Background Mitochondrial dysfunction and energy depletion in the failing heart are innovative therapeutic targets in heart failure management. Elamipretide is a novel tetrapeptide that increases mitochondrial energy; however, its safety, tolerability, and therapeutic effect on cardiac structure and function have not been studied in heart failure with reduced ejection fraction.

Methods and Results In this double-blind, placebo-controlled, ascending-dose trial, patients with heart failure with reduced ejection fraction (ejection fraction, ≤35%) were randomized to either a single 4-hour infusion of elamipretide (cohort 1 [n=8], 0.005; cohort 2 [n=8], 0.05; and cohort 3 [n=8], 0.25 mg·kg⁻¹·h⁻¹) or placebo control (n=12). Safety and efficacy were assessed by clinical, laboratory, and echocardiographic assessments performed at pre-, mid- and end-infusion and 6-, 8-, 12- and 24-hours postinfusion start. Peak plasma concentrations of elamipretide occurred at end-infusion and were undetectable by 24 hours postinfusion. There were no serious adverse events. Blood pressure and heart rate remained stable in all cohorts. Compared with placebo, a significant decrease in left ventricular end-diastolic volume (−18 mL; P=0.009) and end-systolic volume (−14 mL; P=0.005) occurred at end infusion in the highest dose cohort.

Conclusions This is the first study to evaluate elamipretide in heart failure with reduced ejection fraction and demonstrates that a single infusion of elamipretide is safe and well tolerated. High-dose elamipretide resulted in favorable changes in left ventricular volumes that correlated with peak plasma concentrations, supporting a temporal association and dose–effect relationship. Further study of elamipretide is needed to determine long-term safety and efficacy.

Clinical Trial Registration URL: https://www.clinicaltrials.gov. Unique identifier: NCT02388464.

背景技术心脏衰竭中的线粒体功能障碍和能量消耗是心力衰竭治疗中的创新治疗目标。Elamipretide是一种新型的四肽，可增加线粒体能量。然而，在心力衰竭且射血分数降低的情况下，尚未研究其安全性，耐受性以及对心脏结构和功能的治疗作用。

方法和结果在这项双盲，安慰剂对照，递增剂量的试验中，心力衰竭且射血分数降低（射血分数≤35％）的患者被随机分配为每次4小时输注Elamipretide（队列1 [ n = 8]，0.005；群组2 [n = 8]，0.05；群组3 [n = 8]，0.25 mg·kg ^-1 ·h ^-1）或安慰剂对照（n = 12）。在输注前，输注中，输注结束后以及输注开始后6、8、12和24小时通过临床，实验室和超声心动图评估来评估安全性和疗效。Elamipretide的血浆峰值浓度在输注结束时出现，到输注后24小时仍未检测到。没有严重的不良事件。在所有队列中，血压和心率均保持稳定。与安慰剂相比，在最高剂量组的输注结束时，左心室舒张末期容积（−18 mL；P = 0.009）和收缩末期容积（−14 mL；P = 0.005）显着减少。

结论这是第一项评估依拉普肽在心力衰竭中射血分数降低的研究，证明单次输注依拉普肽是安全且耐受性良好的。高剂量的依拉普肽导致左心室容积的有利变化，与峰值血浆浓度相关，支持时间关联和剂量效应关系。为了确定长期安全性和有效性，需要进一步研究Elamipretide。

临床试验注册网址：https : //www.clinicaltrials.gov。唯一标识符：NCT02388464。