Abstract
Introduction:Rats genetically selected and bred for low aerobic capacity (LCR) develop characteristics resembling to the metabolic syndrome and animals with heart failure. Rats selected for high aerobic capacity (HCR) develop athletic characteristics. We hypothesized that LCR rats are more susceptible for ventricular arrhythmias and that this relates to increased diastolic SR Ca2+ leak.Methods:We included 10 LCR and 10 HCR rats. We assessed susceptibility to ventricular fibrillation by burst pacing in Langendorff perfused hearts. In isolated cardiomyocytes we measured Ca2+-handling with FURA2/AM and action potential by di-8-ANEPPS on an inverted epi-fluoresence microscope.Results:LCR rats were more susceptible for ventricular fibrillation and monophasic action potential at the left ventricle was prolonged. Prolongation of the action potential was confirmed in single di-8-ANEPPS loaded cardiomyocytes. Cardiomyocyte function was significantly depressed in LCR rats compared to HCR; fractional shortening was 37% lower and time to 50% relenghtening was 53% longer. Ca2+-handling was impaired by elevated diastolic Ca2+, reduced Ca2+ amplitude and prolonged time to 50% Ca2+ decay. SR Ca2+ content was 21% lower and fractional Ca2+ release was 10% lower in LCR. During caffeine induced Ca2+ transient, we found no difference in Ca2+ decay between the two groups, reflecting unaltered NCX function; nor did we find any changes in the plasma membrane Ca2+, assessed by caffeine induced transients in a 0Na+/0Ca2+ solution. Diastolic Ca2+ removal is mainly attributed to reduced SERCA function by 15% in LCR rats. By measuring diastolic Ca2+ in quiescent myocytes with and without tetracaine we found 46% increased SR Ca2+ leak LCR rats.Conclusion:Impaired Ca2+ handling and increased diastolic SR Ca2+ leak together with prolonged action potential duration may explain increased susceptibility to ventricular arrhythmias in LCR rats with metabolic syndrome.
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