The Cardiac Sarcomere: From development of heritable cardiomyopathies to gene and precision therapies

The cardiac sarcomere forms the fundamental contractile unit of the myocardium, and its precise structural and regulatory integrity is essential for normal cardiac function. Over the past several decades, advances in functional and structural biology, as well as molecular genetics, have improved our understanding of how sarcomeric protein dysfunction gives rise to inherited cardiomyopathies. This review combines current knowledge on sarcomere-associated hypertrophic cardiomyopathy and dilated cardiomyopathy, focusing on clinical presentation, genetic basis, and the mechanisms that link pathogenic variants to phenotypic manifestations. We highlight how disease-associated variants in sarcomeric genes, such as MYBPC3 , MYH7 , TNNC1 , TNNI3 and TNNT2 , perturb force generation, calcium handling, and myofilament turnover, ultimately driving hypertrophic or dilated phenotypes through distinct, yet overlapping, molecular cascades. Emerging sarcomere-targeted small molecular and gene therapies are discussed, including small-molecule myosin modulators, RNA-based strategies, and in vivo gene-editing approaches aimed at halting or reversing disease progression. These sarcomere-directed precision therapeutics are promising avenues in the treatment of inherited cardiomyopathies and other cardiovascular diseases.