CHARACTERIZATION OF A KNOCK-IN MOUSE MODEL OF GENETICALLY DETERMINED SUDDEN CARDIAC DEATH: INSIGHTS FOR THE MANAGEMENT OF PATIENTS WITH CATECHOLAMINERGIC POLYMORPHIC VENTRICULAR TACHYCARDIA (CPVT)

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a genetically determined disorder of the cardiac excitability, manifesting with severe cardiac arrhythmias eventually leading to sudden death. CPVT typically manifests during childhood or adolescence with exercise- or emotion-related syncopal spells. CPVT is a known clinical entity since mid-70’s but only recently its pathophysiology has been brought to light by the discovery, in our lab, of mutations on the RyR2 gene in several CPVT patients. This information has a crucial relevance since it pinpoints the concept that CPVT is due to an abnormal control of calcium fluxes in the cardiac cells. Nonetheless, several poorly defined issues still exist: among the most important we may lists the lack of risk stratification schemes, the limited effectiveness of available therapy and the presence of CPVT patients with unknown gene defects. Recently we have developed a transgenic model of CPVT and we demonstrated that it closely replicates the manifestations of human disease, thus opening new approaches for better understanding of CPVT. This research project will carry out a detailed in vitro and in vivo characterization of our CPVT model with the final endpoint of gain more insights on CPVT pathophysiology and to develop novel therapies. The project will also include clinical investigations aimed at searching for novel CPVT genes, and analyzing genotype-phenotype correlation to identify predictors of response to therapy and risk factors for cardiac events. Furthermore, since CPVT arrhythmias have similar mechanism of selected arrhythmias implicated in sudden death in common disease such as heart failure we may foresee that the results of this project will also have positive fallouts beyond the boundaries of genetically determined arrhythmias.