Cardiac muscle contractility dysfunction underlies several cardiac diseases and addressing this contractile abnormality may provide new therapeutic options. Heart failure with reduced ejection fraction (HFrEF) is characterized by lowered contractility, whereas mutations in the cardiac sarcomere that increase its contractility appear to drive the pathogenesis of most forms of hypertrophic cardiomyopathy (HCM). The lecture will focus on the discovery of three separate small molecules that directly modulate contractility at the cardiac sarcomere in attempts to normalize the underlying dysfunction. Omecamtiv mecarbil is a selective cardiac myosin activator that increases cardiac performance and improves outcomes in patients with HFrEF; CK-136 is a selective cardiac troponin activator intended to address different types of heart failure; and aficamten is a selective cardiac myosin inhibitor designed to treat patients with HCM by restoring the proper degree of contractility within the sarcomere.

Modulation of muscle contractility: The design of novel therapeutics for cardiovascular disease

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