Pathogenic variants in sarcomeric genes drive inherited cardiomyopathies, and emerging sarcomere-targeted small molecules and gene therapies offer promising avenues for precision treatment.
This review summarizes the molecular mechanisms linking sarcomeric gene variants to inherited cardiomyopathies and highlights emerging precision therapies aimed at halting or reversing disease progression.
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.
Shi et al. (Wed,) conducted a review in Inherited cardiomyopathies. Pathogenic variants in sarcomeric genes drive inherited cardiomyopathies, and emerging sarcomere-targeted small molecules and gene therapies offer promising avenues for precision treatment.