Polymorphic ventricular tachycardia and abnormal Ca2+ handling in very-long-chain acyl-CoA dehydrogenase null mice.
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 [(3)H]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 Ca(2+) transient amplitude. These changes were associated with altered Ca(2+) 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 Ca(2+) current characteristics were not different under voltage-clamp conditions in the two VLCAD genotypes. Sarcoplasmic reticulum Ca(2+) load measured as normalized integrated Na(+)/Ca(2+) exchange current after rapid caffeine application was increased by 48% in VLCAD(-/-) cells. We conclude that intracellular Ca(2+) handling represents a possible molecular mechanism of arrhythmias in mice and perhaps in VLCAD-deficient humans.
Werdich
Andreas A
AA
Division of Cardiology, Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, TN 37232-0001, USA.
Baudenbacher
Franz
F
Dzhura
Igor
I
Jeyakumar
Loice H
LH
Kannankeril
Prince J
PJ
Fleischer
Sidney
S
LeGrone
Alison
A
Milatovic
Dejan
D
Aschner
Michael
M
Strauss
Arnold W
AW
Anderson
Mark E
ME
Exil
Vernat J
VJ
D044942:Acyl-CoA Dehydrogenase, Long-Chain / Q000172:deficiency* / Q000235:genetics; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling; D005260:Female; D006352:Heart Ventricles / Q000503:physiopathology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D017180:Tachycardia, Ventricular / Q000503:physiopathology*
D044942:Acyl-CoA Dehydrogenase, Long-Chain; D002118:Calcium