Department of Medicine, Division of Cardiovascular Medicine, Henry Ford Hospital, Detroit, Michigan.
Department of Medicine, Division of Cardiovascular Medicine, Henry Ford Hospital, Detroit, Michigan.
J Card Fail. 2021 Feb;27(2):242-252. doi: 10.1016/j.cardfail.2020.12.008. Epub 2020 Dec 25.
Unlike β- and β-adrenergic receptors (ARs), β-AR stimulation inhibits cardiac contractility and relaxation. In the failing left ventricular (LV) myocardium, β-ARs are upregulated, and can be maladaptive in the setting of decompensation by contributing to LV dysfunction. This study examined the effects of intravenous infusions of the β-AR antagonist APD418 on cardiovascular function and safety in dogs with systolic heart failure (HF).
Three separate studies were performed in 21 dogs with coronary microembolization-induced HF (LV ejection fraction [LVEF] of approximately 35%). Studies 1 and 2 (n = 7 dogs each) were APD418 dose escalation studies (dosing range, 0.35-15.00 mg/kg/h) designed to identify an effective dose of APD418 to be used in study 3. Study 3, the sustained efficacy study, (n = 7 dogs) was a 6-hour constant intravenous infusion of APD418 at a dose of 4.224 mg/kg (0.70 mg/kg/h) measuring key hemodynamic endpoints (e.g., EF, cardiac output, the time velocity integral of the mitral inflow velocity waveform representing early filling to time-velocity integral representing left atrial contraction [Ei/Ai]). Studies 1 and 2 showed a dose-dependent increase of LVEF and Ei/Ai, the latter being an index of LV diastolic function. In study 3, infusion of APD418 over 6 hours increased LVEF from 31 ± 1% to 38 ± 1% (P < .05) and increased Ei/Ai from 3.4 ± 0.4 to 4.9 ± 0.5 (P < .05). Vehicle had no effect on the LVEF or Ei/Ai. In study 3, APD418 had no significant effects on the HR or the systemic blood pressure.
Intravenous infusions of APD418 in dogs with systolic HF elicit significant positive inotropic and lusitropic effects. These findings support the development of APD418 for the in-hospital treatment of patients with an acute exacerbation of chronic HF.
与β-和β-肾上腺素能受体（ARs）不同，β-AR 刺激会抑制心肌的收缩和松弛。在衰竭的左心室（LV）心肌中，β-ARs 上调，并且在失代偿的情况下可能是适应性不良的，导致 LV 功能障碍。本研究探讨了静脉输注β-AR 拮抗剂 APD418 对患有收缩性心力衰竭（HF）的犬心血管功能和安全性的影响。
在 21 只冠状动脉微栓塞诱导的 HF 犬（LV 射血分数[LVEF]约为 35%）中进行了三项独立研究。研究 1 和 2（每组 7 只狗）是 APD418 剂量递增研究（剂量范围，0.35-15.00mg/kg/h），旨在确定用于研究 3 的有效 APD418 剂量。研究 3，持续疗效研究（n=7 只狗）是在 6 小时内以 4.224mg/kg 的剂量（0.70mg/kg/h）持续静脉输注 APD418，测量关键血流动力学终点（例如 EF、心输出量、二尖瓣流入速度波形的速度积分代表早期填充到速度积分代表左心房收缩[Ei/Ai]）。研究 1 和 2 显示 LVEF 和 Ei/Ai 呈剂量依赖性增加，后者是 LV 舒张功能的指标。在研究 3 中，APD418 输注 6 小时后，LVEF 从 31±1%增加到 38±1%（P<0.05），Ei/Ai 从 3.4±0.4 增加到 4.9±0.5（P<0.05）。载体对 LVEF 或 Ei/Ai 没有影响。在研究 3 中，APD418 对 HR 或全身血压没有显著影响。
静脉输注 APD418 可引起收缩性 HF 犬明显的正性肌力和变力作用。这些发现支持 APD418 用于治疗慢性 HF 急性加重的住院患者。
