3 years ago

Long-term aerobic exercise in Calsequestrin2 knockout mice accentuates vagal antagonism during β-adrenergic stimulation which restricts heart rate acceleration and paradoxically increases abnormal ryanodine receptor calcium leak in ventricular myocytes

Long-term aerobic exercise (EX) alters autonomic balance which may not be favorable in heart rate (HR) dependent arrhythmic diseases including Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) due to preexisting bradycardia and increased sensitivity to parasympathetic stimulation. Objective The purpose of this study was to determine if long-term exercise-induced autonomic adaptations modify CPVT susceptibility. Methods We determined exercise-induced parasympathetic effects on HR, arrhythmia incidence and intracellular sarcoplasmic reticulum (SR) Ca2+ leak in atrial (ACM) and ventricular (VCM) cardiomyocytes, in EX Calsequestrin knockout (CASQ2-/-) mice, a model of CPVT. Results While 8-weeks treadmill running improved exercise capacity in EXCPVT mice, incidence and duration of ventricular tachycardia also increased. HR variability (HRV) analyses revealed increased high frequency component of the power spectrum and RMSSD values indicating accentuated vagal antagonism during β-adrenergic stimulation resulting in negligible HR acceleration. In EXCASQ2-/- VCM, peak amplitude of Ca2+ transient (CaT) increased while SR Ca2+ content decreased. Aberrant Ca2+ sparks occurred at baseline which exacerbated with Isoproterenol. Notably, while 10μM of cholinergic agonist, Carbachol, prevented Isoproterenol-induced Ca2+ waves in ACM, SR CaT amplitude, Ca2+ load and Isoproterenol-induced Ca2+ waves paradoxically increased in VCM. In parallel, ventricular ryanodine receptor (RyR2) protein expression increased, while PKA and CaMKII mediated phosphorylation of RyR2 was not significantly altered, which could imply increased number of “leaky” channels. Conclusion Our novel results suggest that long-term exercise in CASQ2-/- mice increases susceptibility to ventricular arrhythmias by accentuating vagal antagonism during β-adrenergic challenge which prevents HR acceleration and exacerbates abnormal RyR2 Ca2+ leak in EXCASQ2-/- VCM.

Publisher URL: www.sciencedirect.com/science

DOI: S1547527117312018

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