In order to determine the structural basis for the RyR2-mediated diastolic SR Ca2+ leak observed in arrhythmic and failing hearts we solved the structures of mutant RyR2 channels that can cause CPVT or HF, including the phosphomimetic RyR2-S2808D mutant channel which results in a cardiomyopathy with reduced cardiac function16 and the CPVT mutant channels RyR2-R420Q and RyR2-R420W34–41. This evidence concerns the gene RYR2 and cardiomyopathy.