Institute for Exercise and Environmental Medicine, Texas Health Presbyterian Hospital Dallas, Dallas, Texas, USA; Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Department of Medicine and Biosystemic Science, School of Medicine, Kyushu University, Fukuoka, Japan; Department of Hematology, Oncology, and Cardiovascular Medicine, School of Medicine, Kyushu University, Fukuoka, Japan.
JACC Heart Fail. 2023 Jul;11(7):760-771. doi: 10.1016/j.jchf.2023.02.006. Epub 2023 Apr 19.
Impaired ventricular relaxation influences left ventricular pressures during exercise in heart failure with preserved ejection fraction (HFpEF). Sarco/endoplasmic reticulum calcium-adenosine triphosphatase (SERCA2a) facilitates myocardial relaxation by increasing calcium reuptake and is impaired in HFpEF.
This study sought to investigate the effects of istaroxime, a SERCA2 agonist, on lusitropic and hemodynamic function during exercise in patients with HFpEF and control subjects.
Eleven control subjects (7 male, 4 female) and 15 patients with HFpEF (8 male, 7 female) performed upright cycle exercise with right-sided heart catheterization. Participants received istaroxime (0.5 μg/kg/min) or saline placebo (single-blind, crossover design). Cardiac output, pulmonary capillary wedge pressure (PCWP), and diastolic function were measured at rest and during submaximal exercise. In an exploratory analysis (Hedge's g), 7 patients with HFpEF received higher-dose istaroxime (1.0 μg/kg/min). End-systolic elastance (Ees) was calculated by dividing systolic blood pressure (SBP) × 0.9 by end-systolic volume (ESV) (on 3-dimensional echocardiography).
Patients with HFpEF had higher PCWP (25 ± 10 mm Hg vs 12 ± 5 mm Hg; P < 0.001) and lower tissue Doppler velocities during exercise. Istaroxime (0.5 μg/kg/min) had no effect on resting or exercise measures in patients with HFpEF or control subjects. Control subjects had a larger increase in Ees (Δ 1.55 ± 0.99 mm Hg/mL vs Δ 0.86 ± 1.31 mm Hg/mL; P = 0.03), driven by lower ESV. Comparing placebo and istaroxime 1.0 μg/kg/min during exercise, PCWP during the 1.0 μg/kg/min istaroxime dose was slightly lower (Δ 2.2 mm Hg; Hedge's g = 0.30). There were no effects on diastolic function, but there were increases in SBP and s', suggesting a mild inotropic effect.
Low-dose istaroxime had no effect on cardiac filling pressure or parameters of relaxation in patients with HFpEF during exercise. Higher doses of istaroxime may have been more effective in reducing exercise PCWP in patients with HFpEF. (Hemodynamic Response to Exercise in HFpEF Patients After Upregulation of SERCA2a; NCT02772068).
舒张功能障碍会影响射血分数保留的心力衰竭（HFpEF）患者运动时的左心室压力。肌浆/内质网钙-三磷酸腺苷酶（SERCA2a）通过增加钙摄取来促进心肌舒张，在 HFpEF 中受到损害。
本研究旨在探讨 SERCA2 激动剂伊司他肟对 HFpEF 患者和对照受试者运动时的正性肌力和血液动力学功能的影响。
11 名对照受试者（7 名男性，4 名女性）和 15 名 HFpEF 患者（8 名男性，7 名女性）进行直立循环运动，并进行右侧心导管检查。参与者接受伊司他肟（0.5μg/kg/min）或生理盐水安慰剂（单盲，交叉设计）。在休息和亚最大运动时测量心输出量、肺毛细血管楔压（PCWP）和舒张功能。在一项探索性分析（Hedge's g）中，7 名 HFpEF 患者接受了更高剂量的伊司他肟（1.0μg/kg/min）。通过将收缩压（SBP）×0.9除以收缩末期容积（ESV）（在三维超声心动图上）计算收缩末期弹性（Ees）。
HFpEF 患者的 PCWP（25±10mmHg vs 12±5mmHg；P<0.001）和运动时的组织多普勒速度较低。伊司他肟（0.5μg/kg/min）对 HFpEF 患者或对照受试者的静息或运动测量值均无影响。对照受试者的 Ees 增加更大（Δ1.55±0.99mmHg/mL vs Δ0.86±1.31mmHg/mL；P=0.03），这是由于 ESV 降低所致。在运动期间比较安慰剂和伊司他肟 1.0μg/kg/min 时，伊司他肟 1.0μg/kg/min 剂量时的 PCWP 略低（Δ2.2mmHg；Hedge's g=0.30）。舒张功能没有影响，但 SBP 和 s'增加，提示有轻微的变力作用。
低剂量伊司他肟对 HFpEF 患者运动时的心脏充盈压或舒张参数没有影响。更高剂量的伊司他肟可能更有效地降低 HFpEF 患者的运动 PCWP。（HFpEF 患者 SERCA2a 上调后运动时的血液动力学反应；NCT02772068）。
