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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) Ca2+ 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 Ca2+ transient (CaT) increased, whereas SR Ca2+ content decreased. Aberrant Ca2+ sparks occurred at baseline, which was exacerbated with isoproterenol. Notably, although 10 μM of the cholinergic agonist carbachol prevented isoproterenol-induced Ca2+ waves in ACM, CaT amplitude, SR Ca2+ load, and isoproterenol-induced Ca2+ 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 Ca2+ leak in EX CASQ2-/- VCM. [ABSTRACT FROM AUTHOR]