Sudden cardiac death (SCD) caused by arrhythmias is a major cause of death in the United States. In recent years the identification of mutations in proteins that form sarcolemmal ion channels in inherited arrhythmic diseases has greatly contributed to the understanding of the substrate for life-threatening arrhythmias. But many questions remain unanswered. This application for funding of a new program project outlines multidisciplinary research on the arrhythmogenic bases of two different inherited diseases, Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) and Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT). The general objective is to determine how alterations of either structural or Ca2+ regulatory proteins translate into electrical abnormalities that ultimately result in life-threatening arrhythmias and SCD. Experimental and numerical approaches will be used to compare and contrast basic cellular and biophysical alterations underlying the possible arrhythmogenic mechanisms in patients suffering from these devastating diseases. Our proposed strategy derives from the idea that understanding the factors involved in the mechanisms of inherited arrhythmias requires an integrative approach. We have therefore assembled a group of three experimental and theoretical research projects that address fundamental questions on the mechanisms of arrhythmias in ARVC and CPVT. Collaborative work proposed under Projects 1 and 3 seeks to demonstrate that ARVC-relevant mutations that disrupt the integrity of the desmosome carry as a consequence the disruption of the gap junction plaque; and that the disruption of the gap junction plaque impairs the propagation of the cardiac action potential, thus creating a substrate for the generation of cardiac rhythm disturbances. To address the problem of CPVT, Projects 2 and 3 will utilize a unique knock in mouse model that recapitulates the phenotype of CPVT, which is characterized by adrenergically mediated rounds of bidirectional (biVT) and polymorphic (PVT) ventricular tachycardias leading to SCD. Mutually complementary work in both projects will test the hypothesis that biVT and PVT in the mouse model, and by inference in CPVT patients, are triggered by delayed afterdepolarizations (DADs) occurring at Purkinje fibers on the right and left branches of the specialized ventricular conducting system. In both ARVC and CPVT, numerical and biological experiments proposed by Project 3 should provide a solid link between the higher and the lower orders of integration. Accomplishing the work being proposed should provide new insight into fundamental mechanisms leading to complex cardiac rhythms and SCD.