CLINICAL, EXPERIMENTAL AND MOLECULAR CHARACTERIZATION OF CATECHOLAMINERGIC POLYMORPHIC VENTRICULAR TACHYCARDIA (CPVT)

Recent data from our laboratory demonstrate that RyR2 is a new disease-related gene involved in an inherited form of cardiac arrhythmias the so-called Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT). This gene plays a pivotal role in the modulation of intracellular calcium handling and in the excitation-contraction coupling in myocardial cells. RyR2 mutations create a vulnerable substrate favoring the development of malignant ventricular arrhythmias and sudden death during exercise and emotion. The association between RyR2 defects and CPVT demonstrates for the first time that abnormal function of proteins controlling intracellular calcium levels predisposes to the development of cardiac arrhythmias and sudden death. The aim of the present research project is to investigate the pathophysiology of CPVT using a global strategy spanning from clinical evaluation to basic research. We plan to pursue our objective by: 1) Developing a national network for recruiting patients and families with CPVT and create a computerised database for data storage and analysis. 2) Performing molecular screening to identify RyR2 mutations and discover new genes responsible for CPVT. 3)Performing in vitro functional studies of RyR2 mutations identified in patients 4) Developing a transgenic mouse model carrying defective RyR2 in order to study the mechanisms of onset of arrhythmias and to identify new therapeutic strategies for CPVT. 5) Performing in vivo and in vitro electrophysiological characterization the genetically modified mice. In summary, our goal is to establish a global research strategy for CPVT targeted to the definition of the epidemiological, genetic and pathophysiological profile of this disease with the final endpoint of identifying new preventive and therapeutic strategies.