 .…”