Chronic myosin activation as an agonist of cardiac mechanosensory pathways

The National Institutes of Health National Heart Lung and Blood Institute awarded Case Western Reserve University $128,916 on December 12, 2025, under the Cardiovascular Diseases Research program (CFDA 93.837) to investigate chronic myosin activation as an agonist of cardiac mechanosensory pathways.

The research examines long-term cardiac effects of myosin activators, specifically danicamtiv, a next-generation therapeutic in clinical trials for heart failure with reduced ejection fraction. Preliminary experiments indicate that three days of myosin activation produces lasting cardiac changes after washout, including shorter isovolumic contraction time, increased left ventricular wall thickness, decreased left ventricular diameter, and inverted ECG T-waves, suggesting potential concentric hypertrophy. The project will investigate whether these persistent effects operate through Z-disk mechanosensation and stress-sensitive ion channels involving muscle LIM protein, which sense force changes and trigger hypertrophy signaling. This research addresses a critical knowledge gap regarding the long-term safety and efficacy of chronic myosin activation therapy for patients who might use such activators lifelong.

The award is structured as a Project Grant, assistance type. Performance occurs at Case Western Reserve University's research facilities in Cleveland, Ohio, operating in affiliation with University Hospitals of Cleveland. The period of performance runs through July 14, 2028.

Abstract

Heart failure with reduced ejection fraction (HFREF) is a condition of decreased left ventricular contractility affecting 32 million people worldwide, causing low exercise tolerance and eventually death. For nearly 40 years, standard HFREF care has primarily managed symptoms. Myosin activation is an emerging therapeutic strategy that directly addresses the contractile deficiency. Unlike failed inotropic therapies targeting non-specific adrenergic and calcium signaling, myosin activators bind directly to cardiac myosin to increase contraction. Currently, danicamtiv, a next-generation myosin activator, is in clinical trials. My experiments and initial clinical results indicate that danicamtiv improves upon the shortcomings of the first-generation activator, omecamtiv mecarbil, which impaired diastolic function. Thus, myosin activation is poised to advance care for HFREF patients. Despite these promising results, the long-term effects of chronic myosin activation on the heart remain unknown. This knowledge GAP is significant for HFREF patients who might use myosin activators for life. My preliminary experiments show that 3 days of myosin activation elicits lasting cardiac effects after a 3-day washout period. These include shorter isovolumic contraction time, increased left ventricular wall thickness, decreased left ventricular diameter, and inverted ECG T-waves. This suggests that chronic myosin activation may stimulate concentric hypertrophy. These persistent effects likely involve Z-disk mechanosensation. The Z-disk anchors excitation-contraction coupling machinery and thin filaments in adjacent sarcomeres. IT senses force through stress-sensitive ION channels and protein complexes involving muscle LIM protein (MLP). Changes in force then trigger cellular responses like hypertrophy via signaling proteins docked at the Z-disk. Since the molecular effects of myosin activation resembles some hypertrophic cardiomyopathy (HCM) myosin mutations, they may share similar cardiac compensation mechanisms and long-term effects. While hypertrophy in HCM is highly pathological, IT may benefit HFREF patients by counteracting left ventricular dilation and atrophy in end-stage HFREF. However, HFREF pathophysiology may limit the heart's adaptation to chronic myosin activation due to dysregulation of Z-disk mechanosensation, excitation-contraction coupling, and metabolism. These lead to my central hypothesis that chronic myosin activation elicits a hypertrophic-like cardiac response via Z-disk mechanosensation, but HFREF pathophysiology will blunt this effect. Aim 1 will test if chronic myosin activation with danicamtiv elicits a hypertrophic-like cardiac response. Aim 2 will utilize mice lacking MLP that develop progressive HFREF to test if disrupted Z-disk mechanosensing and HFREF pathophysiology blunt the response to chronic myosin activation by danicamtiv. Successful completion of these experiments may identify a new mechanism by which myosin activation improves HFREF and inform how to best manage myosin activation therapy in patients to maximize its effectiveness.