Accentuated vagal antagonism paradoxically increases ryanodine receptor calcium leak in long-term exercised Calsequestrin2 knockout mice.

Background: Long-term aerobic exercise alters autonomic balance, which may not be favorable in heart rate (HR)-dependent arrhythmic diseases including catecholaminergic polymorphic ventricular tachycardia (CPVT) because of preexisting bradycardia and increased sensitivity to parasympathetic stimulation.

Objective: The purpose of this study was to determine whether 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) Ca leak in atrial (ACM) and ventricular (VCM) cardiomyocytes, in exercised (EX) calsequestrin knockout (CASQ2) mice, a model of CPVT.

Results: Although 8-week treadmill running improved exercise capacity in EX CPVT mice, the incidence and duration of ventricular tachycardia also increased. HR variability analyses revealed an increased high-frequency component of the power spectrum and root mean square of successive differences in R-R intervals indicating accentuated vagal antagonism during β-adrenergic stimulation resulting in negligible HR acceleration. In EX CASQ2 VCM, peak amplitude of Ca transient (CaT) increased, whereas SR Ca content decreased. Aberrant Ca sparks occurred at baseline, which was exacerbated with isoproterenol. Notably, although 10 μM of the cholinergic agonist carbachol prevented isoproterenol-induced Ca waves in ACM, CaT amplitude, SR Ca load, and isoproterenol-induced Ca waves paradoxically increased in VCM. In parallel, ventricular ryanodine receptor (RyR2) protein expression increased, whereas protein kinase A- and calmodulin-dependent protein kinase II-mediated phosphorylation of RyR2 was not significantly altered, which could imply an 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 Ca leak in EX CASQ2 VCM.