Polymorphic ventricular tachycardia and abnormal Ca2+ handling in very-long-chain acyl-CoA dehydrogenase null mice

Andreas A. Werdich, Franz Baudenbacher, Igor Dzhura, Loice H. Jeyakumar, Prince J. Kannankeril, Sidney Fleischer, Alison LeGrone, Dejan Milatovic, Michael Aschner, Arnold W. Strauss, Mark E. Anderson, Vernat J. Exil

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

Patients with mutations in the mitochondrial very-long-chain acyl-CoA dehydrogenase (VLCAD) gene are at risk for cardiomyopathy, myocardial dysfunction, ventricular tachycardia (VT), and sudden cardiac death. The mechanism is not known. Here we report a novel mechanism of VT in mice lacking VLCAD (VLCAD-/-). These mice exhibited polymorphic VT and increased incidence of VT after isoproterenol infusion. Polymorphic VT was induced in 10 out of 12 VLCAD-/- mice (83%) when isoproterenol was used. One out of 10 VLCAD-/- mice with polymorphic VT had VT with the typical bidirectional morphology. At the molecular level, VLCAD-/- cardiomyocytes showed increased levels of cardiac ryanodine receptor 2, phospholamban, and calsequestrin with increased [3H]ryanodine binding in heart microsomes. At the single cardiomyocyte level, VLCAD-/- cardiomyocytes showed significant increase in diastolic indo 1 and fura 2 fluorescence, with increased Ca2+ transient amplitude. These changes were associated with altered Ca2+ dynamics, to include: faster sarcomere contraction, larger time derivative of the upstroke, and shorter time-to-minimum sarcomere length compared with VLCAD+/+ control cells. The L-type Ca2+ current characteristics were not different under voltage-clamp conditions in the two VLCAD genotypes. Sarcoplasmic reticulum Ca2+ load measured as normalized integrated Na +/Ca2+ exchange current after rapid caffeine application was increased by 48% in VLCAD-/- cells. We conclude that intracellular Ca2+ handling represents a possible molecular mechanism of arrhythmias in mice and perhaps in VLCAD-deficient humans.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume292
Issue number5
DOIs
StatePublished - May 2007
Externally publishedYes

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Long-Chain Acyl-CoA Dehydrogenase
Ventricular Tachycardia
Cardiac Myocytes
Sarcomeres
human ACADVL protein
Isoproterenol
Calsequestrin
Ryanodine
Ryanodine Receptor Calcium Release Channel
Fura-2
Sudden Cardiac Death
Sarcoplasmic Reticulum
Microsomes
Caffeine
Cardiomyopathies
Cardiac Arrhythmias
Fluorescence
Genotype

Keywords

  • Calcium ion
  • Genetics
  • Inborn errors
  • Ryanodine receptor
  • Ventricular tachycardia

ASJC Scopus subject areas

  • Physiology

Cite this

Polymorphic ventricular tachycardia and abnormal Ca2+ handling in very-long-chain acyl-CoA dehydrogenase null mice. / Werdich, Andreas A.; Baudenbacher, Franz; Dzhura, Igor; Jeyakumar, Loice H.; Kannankeril, Prince J.; Fleischer, Sidney; LeGrone, Alison; Milatovic, Dejan; Aschner, Michael; Strauss, Arnold W.; Anderson, Mark E.; Exil, Vernat J.

In: American Journal of Physiology - Heart and Circulatory Physiology, Vol. 292, No. 5, 05.2007.

