Catecholaminergic polymorphic ventricular tachycardia is characterized by stress-triggered syncope and sudden death. Patients with catecholaminergic polymorphic ventricular tachycardia manifest sinoatrial node (SAN) dysfunction, the mechanisms of which remain unexplored.

We investigated SAN [Ca²⁺]_i handling in mice carrying the catecholaminergic polymorphic ventricular tachycardia–linked mutation of ryanodine receptor (RyR2^R4496C) and their wild-type (WT) littermates. In vivo telemetric recordings showed impaired SAN automaticity in RyR2^R4496C mice after isoproterenol injection, analogous to what was observed in catecholaminergic polymorphic ventricular tachycardia patients after exercise. Pacemaker activity was explored by measuring spontaneous [Ca²⁺]_i transients in SAN cells within the intact SAN by confocal microscopy. RyR2^R4496C SAN presented significantly slower pacemaker activity and impaired chronotropic response under β-adrenergic stimulation, accompanied by the appearance of pauses (in spontaneous [Ca²⁺]_i transients and action potentials) in 75% of the cases. Ca²⁺ spark frequency was increased by 2-fold in RyR2^R4496C SAN. Whole-cell patch-clamp experiments performed on isolated RyR2^R4496C SAN cells showed that L-type Ca²⁺ current (I_Ca,L) density was reduced by ≈50%, an effect blunted by internal Ca²⁺ buffering. Isoproterenol dramatically increased the frequency of Ca²⁺ sparks and waves by ≈5 and ≈10-fold, respectively. Interestingly, the sarcoplasmic reticulum Ca²⁺ content was significantly reduced in RyR2^R4496C SAN cells in the presence of isoproterenol, which may contribute to stopping the “Ca²⁺ clock” rhythm generation, originating SAN pauses.

The increased activity of RyR2^R4496C in SAN leads to an unanticipated decrease in SAN automaticity by a Ca²⁺-dependent decrease of I_Ca,L and sarcoplasmic reticulum Ca²⁺ depletion during diastole, identifying subcellular pathophysiological alterations contributing to the SAN dysfunction in catecholaminergic polymorphic ventricular tachycardia patients.