IONIC MECHANISM OF ACTION-POTENTIAL PROLONGATION IN VENTRICULAR MYOCYTES FROM DOGS WITH PACING-INDUCED HEART-FAILURE

Membrane current abnormalities have been described in human heart fail ure. To determine whether similar current changes are observed in a la rge animal model of heart failure, we studied dogs with pacing-induced cardiomyopathy. Myocytes isolated from the midmyocardium of 13 dogs w ith heart failure induced by 3 to 4 weeks of rapid ventricular pacing and from 16 nonpaced control dogs did not differ in cell surface area or resting membrane potential. Nevertheless, action potential duration (APD) was significantly prolonged in myocytes isolated from failing v entricles (APD at 90% repolarization, 1097+/-73 milliseconds [failing hearts, n=30] versus 842+/-56 milliseconds [control hearts, n=25]; P<. 05), and the prominent repolarizing notch in phase 1 was dramatically attenuated. Basal L-type Ca2+ current and whole-cell Na+ current did n ot differ in cells from failing and from control hearts, but significa nt differences in K+ currents were observed. The density of the inward rectifier K+ current (I-KI) was reduced in cells from failing hearts at test potentials below -90 mV (at -150 mV, -19.1+/-2.2 pA/pF [failin g hearts, n=18] versus -32.2+/-5.1 pA/pF [control hearts, n=15]; P<.05 ). The small outward current component of I-KI was also reduced in cel ls from failing hearts (at -60 mV, 1.7+/-0.2 pA/pF [failing hearts] ve rsus 2.5+/-0.2 pA/pF [control hearts]; P<.05). The peak of the Ca2+-in dependent transient outward current (I-to) was dramatically reduced in myocytes isolated from failing hearts compared with nonfailing contro l hearts (at +80 mV, 7.0+/-0.9 pA/pF [failing hearts, n=20] versus 20. 4+/-3.2 pA/pF [control hearts, n=15]; P<.001), while the steady state component was unchanged. There were no significant differences in I-to kinetics or single-channel conductance. A reduction in the number of functional I-to channels was demonstrated by nonstationary fluctuation analysis (0.4+/-0.03 channels per square micrometer [failing hearts, n=5] versus 1.2+/-0.1 channels per square micrometer [control hearts, n=3]; P<.001). Pharmacological reduction of I-to by 4-aminopyridine in control myocytes decreased the notch amplitude and prolonged the APD. Current clamp-release experiments in which current was injected for 8 milliseconds to reproduce the notch sufficed to shorten the APD signi ficantly in cells from failing hearts. These data support the hypothes is that downregulation of I-to in pacing-induced heart failure is at l east partially responsible for the action potential prolongation. Beca use the repolarization abnormalities mimic those in cells isolated fro m failing human ventricular myocardium, canine pacing-induced cardiomy opathy may provide insights into the development of repolarization abn ormalities and the mechanisms of sudden death in patients with heart f ailure.