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 [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.