Molecular, cardiac and neuronal mechanisms underlying catecholaminergic polymorphic ventricular tachycardia

Single-point mutations in cardiac ryanodine receptors (RyR2) can cause catecholaminergic polymorphic ventricular tachycardia (CPVT1), an inheritable, life-threatening arrhythmic disease. Arrhythmias are assumed to arise because RyR2 channels become ‘leaky’.

However, this simplistic overview of CPVT1 masks the complexity of the disease and prevents improved treatments from being developed.

Many studies report the cardiac effects of CPVT1 mutations in mouse models and the clinical manifestations in patients, yet the primary changes in RyR2 ion-channel function are largely undescribed.

Additionally, although there is evidence for a neuronal influence in CPVT1, and patients are sometimes inadvertently treated for epilepsy, the impact of anti-seizure drug (ASD) treatment is unknown.

I propose to characterise the detailed changes to RyR2 channel function that arise from CPVT1 mutations from three distinct RyR2 regions (N-terminal Domain, Helical-Domain-1 and Channel Domain) and which associate with divergent patient symptoms.

In parallel, I will examine the CPVT1-linked changes in neuronal activity in mouse brain slices and investigate the effects of ASDs on RyR2 channel function, on SR Ca2+-release in isolated cardiomyocytes and on cardiac rhythm in vivo.

Our results will provide mechanistic insight into the primary molecular changes of CPVT1 so that treatments can be tuned specifically to individual patient needs.