Direct Sarcomere Modulators Are Promising New Treatments for Cardiomyopathies.

Mutations in sarcomere genes can cause both hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM). However, the complex genotype-phenotype relationships in pathophysiology of cardiomyopathies by gene or mutation location are not fully understood. In addition, it is still unclear how mutations within same molecule result in different clinical phenotypes such as HCM and DCM. To clarify how the initial functional insult caused by a subtle change in one protein component of the sarcomere with a given mutation is critical for the development of proper effective treatments for cardiomyopathies. Fortunately, recent technological advances and the development of direct sarcomere modulators have provided a more detailed understanding of the molecular mechanisms that govern the effects of specific mutations. The direct inhibition of sarcomere contractility may be able to suppress the development and progression of HCM with hypercontractile mutations and improve clinical parameters in patients with HCM. On the other hand, direct activation of sarcomere contractility appears to exert unexpected beneficial effects such as reverse remodeling and lower heart rate without increasing adverse cardiovascular events in patients with systolic heart failure due to DCM. Direct sarcomere modulators that can positively influence the natural history of cardiomyopathies represent promising treatment options.