From Genetic Mutations to Molecular Basis of Heart Failure Treatment: An Overview of the Mechanism and Implication of the Novel Modulators for Cardiac Myosin

Figures

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  Figure 1. Pharmacological and interventional treatment for heart failure with reduced ejection fraction: The red arrows indicate a combination of the four drugs that should be initiated early in HFrEF patients. The dotted arrows indicate the additional drugs and interventional therapies for individualized treatment for specific populations.

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  Figure 2. Cardiac excitation-contraction coupling: Action potential transmits directly from adjacent cells (step 1). Calcium enters cardiomyocyte through voltage-gated L-type Ca2+ channels (step 2). The initial influx of Ca2+ stimulates efflux of Ca2+ from ryanodine receptor type-2 channels on the sarcoplasmic reticulum (step 3) resulting in contraction of the heart (step 4). As the contraction ends (step 5), the Ca2+ reuptake is completed by sarcoplasmic/endoplasmic reticulum Ca2+-ATPase 2a (SERCA2a) (step 6). The sodium-calcium exchanger removes Ca2+ from cells (step 7).

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  Figure 3. (Panel A): A schematic of two myosin conformations and associated energy consumption throughout the cardiac cycle: A pair of myosin molecules is depicted, with each head denoted as blocked (BH) or free (FH). The disordered relaxed state (DRX) insulates the BH, resulting in inhibition of ATPase (denoted by a blue dot), while FH retains adenosine triphosphate (ATP) hydrolysis activity and triggers actomyosin function modulating by myosin binding protein C (MyBPC). The super-relaxed state (SRX) insulates both BH and FH, and energy conservation is maximized because both myosin ATPase domains are inhibited. Hypertrophic cardiomyopathy variants preferentially shift conformation toward the DRX, resulting in hypercontractility, impaired relaxation, and excessive energy consumption. Mavacamten can stabilize the SRX state, attenuate hypercontractility, and improve compliance in cardiomyocytes. (Panel B): Biochemical cycle of cardiac myosin. During diastole, one head of myosin hydrolyzes ATP to adenosine diphosphate (ADP) and inorganic phosphate (Pi) (Step 1). Actin becomes accessible, and the head of myosin binds to it and forms the “pre-powerstroke” state. During systole, a subset of…