Department of Cardiology, Amsterdam University Medical Centers, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
Amsterdam Cardiovascular Sciences, Amsterdam, The Netherlands.
ESC Heart Fail. 2023 Oct;10(5):2998-3010. doi: 10.1002/ehf2.14418. Epub 2023 Aug 2.
Impaired myocardial energy homeostasis plays an import role in the pathophysiology of heart failure with preserved ejection fraction (HFpEF). Left ventricular relaxation has a high energy demand, and left ventricular diastolic dysfunction has been related to impaired energy homeostasis. This study investigated whether trimetazidine, a fatty acid oxidation inhibitor, could improve myocardial energy homeostasis and consequently improve exercise haemodynamics in patients with HFpEF.
The DoPING-HFpEF trial was a phase II single-centre, double-blind, placebo-controlled, randomized cross-over trial. Patients were randomized to trimetazidine treatment or placebo for 3 months and switched after a 2-week wash-out period. The primary endpoint was change in pulmonary capillary wedge pressure, measured with right heart catheterization at multiple stages of bicycling exercise. Secondary endpoint was change in myocardial phosphocreatine/adenosine triphosphate, an index of the myocardial energy status, measured with phosphorus-31 magnetic resonance spectroscopy. The study included 25 patients (10/15 males/females; mean (standard deviation) age, 66 (10) years; body mass index, 29.8 (4.5) kg/m ); with the diagnosis of HFpEF confirmed with (exercise) right heart catheterization either before or during the trial. There was no effect of trimetazidine on the primary outcome pulmonary capillary wedge pressure at multiple levels of exercise (mean change 0 [95% confidence interval, 95% CI -2, 2] mmHg over multiple levels of exercise, P = 0.60). Myocardial phosphocreatine/adenosine triphosphate in the trimetazidine arm was similar to placebo (1.08 [0.76, 1.76] vs. 1.30 [0.95, 1.86], P = 0.08). There was no change by trimetazidine compared with placebo in the exploratory parameters: 6-min walking distance (mean change of -6 [95% CI -18, 7] m vs. -5 [95% CI -22, 22] m, respectively, P = 0.93), N-terminal pro-B-type natriuretic peptide (5 (-156, 166) ng/L vs. -13 (-172, 147) ng/L, P = 0.70), overall quality-of-life (KCCQ and EQ-5D-5L, P = 0.78 and P = 0.51, respectively), parameters for diastolic function measured with echocardiography and cardiac magnetic resonance, or metabolic parameters.
Trimetazidine did not improve myocardial energy homeostasis and did not improve exercise haemodynamics in patients with HFpEF.
心肌能量代谢稳态受损在射血分数保留的心力衰竭（HFpEF）的病理生理学中起着重要作用。左心室舒张需要很高的能量需求，左心室舒张功能障碍与能量代谢稳态受损有关。本研究旨在探讨曲美他嗪，一种脂肪酸氧化抑制剂，是否可以改善 HFpEF 患者的心肌能量代谢稳态，并由此改善运动血液动力学。
DoPING-HFpEF 试验是一项 II 期、单中心、双盲、安慰剂对照、随机交叉试验。患者被随机分配接受曲美他嗪治疗或安慰剂治疗 3 个月，并在 2 周洗脱期后进行切换。主要终点是通过右心导管在多次自行车运动阶段测量的肺毛细血管楔压变化。次要终点是用磷-31 磁共振波谱测量的心肌磷酸肌酸/三磷酸腺苷的变化，该指标反映心肌能量状态。该研究纳入了 25 名患者（10/15 名男性/女性；平均（标准差）年龄 66（10）岁；体重指数 29.8（4.5）kg/m ）；通过（运动）右心导管检查在试验前或试验期间确诊为 HFpEF。曲美他嗪对运动多个水平的主要结局肺毛细血管楔压没有影响（运动多个水平的平均变化 0[95%置信区间，95%CI-2，2]mmHg，P=0.60）。曲美他嗪组的心肌磷酸肌酸/三磷酸腺苷与安慰剂相似（1.08[0.76，1.76]比 1.30[0.95，1.86]，P=0.08）。与安慰剂相比，曲美他嗪没有改变探索性参数：6 分钟步行距离（平均变化-6[95%CI-18，7]m 与-5[95%CI-22，22]m，分别，P=0.93）、N 末端 B 型利钠肽前体（5（-156，166）ng/L 与-13（-172，147）ng/L，P=0.70）、整体生活质量（KCCQ 和 EQ-5D-5L，P=0.78 和 P=0.51）、超声心动图和心脏磁共振测量的舒张功能参数，或代谢参数。
曲美他嗪不能改善 HFpEF 患者的心肌能量代谢稳态，也不能改善运动血液动力学。
