Cellular basis of ventricular arrhythmias and abnormal automaticity in heart failure.
The high incidence of sudden death in heart failure may reflect an increased propensity to abnormal repolarization and long Q-T interval-related arrhythmias. If so, cells from failing hearts would logically be expected to exhibit a heightened susceptibility to early afterdepolarizations (EAD). We found that midmyocardial ventricular cells isolated from dogs with pacing-induced heart failure exhibited an increased action potential duration and many more EAD than cells from nonpaced controls; this was the case both under basal conditions (P < 0.01) and after lowering external K(+) concentration ([K(+)](o)) to 2 mM and exposing cells to cesium (3 mM; P < 0.05). An unexpected finding was the occurrence of spontaneous depolarizations (SD, >5 mV) from the resting potential that were not coupled to prior action potentials. These SD were observed in 20% of failing cells (n = 5 of 25) under basal ionic conditions but in none of the normal cells (n = 0 of 27, P < 0.05). The net inward current that underlies SD is not triggered by Ca(2+) oscillations and thus differs fundamentally from the currents that underlie delayed afterdepolarizations. We conclude that cardiomyopathic canine ventricular cells are intrinsically predisposed to EAD and SD. Because EAD have been linked to the pathogenesis of torsade de pointes, our results support the hypothesis that sudden death in heart failure often arises from abnormalities of repolarization. The frequent occurrence of SD points to a novel cellular mechanism for abnormal automaticity in heart failure.
Nuss
H B
HB
Department of Medicine, Section of Molecular and Cellular Cardiology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
Kääb
S
S
Kass
D A
DA
Tomaselli
G F
GF
Marbán
E
E
D000200:Action Potentials / Q000187:drug effects / Q000502:physiology*; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000503:physiopathology*; D002118:Calcium / Q000378:metabolism; D002586:Cesium / Q000008:administration & dosage; D004285:Dogs; D004594:Electrophysiology; D006321:Heart / Q000502:physiology / Q000503:physiopathology; D006333:Heart Failure / Q000503:physiopathology*; D007552:Isotonic Solutions / Q000494:pharmacology; D009206:Myocardium / Q000166:cytology; D013997:Time Factors
D007552:Isotonic Solutions; C037692:Tyrode's solution; D002586:Cesium; D002118:Calcium