Transcriptional and functional effects of mavacamten in multiple porcine and human models with hypertrophic cardiomyopathy

作者：Е. А. Киселев, Wilson Agyapong, Bjarne Jürgens, Elisa Mohr, Shambhabi Chatterjee, Hannah Jill Hunkler, J. Salman, Giuseppe Cipriano, Marco Bentele, Junqing Liu, Jonas Specht, Kaja S. Menge, Florian J. G. Waleczek, Jonas A. Haas, Anselm A. Derda, Kristina Sonnenschein, Anika Gietz, Susanne Neumüller, Angelika Pfanne, Oliver Beetz, Michael Pflaum, Bettina Wiegmann, Yiangos Psaras, Christopher N. Toepfer, Robert Zweigerdt, Ante Radocaj, Theresia Kraft, André Zeug, Evgeni Ponimaskin, Wilhelm Korte, Alexander Horke, Arjang Ruhparwar, Maximilian Fuchs, Ke Xiao, Christian Bär, Natalie Weber, Thomas Thum · 发表于：British Journal of Pharmacology · 年份：2025 · DOI：10.1111/bph.70247 · 被引用次数：2 · 研究领域：Cardiomyopathy and Myosin Studies、Cardiac Fibrosis and Remodeling、Cardiac electrophysiology and arrhythmias

BACKGROUND AND PURPOSE: Mavacamten (MAVA) is a novel small molecule inhibitor of cardiac myosin, mitigating cardiomyocyte hypercontractility in patients with hypertrophic obstructive cardiomyopathy (HOCM). Despite its recent approval for clinical use, the transcriptional and functional impacts of MAVA remain not well understood. In this study we investigate the effects of MAVA across diverse cardiac models, including healthy female porcine cardiomyocytes and myocardial slices, human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), cardiac organoids and living myocardial slices (LMSs) derived from patients with HOCM. EXPERIMENTAL APPROACH: Long-term LMS culture facilitated continuous force measurements, while SarcTrack and MUSCLEMOTION analyses were used to evaluate contractility in cardiomyocytes and cardiac organoids. Transcriptome profiling of MAVA-treated HOCM hiPSC-CMs and HOCM LMSs allowed in-depth examination of gene expression signatures in response to MAVA treatment. KEY RESULTS: Across all models tested, MAVA demonstrated robust force inhibition. In primary disease models, MAVA showed little effect on time to peak or relaxation times and even reduced contraction and relaxation velocities. By contrast, in engineered human HOCM models, MAVA accelerated both contraction and relaxation, suggesting potential model-specific effects. Transcriptome analyses revealed that MAVA treatment not only influenced contraction regulation but also significantly altered...