| First Author | Werdich AA | Year | 2007 |
| Journal | Am J Physiol Heart Circ Physiol | Volume | 292 |
| Issue | 5 | Pages | H2202-11 |
| PubMed ID | 17209005 | Mgi Jnum | J:125923 |
| Mgi Id | MGI:3760202 | Doi | 10.1152/ajpheart.00382.2006 |
| Citation | Werdich AA, et al. (2007) Polymorphic ventricular tachycardia and abnormal Ca2+ handling in very-long-chain acyl-CoA dehydrogenase null mice. Am J Physiol Heart Circ Physiol 292(5):H2202-11 |
| abstractText | 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. |
