Ionic mechanism of action potential prolongation in ventricular myocytes from dogs with pacing-induced heart failure

Stefan Kääb, H. Bradley Nuss, Nipavan Chiamvimonvat, Brian O'Rourke, Peter H. Pak, David A. Kass, Eduardo Marban, Gordon F. Tomaselli

Research output: Contribution to journalArticle

459 Citations (Scopus)

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 I 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 (I(K1)) 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 I(K1) 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 Ca2+-independent transient outward current (I(to)) 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 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 significantly in cells from failing hearts. These data support the hypothesis that downregulation of I(to) 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.

Original languageEnglish (US)
Pages (from-to)262-273
Number of pages12
JournalCirculation Research
Volume78
Issue number2
DOIs
StatePublished - Jan 1 1996
Externally publishedYes

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Muscle Cells
Action Potentials
Heart Failure
Dogs
Cardiomyopathies
4-Aminopyridine
Sudden Death
Membrane Potentials
Canidae
Myocardium
Down-Regulation
Animal Models

Keywords

  • action potential
  • animal model
  • heart failure
  • K current
  • transient outward current

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Ionic mechanism of action potential prolongation in ventricular myocytes from dogs with pacing-induced heart failure. / Kääb, Stefan; Nuss, H. Bradley; Chiamvimonvat, Nipavan; O'Rourke, Brian; Pak, Peter H.; Kass, David A.; Marban, Eduardo; Tomaselli, Gordon F.

In: Circulation Research, Vol. 78, No. 2, 01.01.1996, p. 262-273.

Research output: Contribution to journalArticle

Kääb, Stefan ; Nuss, H. Bradley ; Chiamvimonvat, Nipavan ; O'Rourke, Brian ; Pak, Peter H. ; Kass, David A. ; Marban, Eduardo ; Tomaselli, Gordon F. / Ionic mechanism of action potential prolongation in ventricular myocytes from dogs with pacing-induced heart failure. In: Circulation Research. 1996 ; Vol. 78, No. 2. pp. 262-273.
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AU - Kääb, Stefan

AU - Nuss, H. Bradley

AU - Chiamvimonvat, Nipavan

AU - O'Rourke, Brian

AU - Pak, Peter H.

AU - Kass, David A.

AU - Marban, Eduardo

AU - Tomaselli, Gordon F.

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N2 - 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 I 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 (I(K1)) 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 I(K1) 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 Ca2+-independent transient outward current (I(to)) 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 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 significantly in cells from failing hearts. These data support the hypothesis that downregulation of I(to) 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.

AB - 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 I 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 (I(K1)) 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 I(K1) 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 Ca2+-independent transient outward current (I(to)) 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 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 significantly in cells from failing hearts. These data support the hypothesis that downregulation of I(to) 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.

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