Intracellular calcium-triggered arrhythmia: new insights from catecholaminergic polymorphic ventricular tachycardia. – ARyRthmia

CPVT is an autosomally inherited cardiac disease characterized by exercise- or stress-induced tachyarrhythmia episodes in the absence of apparent structural heart disease or prolonged QT interval.The disease is highly malignant, often manifesting for the first time in childhood or adolescence through syncopal events and/or SCD. Although the disease is not physically incapacitating, CPVT patients have a mortality rate of ~30-50% by the age of 35 years. Early diagnosis of mutant carriers is therefore critical. ß-blockers, the standard therapy in CPVT, provides only partial protection against arrhythmias and implantable cardioverters defibrillators (ICD), although capable of improving survival, do so at considerable cost and with low efficiency.The autosomal dominant variant of CPVT (CPVT1) is caused by mutations in RYR2, the gene encoding for the cardiac isoform of the RyR (RyR2), but CPVT is clearly an arrhythmogenic disorder stemming from intracellular Ca2+ mishandling, as mutations in CSQ2, the gene encoding for cardiac calsequestrin, the main Ca2+ buffering protein of the SR, also cause an autosomal recessive form of the disease (CPVT2).
Ca2+-dependent arrhythmias in CPVT are the product of complex electro-mechanical phenomena emerging only at higher levels of biological organization. An in-depth approach to investigate these phenomena cannot be accomplished in any single laboratory. Therefore, we have assembled a group of experienced and internationally distinguished investigators using state-of the art techniques to continue existing and initiate new collaborations. These investigators are major experts in areas that span the whole spectrum of cardiac electrophysiology from the molecule to the bedside. They will confront the vital problem of Ca2+-dependent arrhythmias in a highly synergistic and systematic way.
The Central Objective of this research program is to elucidate the mechanisms of the life-threatening ventricular arrhythmias that develop in patients with CPVT to provide a solid rationale for new and effective therapies. We expect to show that in CPVT patients the disruption of the signaling molecules that control the excitation-contraction coupling process leads to electrophysiological with consequent altered cardiac excitation, thus creating a substrate for the generation of cardiac rhythm disturbances.