Rats selectively bred for inborn Low Capacity of Running (LCR) display a series of poor health indices whereas rats selected for High Capacity of Running (HCR) display a healthy profile. We hypothesized that selection of low aerobic capacity over generations leads to a phenotype with increased diastolic Ca2+ leak that trigger arrhythmia. METHODS: We used rats selected for HCR (N=10) or LCR (N=10) to determine the effect of inborn aerobic capacity on Ca2+ leak and susceptibility of ventricular arrhythmia. We studied isolated FURA2/AM loaded cardiomyocytes to detect Ca2+ -handling and function on an inverted epi-fluorescence microscope. To determine arrhythmogenicity we did a final experiment with electrical burst pacing in Langendorff perfused hearts. RESULTS: Ca2+ -handling was impaired by reduced Ca2+ amplitude, prolonged time to 50% Ca2+ decay, and reduced sarcoplasmic reticulum (SR) Ca2+ -content. Impaired Ca2+ removal was influenced by reduced SR Ca2+ ATP-ase 2a (SERCA2a) function and increased sodium/Ca2+ -exchanger (NCX) in LCR rats. Diastolic Ca2 leak was 87% higher in LCR rats. The leak was reduced by CaMKII inhibition. Expression levels of phosphorylated theorine-286 CaMKII levels and increased RyR2 phosphorylation at the Serine-2814 site mechanistically support our findings of increased leak in LCR. LCR rats had significantly higher incidence of ventricular fibrillation. CONCLUSION: Selection of inborn low aerobic capacity over generations leads to a phenotype with increased risk of ventricular fibrillation. Increased phosphorylation of CaMKII at serine-2814 at the cardiac ryanodine receptor appears as an important mechanism of impaired Ca2+ handling and diastolic Ca2+ leak that results in increased susceptibility to ventricular fibrillation.
|Titolo:||Reduced aerobic capacity causes leaky ryanodine receptors that trigger arrhythmia in a rat strain artificially selected and bred for low aerobic running capacity|
|Parole Chiave:||Heart Failure; Calcium metabolism; Inotropism|
|Settore Scientifico Disciplinare:||Settore MED/11 - Malattie dell'Apparato Cardiovascolare|
|Data di pubblicazione:||apr-2014|
|Digital Object Identifier (DOI):||10.1111/apha.12238|
|Appare nelle tipologie:||01 - Articolo su periodico|