Research output: Contribution to journalArticle

Werdich, AA, Baudenbacher, F, Dzhura, I, Jeyakumar, LH, Kannankeril, PJ, Fleischer, S, LeGrone, A, Milatovic, D, Aschner, M, Strauss, AW, Anderson, ME & Exil, VJ 2007, 'Polymorphic ventricular tachycardia and abnormal Ca2+ handling in very-long-chain acyl-CoA dehydrogenase null mice', American Journal of Physiology - Heart and Circulatory Physiology, vol. 292, no. 5. https://doi.org/10.1152/ajpheart.00382.2006
Werdich, Andreas A. ; Baudenbacher, Franz ; Dzhura, Igor ; Jeyakumar, Loice H. ; Kannankeril, Prince J. ; Fleischer, Sidney ; LeGrone, Alison ; Milatovic, Dejan ; Aschner, Michael ; Strauss, Arnold W. ; Anderson, Mark E. ; Exil, Vernat J. / Polymorphic ventricular tachycardia and abnormal Ca2+ handling in very-long-chain acyl-CoA dehydrogenase null mice. In: American Journal of Physiology - Heart and Circulatory Physiology. 2007 ; Vol. 292, No. 5.
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abstract = "Patients with mutations in the mitochondrial very-long-chain acyl-CoA dehydrogenase (VLCAD) gene are at risk for cardiomyopathy, myocardial dysfunction, ventricular tachycardia (VT), and sudden cardiac death. The mechanism is not known. Here we report a novel mechanism of VT in mice lacking VLCAD (VLCAD-/-). These mice exhibited polymorphic VT and increased incidence of VT after isoproterenol infusion. Polymorphic VT was induced in 10 out of 12 VLCAD-/- mice (83{\%}) when isoproterenol was used. One out of 10 VLCAD-/- mice with polymorphic VT had VT with the typical bidirectional morphology. At the molecular level, VLCAD-/- cardiomyocytes showed increased levels of cardiac ryanodine receptor 2, phospholamban, and calsequestrin with increased [3H]ryanodine binding in heart microsomes. At the single cardiomyocyte level, VLCAD-/- cardiomyocytes showed significant increase in diastolic indo 1 and fura 2 fluorescence, with increased Ca2+ transient amplitude. These changes were associated with altered Ca2+ dynamics, to include: faster sarcomere contraction, larger time derivative of the upstroke, and shorter time-to-minimum sarcomere length compared with VLCAD+/+ control cells. The L-type Ca2+ current characteristics were not different under voltage-clamp conditions in the two VLCAD genotypes. Sarcoplasmic reticulum Ca2+ load measured as normalized integrated Na +/Ca2+ exchange current after rapid caffeine application was increased by 48{\%} in VLCAD-/- cells. We conclude that intracellular Ca2+ handling represents a possible molecular mechanism of arrhythmias in mice and perhaps in VLCAD-deficient humans.",
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AU - Jeyakumar, Loice H.

AU - Kannankeril, Prince J.

AU - Fleischer, Sidney

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AU - Milatovic, Dejan

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AB - Patients with mutations in the mitochondrial very-long-chain acyl-CoA dehydrogenase (VLCAD) gene are at risk for cardiomyopathy, myocardial dysfunction, ventricular tachycardia (VT), and sudden cardiac death. The mechanism is not known. Here we report a novel mechanism of VT in mice lacking VLCAD (VLCAD-/-). These mice exhibited polymorphic VT and increased incidence of VT after isoproterenol infusion. Polymorphic VT was induced in 10 out of 12 VLCAD-/- mice (83%) when isoproterenol was used. One out of 10 VLCAD-/- mice with polymorphic VT had VT with the typical bidirectional morphology. At the molecular level, VLCAD-/- cardiomyocytes showed increased levels of cardiac ryanodine receptor 2, phospholamban, and calsequestrin with increased [3H]ryanodine binding in heart microsomes. At the single cardiomyocyte level, VLCAD-/- cardiomyocytes showed significant increase in diastolic indo 1 and fura 2 fluorescence, with increased Ca2+ transient amplitude. These changes were associated with altered Ca2+ dynamics, to include: faster sarcomere contraction, larger time derivative of the upstroke, and shorter time-to-minimum sarcomere length compared with VLCAD+/+ control cells. The L-type Ca2+ current characteristics were not different under voltage-clamp conditions in the two VLCAD genotypes. Sarcoplasmic reticulum Ca2+ load measured as normalized integrated Na +/Ca2+ exchange current after rapid caffeine application was increased by 48% in VLCAD-/- cells. We conclude that intracellular Ca2+ handling represents a possible molecular mechanism of arrhythmias in mice and perhaps in VLCAD-deficient humans.

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