d-Sotalol Induces Marked Action Potential Prolongation and Early Afterdepolarizations in M but Not Epicardial or Endocardial Cells of the Canine Ventricle

Abstract

BACKGROUND: Despite its class III antiarrhythmic actions, experimental and clinical studies have shown that d-sotalol can also be proarrhythmic; a recent clinical trial that evaluated d-sotalol in postmyocardial patients (SWORD) had to be prematurely interrupted because of the excess mortality in the treated group. Previous studies have demonstrated the existence of a marked heterogeneity across the ventricular wall; epicardial, endocardial, and M cells have been shown to display distinct electrophysiologic characteristics and pharmacologic behavior. The present study was designed to test the hypothesis that M cells are the primary target for the class III actions of d-sotalol in canine ventricular myocardium and may contribute to its proarrhythmic effects. METHODS AND RESULTS: We used standard microelectrode techniques to record transmembrane activity from endocardial, epicardial, midmyocardial, and transmural strips, isolated from the canine left ventricle. d-Sotalol (100 µM, 60 minutes of exposure, [K(+)]o = 4 mM) prolongs the action potential in the three cell types, but more so in M than epicardial or endocardial cells, especially at the slower rates. At a basic cycle length of 2000 ms, action potential duration after 90% repolarization increases from 199 +/- 20 to 247.5 +/- 28 ms in epicardium (n = 10), from 212 +/- 26 to 274 +/- 27 ms in endocardium (n = 11), and from 309 +/- 65 to 533 +/- 207 ms in M cells (n = 13). d-Sotalol produces a marked steepening of action potential duration-rate relationships of M cells and an upward shift of restitution of action potential duration curves, more accentuated in M cells. Early afterdepolarizations were observed at slow rates (basic cycle lengths > 1000 ms) in 7 of 13 M cell preparation s(54%) but not in endocardial or epicardial preparations. A sudden acceleration of the rate could also induce a transient prolongation of the action potential and early afterdepolarization activity. CONCLUSION: In canine ventricular tissues, d-sotalol manifests its class III effects preferentially in the M cells, leading to the development of early afterdepolarizations and a marked increase in transmural dispersion of repolarization. The data suggest an important role of M cells in the proarrhythmic effects of the drug.

Comparison of the cellular electrophysiological characteristics of canine left ventricular epicardium, M cells, endocardium and Purkinje fibres

“…1991 , Furukawa et al . 1991 , Krishnan & Antzelevitch 1991, Sicouri & Antzelevitch 1991b, 1993, Antzelevitch & Di Diego 1992, Sicouri et al . 1997 ).…”

“…1994 ). Midmyocardial or M cells, a unique and distinct subpopulation of cells in the deep subepicardial layers of the canine ventricle have been identified by Sicouri and Antzelevitch, and were found to have electrophysiological features intermediate between those of myocardial and Purkinje cells ( Sicouri & Antzelevitch 1991a) and pharmacological responsiveness different from that of either epicardium or endocardium ( Sicouri & Antzelevitch 1991b, 1993, Sicouri et al . 1997 ).…”

Low-dose carvedilol reduces transmural heterogeneity of ventricular repolarization in congestive heart failure

“…However, the extension of MAPD in the midmyocardium is more obvious, which is bound to result in an increase of myocardial heterogeneity and induce fatal arrhythmia such as ventricular tachycardia and ventricular fibrillation [23,24] . Contrarily, carveldilol, a nonselective alpha-and beta-adrenoceptor antagonist, produces a significant reduction in SCD in CHF patients [1,2] .…”

Repolarization of the cardiac action potential. Does an increase in repolarization capacity constitute a new anti‐arrhythmic principle?

“…EADs can also be observed under special conditions with rapid pacing such as in acquired and congenital LQTS and in situations with increased sympathetic drive (Ben‐David & Zipes 1990, Shimizu et al. 1991, Sicouri et al. 1997, Volders et al.…”

“…WL, wavelength; ERP, effective refractory period; CV, conduction velocity. conditions with rapid pacing such as in acquired and congenital LQTS and in situations with increased sympathetic drive (Ben-David & Zipes 1990, Shimizu et al 1991, Sicouri et al 1997, Volders et al 1997, Burashnikov & Antzelevitch 1998. Delayed afterdepolarizations describe afterdepolarizations that takes place after complete repolarization of the action potential (Figure 7a).…”