Targeting the sarcomere in inherited cardiomyopathies

Abstract

Variants in >12 genes encoding sarcomeric proteins can cause various cardiomyopathies. The two most common are hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM). Current therapeutics do not target the root causes of these diseases, but attempt to prevent disease progression and/or to manage symptoms. Accordingly, novel approaches are being developed to treat the cardiac muscle dysfunction directly. Challenges to developing therapeutics for these diseases include the diverse mechanisms of pathogenesis, some of which are still being debated and defined. Four small molecules that modulate the myosin motor protein in the cardiac sarcomere have shown great promise in the settings of HCM and DCM, regardless of the underlying genetic pathogenesis, and similar approaches are being developed to target other components of the sarcomere. In the setting of HCM, mavacamten and aficamten bind to the myosin motor and decrease the ATPase activity of myosin. In the setting of DCM, omecamtiv mecarbil and danicamtiv increase myosin activity in cardiac muscle (but omecamtiv mecarbil decreases myosin activity in vitro). In this Review, we discuss the therapeutic strategies to alter sarcomere contractile activity and summarize the data indicating that targeting one protein in the sarcomere can be effective in treating patients with genetic variants in other sarcomeric proteins, as well as in patients with non-sarcomere-based disease.

Fig. 1 ∣. The cardiac sarcomere and its components.

The cardiac sarcomere is made up primarily of regulatory thin filaments, force-generating thick filaments (myosin), regulatory myosin-binding protein C and tension-sensing titin. Variants in the genes encoding these proteins are linked to various genetic cardiomyopathies, such as hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM), which are typically characterized by a unique molecular mechanism of disease. Therefore, these proteins are potential druggable targets for treating cardiomyopathies.

Fig. 2 ∣. The functional states of myosin.

a ∣ Myosin molecules exist in an equilibrium between three distinct ATP-utilization states: the actin-bound state (green), the disordered relaxed (DRX) state (orange) and the super-relaxed (SRX) state (red). The SRX state can be divided into the folded back, interacting heads motif (IHM) structure or by another, undefined structural state. These states are defined by specific myosin ATPase activities, in which the activity in the actin-bound state is ~100-fold faster than in the DRX state and nearly 1,000-fold faster than in the SRX state. These differences in ATPase activity govern ATP utilization of the sarcomere and the heart. b ∣ The simulated ATPase activity for each state is shown as a function of time. The black curve depicts the myosin ATPase activity of cardiac muscle based on the physiological distribution of myosin heads between the three states. Adapted with permission from REF..

Fig. 3 ∣. The molecular mechanisms of myosin modulation by targeted small molecules.

The myosin heavy chain has a primary role in muscle contraction through the formation of force-generating cross-bridges with actin thin filaments. The steps in the chemomechanical ATPase cycle of myosin are depicted in the context of the basic structural changes, energetics and their role in force production. Small molecules have been developed that target cardiac myosin. Aficamten, blebbistatin and mavacamten all decrease the rate of inorganic phosphate (P_i) release from myosin, leading to reduced ATPase activity of myosin and contractile force production^-,,,. Additionally, mavacamten increases the population of myosin heads in the autoinhibited, super-relaxed (SRX) state^,, whereas blebbistatin, and probably also aficamten, exert their inhibitory effects in an SRX-independent mechanism in cardiac muscle^,. Danicamtiv and omecamtiv mecarbil both increase the rate of P_i release from myosin, thereby increasing the ATPase activity and contractile force^-,,. Danicamtiv also increases the number of myosin heads available for actomyosin cross-bridge formation, which contributes to the increase in contractile force. DRX, disordered relaxed state of myosin.