2. Academic Validation
  3. Biomechanical response of ultrathin slices of hypertrophic cardiomyopathy tissue to myosin modulator mavacamten

Biomechanical response of ultrathin slices of hypertrophic cardiomyopathy tissue to myosin modulator mavacamten

  • Biomed Pharmacother. 2023 Dec 21:170:116036. doi: 10.1016/j.biopha.2023.116036.
Jorik H Amesz 1,  Sanne J J Langmuur 2,  Lu Zhang 3,  Olivier C Manintveld 4,  Arend F L Schinkel 4,  Peter L de Jong 5,  Natasja M S de Groot 6,  Yannick J H J Taverne 7
Affiliations

Affiliations

  • 1 Translational Cardiothoracic Surgery Research Lab, Department of Cardiothoracic Surgery, Erasmus University Medical Center, Rotterdam, the Netherlands; Translational Electrophysiology Lab, Department of Cardiology, Erasmus University Medical Center, Rotterdam, the Netherlands; Department of Cardiothoracic Surgery, Erasmus University Medical Center, Rotterdam, the Netherlands.
  • 2 Translational Cardiothoracic Surgery Research Lab, Department of Cardiothoracic Surgery, Erasmus University Medical Center, Rotterdam, the Netherlands; Department of Cardiothoracic Surgery, Erasmus University Medical Center, Rotterdam, the Netherlands.
  • 3 Translational Electrophysiology Lab, Department of Cardiology, Erasmus University Medical Center, Rotterdam, the Netherlands.
  • 4 Department of Cardiology, Erasmus University Medical Center, Rotterdam, the Netherlands.
  • 5 Department of Cardiothoracic Surgery, Erasmus University Medical Center, Rotterdam, the Netherlands.
  • 6 Translational Electrophysiology Lab, Department of Cardiology, Erasmus University Medical Center, Rotterdam, the Netherlands; Department of Cardiology, Erasmus University Medical Center, Rotterdam, the Netherlands.
  • 7 Translational Cardiothoracic Surgery Research Lab, Department of Cardiothoracic Surgery, Erasmus University Medical Center, Rotterdam, the Netherlands; Department of Cardiothoracic Surgery, Erasmus University Medical Center, Rotterdam, the Netherlands. Electronic address: y.j.h.j.taverne@erasmusmc.nl.
PMID: 38134635 DOI: 10.1016/j.biopha.2023.116036
Abstract

Hypertrophic cardiomyopathy (HCM) is the most common inherited myocardial disorder of the heart, but effective treatment options remain limited. Mavacamten, a direct Myosin modulator, has been presented as novel pharmacological therapy for HCM. The aim of this study was to analyze the biomechanical response of HCM tissue to Mavacamten using living myocardial slices (LMS). LMS (n = 58) from patients with HCM (n = 10) were cultured under electromechanical stimulation, and Verapamil and Mavacamten were administered on consecutive days to evaluate their effects on cardiac biomechanics. Mavacamten and Verapamil reduced contractile force and dF/dt and increased time-to-relaxation in a similar manner. Yet, the time-to-peak of the cardiac contraction was prolonged after administration of Mavacamten (221.0 ms (208.8 - 236.3) vs. 237.7 (221.0 - 254.7), p = 0.004). In addition, Mavacamten prolonged the functional refractory period (FRP) (330 ms (304 - 351) vs. 355 ms (313 - 370), p = 0.023) and better preserved twitch force with increasing stimulation frequencies, compared to Verapamil. As such, Mavacamten reduced (hyper-)contractility and prolonged contraction duration of HCM LMS, suggesting a reduction in cardiac wall stress. Also, Mavacamten might protect against the development of ventricular tachyarrhythmias due to prolongation of the FRP, and improve toleration of tachycardia due to better preservation of twitch force at tachycardiac stimulation frequencies.

Keywords

Hypertrophic cardiomyopathy; Living myocardial slices; Myosin modulators; Translational research.

Figures
Products