Rats selectively bred for low aerobic capacity(LCR) develop characteristics resembling the metabolic syndrome and animals with cardiac dysfunction. Rats selected for high aerobic capacity (HCR) develop athletic characteristics. We hypothesized that LCR rats are more susceptible for ventricular arrhythmias and this relates to increased diastolic SR Ca2+ leak.Methods and results
We assessed susceptibility to ventricular fibrillation by burst pacing in Langendorff perfused hearts and observed that LCR rats were more susceptible for ventricular fibrillation. In isolated cardiomyocytes we measured Ca2+-handling with FURA2/AM on an inverted epi-fluorescence microscope. Cardiomyocyte function was significantly depressed in LCR rats compared to HCR; fractional shortening was 37% lower and time to 50% relenghtening was 53% longer. In line with impaired contractile function, Ca2+ amplitude and SR Ca2+ content was reduced by 21% and a prolonged decay. During sustained caffeine-stimulation, Ca2+ decay in LCR rats were faster, reflecting increased NCX function. SERCA-2a function was, however, significantly impaired (38% reduction). Furthermore, T-tubule density and synchrony of twitch Ca2+ release was reduced in LCR. By measuring diastolic Ca2+ in quiescent myocytes with and without tetracaine we found 87% more SR Ca2+ leak in LCR rats compared to HCR. The diastolic Ca2+-leak was reduced after CaMKII inhibition, but not by PKA-inhibition. CaMKII activation was confirmed by Western blot analyses displaying increased theorine-286 phosphorylation on CaMKII and increased RyR-phosphorylation at the Serine-2814 site.Conclusion
Impaired Ca2+ handling and increased diastolic SR Ca2+ leak together with increased NCX function may explain increased susceptibility to ventricular arrhythmias in LCR rats with metabolic syndrome. CaMKII is a central player of increased diastolic Ca2+-leak and may serve as a potential target for reducing ventricular fibrillation in these rats.