NAD metabolism in inherited cardiomyopathies

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The heart is the most energy consuming organ of the body. Under physiological conditions, proper heart function results from the fine orchestration of ion fluxes, the contractile apparatus, and mitochondrial metabolism in cardiomyocytes. In heart failure (HF), these equilibria are critically disturbed, and energetic mismatch can lead to oxidative stress, maladaptive signalling, structural remodelling and contractile dysfunction. In inherited cardiomyopathies, defects in the sarcomeric apparatus, mitochondrial metabolism or signalling molecules can induce HF with variable phenotypes, spanning from reduced to preserved or even hyperdynamic contractile function. A central molecule to cardiac energy metabolism, redox regulation and signalling is nicotinamide adenine dinucleotide (NAD). Previous studies from members of this consortium revealed that in HF, NAD metabolism is disturbed, and that NAD supplementation improves the cardiac phenotype. However, it is unclear whether these effects are caused by influencing NAD-dependent signaling events or redox regulation interfacing with excitation-contraction coupling, or both. In NADINCARD, three teams combine their complementary expertise to explore the role of NAD metabolism and signalling at the cellular and subcellular level in cardiomyocytes, using animal and human cell-based models of hereditary cardiomyopathies. NADINCARD will identify critical regulatory mechanisms, relevant targets and metabolic pathways governing heart function. We expect that this fundamental research will be translated into long-term opportunities for prevention, screening, monitoring, diagnosis and therapy of inherited cardiomyopathies.