HomeCirculationVol. 144, No. 10Myosin Modulation in Hypertrophic Cardiomyopathy and Systolic Heart Failure: Getting Inside the Engine Free AccessArticle CommentaryPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyRedditDiggEmail Jump toFree AccessArticle CommentaryPDF/EPUBMyosin Modulation in Hypertrophic Cardiomyopathy and Systolic Heart Failure: Getting Inside the Engine Matthew J. Daniels, BSc, MA, MB, BChir, PhD Luca Fusi, PhD Christopher Semsarian, MBBS, PhD, MPH Srihari S. NaiduMD Matthew J. DanielsMatthew J. Daniels Correspondence to: Matthew Daniels, BSc, MA, MB, BChir, PhD, Division of Cardiovascular Sciences, Room 3.20, Core Technology Facility, 46 Grafton Street, University of Manchester, Manchester M13 9NT, United Kingdom. Email E-mail Address: [email protected] https://orcid.org/0000-0002-9250-6214 Manchester Heart Centre, Manchester Royal Infirmary, Manchester University NHS Foundation Trust, United Kingdom (M.J.D.). Division of Cardiovascular Sciences, Manchester Academic Health Sciences Center (M.J.D.), University of Manchester, Manchester, United Kingdom. Division of Cell Matrix Biology and Regenerative Medicine (M.J.D.), University of Manchester, Manchester, United Kingdom. Search for more papers by this author , Luca FusiLuca Fusi https://orcid.org/0000-0003-3992-0114 Randall Center for Cell and Molecular Biophysics and BHF Center for Research Excellence, King’s College London, United Kingdom (L.F.). Search for more papers by this author , Christopher SemsarianChristopher Semsarian Agnes Ginges Centre for Molecular Cardiology at Centenary Institute, The University of Sydney, Australia (C.S.). Search for more papers by this author and Srihari S. NaiduSrihari S. Naidu https://orcid.org/0000-0003-4073-5143 Hypertrophic Cardiomyopathy Center, Department of Cardiology, Westchester Medical Center, Valhalla, NY (S.S.N.). Search for more papers by this author Originally published7 Sep 2021https://doi.org/10.1161/CIRCULATIONAHA.121.056324Circulation. 2021;144:759–762The 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.Download figureDownload PowerPointFigure. Myofilament activation and modulation. A, Contractility of the whole heart, in this case a heart with hypertrophic cardiomyopathy (HCM) and massive septal thickening, arises from the coordinated activation of myosin motors organized into regular sarcomere arrays in single cardiomyocytes. B, Force production is controlled by regulating myosin activity. Actin stimulates the myosin ATPase. Actin availability is controlled by fluctuating calcium levels, which via the troponin complex in the thin filament regulate a molecular clutch shielding actin (purple balls) from myosin in low diastolic calcium (Ca++) and exposing it in high systolic Ca++. Myosin is bundled, forming the thick filament. The exposed head contains the motor domain, which cycles among “superrelaxed” off (red), “relaxed” on (pink), and “active” force-producing states (green). In diastole, the off state predominates. In systole, as the myofilament activates, an intrinsic thick filament mechanism facilitates the transition between off and on (). Peak contractility occurs with 1:10 myosin heads active. Small molecule modulators of this system are in clinical evaluation. Omecamtiv mecarbil, a myosin ATPase activator, increases force production by stimulating transition . Mavacamten, a myosin ATPase inhibitor, stabilizes the superrelaxed off state . C, HCM-causing variants typically reduce myosin locked in the off state. With more myosin active, force production in systole and diastole increases (more green, fewer red myosin heads). D, Restoring the balance of myosin activation in HCM, using myosin ATPase inhibitors such as mavacamten, reduces force production (and adenosine triphosphate consumption) in systole and diastole (more red, less green).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. If output is a numbers game, how do you pack a cell full of engines sufficient for a burst of activity but allow the whole system to idle most of the time? How do you hardwire changes needed for prolonged elevations in activity such as pregnancy while retaining the ability to handle variations in preload that come from breathing? Distinct control mechanisms (clutches, gears, and accelerators) are needed.Actin is both the road that myosin drives on and the stimulator of myosin–ATPase activity that powers movement. The engine only burns fuel when it has road to run on. The 100-fold variation in ATPase activity between systole and diastole results from a molecular clutch under the control of calcium (Ca2+) housed in the thin filament troponin complex. This permits the interaction between motor and road in high systolic (1.0 μM) calcium, but disengages it in low (0.1 μM) diastolic calcium (Figure [B]).Other inputs tune this, notably the adrenergic system, which directs phosphorylation of myofilament components and changes intracellular calcium thresholds. Tuning adjustments take time and are used when sustained changes (shifting gears) in contractility are required. These molecular gears ensure durable changes in cardiac output but are too slow for beat-to-beat control.1Myofilament-Based Regulation of Cardiac ContractilityThe molecular accelerator/brake that underpins the Frank-Starling mechanism is housed in myosin itself. Myosin cycles among off (cannot bind actin), on (can bind actin), and active states (Figure [B]). In diastole, most of the 294 myosin motors in each half-sarcomere-thick filament are in the off state. In systole, a fraction of these are recruited for contraction; typically, only ≈30 motors per half filament bear the peak force.1 Although only 10% of all motors are attached to actin at peak force, this does not mean that 90% do nothing. As ≈400 ATP molecules per half filament are consumed during contraction, each motor probably undergoes 