Molecular mechanism of sarcomeric cardiomyopathies

In the early 1990s, researchers identified a genetic basis for hypertrophic cardiomyopathy (HCM) (Geisterfer-Lowrance et al., Cell, 62(5):999-1006, 1990). They proposed that mutations in sarcomeric genes are causal for the hypertrophic phenotype. This opened the door to a new understanding of the disease pathology (Seidman and Seidman, Cell, 104(4):557-67, 2001). Experimentation into the molecular mechanisms of these mutations, along with increased genetic testing, revealed that sarcomeric gene mutations are also causal for dilated cardiomyopathy (DCM) and restrictive cardiomyopathy (RCM). This led to the redefining of these familial diseases as sarcomeric cardiomyopathies (Tardiff et al., Cardiovasc Res, 105(4):457-70, 2015; van der Velden et al., Cardiovasc Res, 105(4):449-56, 2015). This chapter provides an overview of the molecular mechanisms of sarcomeric cardiomyopathies and experimental therapies that target these mechanisms.