HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: 292/5/H2202    most recent 00382.2006v2 00382.2006v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (6) Citing Articles via Google Scholar Google Scholar Articles by Werdich, A. A. Articles by Exil, V. J. Search for Related Content PubMed PubMed Citation Articles by Werdich, A. A. Articles by Exil, V. J.

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

³Division of Cardiology, Department of Pediatrics, Vanderbilt University School of Medicine, Nashville; ²Division of Gastroenterology, Vanderbilt University Medical Center, Nashville; Departments of ¹Biomedical Engineering and ⁴Biological Sciences, Vanderbilt University, Nashville, Tennessee; and ⁵Division of Cardiology, Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, Iowa

Submitted 10 April 2006 ; accepted in final form 26 December 2006

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.

genetics; inborn errors; ryanodine receptor; calcium ion; ventricular tachycardia

This article has been cited by other articles:

				F. ter Veld, S. Primassin, L. Hoffmann, E. Mayatepek, and U. Spiekerkoetter Corresponding increase in long-chain acyl-CoA and acylcarnitine after exercise in muscle from VLCAD mice J. Lipid Res., August 1, 2009; 50(8): 1556 - 1562. [Abstract] [Full Text] [PDF]

				A. A. Werdich, E. A. Lima, I. Dzhura, M. V. Singh, J. Li, M. E. Anderson, and F. J. Baudenbacher Differential effects of phospholamban and Ca2+/calmodulin-dependent kinase II on [Ca2+]i transients in cardiac myocytes at physiological stimulation frequencies Am J Physiol Heart Circ Physiol, May 1, 2008; 294(5): H2352 - H2362. [Abstract] [Full Text] [PDF]