Idiopathic dilated cardiomyopathy (iDCM) is the most common cause of heart failure in the young/middle age population. A genetic basis is found in 20-50% of iDCM cases. Unfortunately, there is no effective therapy to reverse iDCM. The heart is a metabolically demanding organ and mitochondria are paramount to the survival and activity of cardiomyocytes. In a former collaboration, partners of this consortium identified imbalanced mitochondrial dynamics (fusion and fission) and mitochondrial fragmentation as an underlying cause of iDCM in mice. A cardiac metabolic switch was involved in the iDCM pathogenesis. More importantly, a simple dietary approach based on high fat diet was able to inhibit this metabolic switch and prevent iDCM. The proposed work program seeks to uncover the nature of these cardioprotective dietary elements in small and large animal models with the ultimate aim of developing a novel therapy to treat iDCM in humans. Mice with overt iDCM will be fed diets composed of different substrates (fatty acids, carbohydrates, and proteins) and different compositions of fatty acids in order to pinpoint the dietary components responsible for cardioprotection. Porcine iDCM models will expand the translational relevance of these discoveries. Screening of iDCM patients for germline mutations affecting mitochondrial dynamics will be tested in vitro to evaluate the impact on mitochondrial fusion and fission. Overall, this project will provide the foundation for future clinical trial testing a simple, cost-effective therapy aimed at curbing the heart failure epidemic.