1 or 2 cycles per heartbeat.1 Transitions between the on and off states are influenced by MYBPC3 (myosin binding protein C), the myosin regulatory light chain (and kinase), and on a beat-to-beat basis by a mechanosensitive mechanism residing in the thick filament that enables force-dependent recruitment of myosin heads from the off state.1Diseases of the MyofilamentHypertrophic cardiomyopathy (HCM) is an inherited disease, typically caused by pathogenic variants of the thick (≈70%) and thin filament (≈20%). HCM cardiomyocytes expend more energy in systole and diastole. Because ATP consumption/force production comes from myosin, genetic changes facilitating longer or stronger interactions with actin, or that encourage more myosin heads to participate in any given contractile cycle, could cause this.Most HCM-causing variants increase the proportion of active myosin (more accelerator, less brake), resulting in both diastolic dysfunction and hypercontractility (Figure [C]). MYH7 pathogenic variants reduce how much myosin is sequestered into the off state or reduce sensitivity to the molecular signal coming from MYBPC3 (less brake), which promotes this transition.2MYBPC3 pathogenic variants by contrast exert less influence on MYH7 (reducing the proportion in the off state) or bring thick and thin filaments closer together, promoting actin/myosin interaction. Conversely, some thin filament mutations increase the amount of Ca++, and the duration it is held, in the sarcomere,3 triggering hypercontractility through actin availability.A subset of inherited dilated cardiomyopathy is attributable to pathogenic variants in the same myofilament genes, but with opposite molecular effects on contractility.Direct Pharmacologic Modulation of the Myofilament in Theory and PracticeEstablished negative or positive inotropes target the engine indirectly via the gears, without delivering a prognostic effect in various conditions aside from the proven, yet counterintuitive, role of β-blockade in chronic systolic heart failure. Controlling the engine directly via the accelerator/brake may be clinically useful, is now biologically plausible, and is potentially free from some of the undesirable effects of existing inotropes, such as effects on heart rate.If most motors are idle, and only 10% needed for peak force, could recruitment perhaps be increased pharmacologically with clinical benefits in systolic heart failure? Conversely, in advanced systolic heart failure, if the control systems drive the engine to destruction, rather than push it harder, β-blocker data might suggest a value of preventing the engine overheating by suppressing the motor. This hypothesis could be tested in HCM disease states, which rev the engine continuously (Figure [C]), and indeed a number of small molecules targeting the myofilament are now developed and in clinical trials.Several broad classes of myofilament therapeutics exist. Myosin activators include omecamtiv mecarbil. The phase III GALACTIC-HF (Registrational Study With Omecamtiv Mecarbil [AMG 423] to Treat Chronic Heart Failure With Reduced Ejection Fraction) in chronic systolic heart failure reported a modest reduction in heart failure hospitalizations without reducing heart failure deaths or improving quality of life4; the phase IIa study of danicamtiv reported favorable echocardiographic remodeling. Myosin inhibitors include mavacamten (which increases the proportion of myosin in the off state [Figure (D)]). The phase III EXPLORER-HCM (Clinical Study to Evaluate Mavacamten [MYK-461] in Adults With Symptomatic Obstructive Hypertrophic Cardiomyopathy) for symptomatic obstructive HCM reported reduced left ventricular outflow tract gradients, with improved heart failure biomarkers, symptoms, exercise performance, and health status,5 but with a narrow therapeutic window, and limited additional benefit in patients tolerating β-blockers. Shorter half-life mavacamten-like molecules (eg, MYK-581, MYK-224) are in early evaluation, the most progressed being CK-274, with a completed but not yet reported phase II study. Calcium sensitizers and desensitizers that work on the clutch are also in development but fall outside the scope of this article.SummaryThe contractile apparatus responds rapidly, and reversibly, to fluctuating preload and afterload using molecular accelerators and brakes to control the engine at any particular gear. It is now possible to stimulate or suppress the engine directly with a novel class of myocardial therapeutics. This conceptual framework of clutch, gears, and accelerators or brakes should help clinicians understand and categorize future directions in sarcomeric therapies for systolic and diastolic dysfunction.AcknowledgmentsDr Semsarian is the recipient of a National Health and Medical Research Council Practitioner Fellowship (number 1154992). Dr Fusi was funded by a Sir Henry Dale Fellowship awarded by the Wellcome Trust and the Royal Society (number 210464/Z/18/Z).Sources of FundingNone.Disclosures Drs Fusi and Semsarian report no disclosures. Dr Daniels reports advisory board fees from Bristol Myers Squibb. Dr Naidu reports consultancy fees from Bristol Myers Squibb and Cytokinetics and is a member of the executive committee of VALOR (A Study to Evaluate Mavacamten in Adults With Symptomatic Obstructive HCM Who Are Eligible for Septal Resuction Therapy), sponsored by Bristol Myers Squibb.Footnoteshttps://www.ahajournals.org/journal/circThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.For Sources of Funding and Disclosures, see page 761.Correspondence to: Matthew Daniels, BSc, MA, MB, BChir, PhD, Division of Cardiovascular Sciences, Room 3.20, Core Technology Facility, 46 Grafton Street, University of Manchester, Manchester M13 9NT, United Kingdom. Email matthew.[email protected]ac.uk
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