Ionic Mechanism of Action Potential Prolongation in Ventricular Myocytes From Dogs With Pacing-Induced Heart Failure

Abstract

Membrane current abnormalities have been described in human heart failure. To determine whether similar current changes are observed in a large animal model of heart failure, we studied dogs with pacing-induced cardiomyopathy. Myocytes isolated from the midmyocardium of 13 dogs with 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 ventricles (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 not differ in cells from failing and from control hearts, but significant differences in K+ currents were observed. The density of the inward rectifier K+ current (IKl) was reduced in cells from failing hearts at test potentials below -90 mV (at -150 mV, -19.1 +/- 2.2 pA/pF [failing hearts, n = 18] versus -32.2 +/- 5.1 pA/pF [control hearts, n = 15]; P < .05). The small outward current component of IKl was also reduced in cells from failing hearts (at -60 mV, 1.7 +/- 0.2 pA/pF [failing hearts] versus 2.5 +/- 0.2 pA/pF [control hearts]; P < .05). The peak of the Ca(2+)-independent transient outward current (Ito) was dramatically reduced in myocytes isolated from failing hearts compared with nonfailing control 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 Ito kinetics or single-channel conductance. A reduction in the number of functional Ito 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 Ito 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 significantly in cells from failing hearts. These data support the hypothesis that downregulation of Ito in pacing-induced heart failure is at least partially responsible for the action potential prolongation. Because the repolarization abnormalities mimic those in cells isolated from failing human ventricular myocardium, canine pacing-induced cardiomyopathy may provide insights into the development of repolarization abnormalities and the mechanisms of sudden death in patients with heart failure.

Reduction in Kv Current Enhances the Temporal Dispersion of the Action Potential in Diabetic Myocytes: Insights From a Novel Repolarization Algorithm

“…Our electrophysiological data support the possibility that similar alterations occur in the STZ‐hyperglycemic mouse model employed here. Importantly, reduction in the outward K + Kv currents and prolongation of AP duration in mammals appear to be a conserved response to a variety of physio‐ and pathological conditions dictated by an increase in workload of the myocardium, including ischemic cardiomyopathy,60, 61 hypertension,62 pressure overload,63 aging,20, 64 and heart failure 18, 65, 66. Thus, the enhanced beat‐to‐beat variability observed in diabetic myocytes may represent a feature shared with other diseased conditions.…”

Transcriptomic profiling of the canine tachycardia-induced heart failure model: global comparison to human and murine heart failure

“…Heart failure was induced by rapid pacing from the RV following the protocols approved by Johns Hopkins University Animal Care and Use Committee [23]. Briefly, animals were intubated and anesthetized; blood oxygen saturation and expired CO 2 were kept within the physiological range throughout the procedure.…”

“…Tissue samples from the hearts of four unoperated normal dogs were similarly obtained. We have previously shown that sham operated and unoperated controls exhibit similar mechanical, neurohumoral and electrophysiological phenotypes, thus to reduce cost and morbidity for the animals unoperated controls were used [9,11,23,24]. The canine pacing tachycardia model is characterized by systolic LV failure, preserved RV systolic function and no significant inflammation or fibrosis [24].…”

The role of arrhythmias in the progression of heart failure

“…a'i the lQ~a.J:d t:.ec:tifut:. CJl..t:.-rent, X KI , and the transient outward current, ITO' [5,6]; as well as a decrease in Na/K pump current [7]. It should be pointed out that the clinical relevance of the prolongation of action potential duration is still uncertain, since it has been shown to be present mostly at long, and often unphysiologic, cycle lengths.…”