Reduced aerobic capacity causes leaky ryanodine receptors that trigger arrhythmia in a rat strain artificially selected and bred for low aerobic running capacity

Høydal, M.A., Stølen, T.O., Johnsen, A.B., Alvez, M., Catalucci, D., Condorelli, G., Koch, L.G., Britton, S.L., Smith, G.L. and Wisløff, U. (2014) Reduced aerobic capacity causes leaky ryanodine receptors that trigger arrhythmia in a rat strain artificially selected and bred for low aerobic running capacity. Acta Physiologica, 210(4), pp. 854-864. (doi:10.1111/apha.12238)

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Abstract

Aim: 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 Fura-2/AM-loaded cardiomyocytes to detect Ca2+ handling and function on an inverted epifluorescence 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 threonine 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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Smith, Professor Godfrey
Authors: Høydal, M.A., Stølen, T.O., Johnsen, A.B., Alvez, M., Catalucci, D., Condorelli, G., Koch, L.G., Britton, S.L., Smith, G.L., and Wisløff, U.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
Journal Name:Acta Physiologica
Publisher:Wiley-Blackwell
ISSN:1748-1708
ISSN (Online):1748-1716

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