Paradoxical Effect of Increased Diastolic Ca Release and Decreased Sinoatrial Node Activity in a Mouse Model of Catecholaminergic Polymorphic Ventricular Tachycardia

Catecholaminergic polymorphic ventricular tachycardia is a congenital arrhythmogenic disease linked to -adrenergic–induced ventricular arrhythmias that has a high mortality in children and young adults when untreated. As common features of the catecholaminergic polymorphic ventricular tachycardia phenotype, supraventricular arrhythmias have also been described in catecholaminergic polymorphic ventricular tachycardia patients. The reason why ventricular myocytes exhibit stress-induced hyperactivity (ventricular ectopies and tachycardia) whereas sinoatrial node is often hypoactive (sinus bradycardia) remains elusive. Here, we explored for the first time [Ca ]i activity of sinoatrial node cells in intact tissues obtained from a mouse bearing the RyR2 catecholaminergic polymorphic ventricular tachycardia mutation. Our results indicate that RyR2 mice manifest a high incidence of sinoatrial node dysrhythmia (pauses) and an impaired positive chronotropic response to -adrenergic stimulation. In RyR2 sinoatrial node, there is an aberrant Ca homeostasis characterized by an increase in the diastolic Ca release at any time during the diastolic period. This almost continuous and low-grade Ca leakage unloads the sarcoplasmic reticulum, which in turn hampers action potential triggering and decreases the sinus rate. We provide here a mechanistic rationale for sinoatrial node dysfunction in catecholaminergic polymorphic ventricular tachycardia patients. Future work should focus on testing pharmacological approaches to treat dysfunction of heart automaticity using this novel ex vivo physiological preparation. See p 392.