A Tale of Two Myosin-Targeting Cardiac Drugs: A Rationale for Sarcomere Mechanistic Investigation

Cardiomyopathies refers to diseases of the heart muscle and based on structure and function can be classified into 3 major subtypes, which are dilated, hypertrophic, and arrhythmogenic (reviewed in (1)).  Cardiomyopathies result in distorted cardiac output due to impaired ventricular function, impaired filling, or a combination of both.  Current available pharmacological treatments for adult cardiomyopathies focus on the symptomatic features of the disease rather than targeting the underlying mechanistic defects; thus, they provide little success in altering disease progression.  Cardiomyocytes (cardiac specific muscle cells) change their length and load to generate the contractile force during each heartbeat.  The force generators within cardiomyocytes are cardiac muscle fibers, which are themselves comprised of individual repeating units called sarcomeres (reviewed in (2)). The sarcomere complex is divided into two main components which are the actin thin filaments and the myosin thick filaments.  As abnormal contraction is a major pathologic consequence of cardiomyopathies, an intriguing hypothesis is that specifically targeting sarcomere proteins may be more effective at altering disease progression.

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