Myosin Modulation in Hypertrophic Cardiomyopathy and Systolic Heart Failure: Getting Inside the Engine
Matthew J. Daniels, Luca Fusi, Christopher Semsarian, Srihari S. Naidu
Abstract
he palpable heartbeat requires synchronous activation, and inactivation, of trillions of motors, compartmentalized in billions of cardiomyocytes, in a fraction of a second.To bring the biophysical concepts of myocardial contraction in health and disease closer to the practicing cardiologist, we draw parallels with motor vehicles to discuss both recent advances describing how the heart modulates itself and a new era of myocardial therapeutics.Contraction requires 2 proteins: myosin and actin.MYH7 (myosin) is the molecular engine of the heart, converting the chemical energy of adenosine triphosphate (ATP) into movement.Force production at the level of the cardiomyocyte occurs when millions of myosin engines combine, pulling each of ≈50 sarcomeres per heart cell ≈10% of their resting length closer (Figure [A]).Mechanical work changes rapidly and reversibly.This is most obvious within a heartbeat, between systole (contraction) and diastole (relaxation).The Frank-Starling mechanism adjusts performance beat to beat in response to changing preload and afterload.Cardiac adaptation to pregnancy, exercise, or injury develops over longer periods.Here, we simplify what happens under the hood and explain how this applies to patients.The way myosin works dictates how the heart regulates force production.Myosin takes fixed steps (≈10 nm) that generate small amounts of force (picoNewton range), using an ATP hydrolysis mechanism that is slow (10 s -1 ).Flexibility requires variable recruitment of myosin motors.Therein lies the challenge of regulation. MYOFILAMENT-BASED REGULATION OF CARDIAC CONTRACTILITYThe molecular accelerator/brake that underpins the Frank-Starling mechanism is housed in myosin itself.