FURTHER OBSERVATIONS TO ELUCIDATE THE ROLE OF INTERVENTRICULAR DISPERSION OF REPOLARIZATION AND EARLY AFTERDEPOLARIZATIONS IN THE GENESIS OF ACQUIRED TORSADE-DE-POINTES ARRHYTHMIAS - A COMPARISON BETWEEN ALMOKALANT AND D-SOTALOL USING THE DOG AS ITS OWN CONTROL

Objectives. We sought to further elucidate the role of early afterdepo larizations (EADs) and interventricular dispersion of repolarization ( Delta APD) in the genesis of acquired torsade de pointes (TdP) arrhyth mias. Background. Administration of class III agents can be associated with TdP. We developed a dog model in which TdP can be reproducibly i nduced by pacing after d-sotalol. This model shows reproducible result s over weeks. Methods. In 14 anesthetized dogs with chronic complete a trioventricular block two separate experiments were performed in which d-sotalol (2 mg/kg body weight) or almokalant (0.12 mg/kg) was admini stered. Monophasic action potentials were simultaneously recorded from the endocardium of the right and left ventricle to register EADs and to measure the action potential duration (APD). Delta APD was defined as the APD of the left ventricle minus that of the right ventricle. Re sults. Baseline conditions were identical in the serially performed ex periments. The cycle length and QT time increased by 16% and 26% after d-sotalol and by 15% and 31% after almokalant, respectively. After bo th drugs the action potential of the left ventricle prolonged more tha n that of the right ventricle, thereby increasing Delta APD (almokalan t [mean +/- SD]: 110 +/- 60 ms; d-sotalol: 80 +/- 45 ms, p < 0.05). Th e incidence of EADs (18 of 22 vs. 11 of 24, p < 0.05) and single ectop ic beats (EBs) (1.5 +/- 2 vs. 24 +/- 32, p < 0.01) was more frequently observed after almokalant than after d-sotalol. Moreover, multiple EB s only occurred after almokalant. These beats interfered with the basi c rhythm, leading to dynamic changes in left ventricular APD and to ad ditional increases in Delta APD. Spontaneous TdP was observed in 9 of 14 dogs after almokalant and could be increased to 12 of 14 with progr ammed electrical stimulation. After d-sotalol, TdP could only be induc ed by programmed electrical stimulation (5 of 14, p < 0.05). Conclusio ns. In the same dog, almokalant induced more delay in repolarization, more EADs, multiple EBs and more ventricular inhomogeneity in APD than d-sotalol. These changes were related to a higher incidence of TdP an d thereby confirm a strong association of the occurrence of EADs, mult iple EBs and Delta APD in the genesis of TdP. These findings also show the possible value of our model for evaluating the proarrhythmic pote ntial of different drugs. (C) 1997 by the American College of Cardiolo gy.