Amesz Jorik H, Langmuur Sanne J J, Bierhuizen Mark F A, de Groot Natasja M S, Manintveld Olivier C, Taverne Yannick J H J
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.
J Mol Cell Cardiol Plus. 2023 Jul 22;5:100040. doi: 10.1016/j.jmccpl.2023.100040. eCollection 2023 Sep.
Heart failure (HF) is a rapidly growing pandemic while medical treatment options remain limited. Omecamtiv mecarbil (OM) is a novel HF drug that directly targets the myosin heads of the cardiac muscle. This study used living myocardial slices (LMS) from patients with HF to evaluate the direct biomechanical effects of OM as compared to dobutamine. LMS were produced from patients with end-stage HF undergoing cardiac transplantation or left ventricular assist device implantation and cultured under electromechanical stimulation (diastolic preload: ca. 1 mN, stimulation frequency: 0.5 Hz). Dobutamine and omecamtiv mecarbil (OM) were administered on consecutive days and biomechanical effects were continuously recorded with dedicated force transducers. OM and dobutamine significantly increased contractile force to a similar maximum force, but OM also increased median time-to-peak with 48 % ( = 0.046) and time-to-relaxation with 68 % ( = 0.045). OM administration led to impaired relaxation of HF LMS with increasing stimulation frequencies, which was not observed with dobutamine. Furthermore, the functional refractory period was significantly shorter after administration of OM compared to dobutamine (235 ms (200-265) vs. 270 ms (259-283), = 0.035). In conclusion, OM increased contractile force and systolic duration of HF LMS, indicating an improvement in cardiac function and normalization of systolic time intervals in patients with HF. Conversely, OM slowed relaxation, which could lead to diastolic filling abnormalities. As such, OM showed benefits on systolic function on one hand but potential hindrances of diastolic function on the other hand.
心力衰竭（HF）是一种迅速蔓延的流行病，而医疗治疗选择仍然有限。奥米卡替麦卡比（OM）是一种新型的HF药物，直接作用于心肌的肌球蛋白头部。本研究使用HF患者的活心肌切片（LMS）来评估OM与多巴酚丁胺相比的直接生物力学效应。LMS取自接受心脏移植或左心室辅助装置植入的终末期HF患者，并在机电刺激下培养（舒张期预负荷：约1 mN，刺激频率：0.5 Hz）。连续几天给予多巴酚丁胺和奥米卡替麦卡比（OM），并用专用力传感器连续记录生物力学效应。OM和多巴酚丁胺均显著增加收缩力至相似的最大力，但OM还使达到峰值的中位时间增加了48%（P = 0.046），舒张时间增加了68%（P = 0.045）。随着刺激频率增加，OM给药导致HF LMS舒张受损，而多巴酚丁胺未观察到这种情况。此外，与多巴酚丁胺相比，OM给药后的功能不应期显著缩短（235 ms（200 - 265）vs. 270 ms（259 - 283），P = 0.035）。总之，OM增加了HF LMS收缩力和收缩期持续时间，表明HF患者心脏功能改善且收缩时间间期正常化。相反，OM减缓了舒张，这可能导致舒张期充盈异常。因此，OM一方面对收缩功能有好处，但另一方面可能对舒张功能有潜在阻碍。
