Cardiac myosin inhibitor, mavacamten, improves myocardial relaxation in mouse HFpEF model

Abstract

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): National Medical Research Council (NMRC) Background / Introduction There are currently no treatments for directly improving diastolic dysfunction in heart failure with preserved ejection fraction (HFpEF). Improving myocardial relaxation via manipulating sarcomere function has great potential to unveil novel targets for treating HFpEF. Mavacamten, a small molecule inhibitor of myosin ATPase, has been developed through drug screening as a treatment for hypertrophic cardiomyopathy (HCM), and it is currently being tested in HFpEF patients. Interestingly, emerging evidence suggests that mavacamten may not only modulate contractility but may also modulate myocardial relaxation. Purpose The aim of this study was to investigate whether mavacamten directly modulates sarcomere mechanical properties to improve myocardial relaxation in a mouse HFpEF model. Methods Eight to ten weeks old adult male C57Bl/6 mice were fed with (1) standard diet or (2) high-fat diet (HFD) + L-NAME to induce HFpEF (n=10 mice/group). Cardiac function was assessed by transthoracic two-dimensional echocardiography at baseline and after 15 weeks. Mouse myofibrils (n=10-15 per animals) were obtained from control and HFpEF mice using a triton X-100-based skinning method. The contractile function of the sarcomere with or without the presence of mavacamten were investigated using a myofibril mechanical system. General myofibril mechanical parameters measured included resting and maximal tension (RT, FMAX, mN/mm2), rate constant of tension development (kACT, S-1), duration of linear relaxation phase (tLIN, mSec) and rate constant of linear and exponential phase relaxation (linear and exponential kREL, S-1). Furthermore, force production as a function of the bathing Ca2+ concentration (pCa 4.5-9.0) was measured to determine the Ca2+ sensitivity of the myofibrils. Results As previously reported, C57Bl/6 mice fed with HFD + L-NAME developed cardiac hypertrophy, diastolic dysfunction, exercise intolerance despite having preserved systolic function at 15 weeks. Mechanical analysis showed myofibrils isolated from HFpEF mice has mildly reduced force generation, significantly higher stiffness and elevated Ca2+ sensitivity, compared with control animals. Ex vivo treatment of mavacamten completely normalised Ca2+ sensitivity of the myofibrils from HFpEF animals. Interestingly, mavacamten treatment further accelerated the rate of linear phase relaxation (linear kREL). Conclusion This is the first study to characterise in detail the mechanical properties of myofibrils in a mouse HFpEF model. We demonstrated myosin ATPase inhibition using mavacamten could normalise elevated Ca2+ sensitivity as well as facilitate relaxation kinetics at the sarcomere level in HFpEF. These findings position mavacamten to be a potential therapeutic intervention for improving diastolic function in patients with HFpEF.