ミオシンモジュレーターの健常並びに不全ヒト心臓における収縮力及びCa²⁺トランジェントへの作用

抄録

Understanding the impact of myosin modulators (myotropes) on human heart biology is key to the successful development of drugs targeting heart failure (HF) and obstructive hypertrophic cardiomyopathy (OHCM). Omecamtiv mecarbil (OM; positive myotrope; Ph3 for HFrEF) increased contractility (EC₅₀=0.6µM) in isolated ventricular myocytes from organ donors, while negative myotropes exerted differential effects: Blebbistatin (BBS), N-benzyl-p-toluene sulphonamide and mavacamten (MAVA; approved for OHCM) decreased contractility (IC₅₀s 2.6, 16 and 0.2µM, respectively), hydroxy-BBS, (S)-3'-aminoBBS and para-amino-BBS caused biphasic responses. While none of the myotropes impacted peak amplitude of Ca²⁺ transients, controls increased (isoproterenol) and decreased (verapamil) peak Ca²⁺ amplitude. Moreover, OM generated similar increases in isometric force of ventricular trabeculae across healthy, HFrEF and HFpEF donor hearts. In contrast to OM, MAVA generated different force decreases between normal and HFpEF vs. HFrEF trabeculae. Thus, our data support the use of primary human heart preparations early in development to maximize clinical success of the most promising novel myotropes through evaluation of mechanism of action, structure-activity relationship stratification, and differential impact across related disease-states.