Chronic myosin activation as an agonist of cardiac mechanosensory pathways

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. Project Number: 1F31HL179787-01 | Fiscal Year: 2025 | NIH Institute/Center: National Heart Lung and Blood Institute (NHLBI) | Principal Investigator: Joshua Holmes | Institution: CASE WESTERN RESERVE UNIVERSITY, CLEVELAND, OH | Award Amount: $42,780 | Activity Code: F31 | Study Section: Special Emphasis Panel[ZRG1 F10A-R (20)] View on NIH RePORTER: https://reporter.nih.gov/project-details/1F31HL17978701