Knuiman Pim, Straw Sam, Gierula John, Koshy Aaron, Roberts Lee D, Witte Klaus K, Ferguson Carrie, Bowen Thomas Scott
Leeds School of Biomedical Sciences, Faculty of Biological Sciences, University of Leeds, Leeds, LS2 9JT, UK.
Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, Leeds, UK.
ESC Heart Fail. 2021 Apr;8(2):898-907. doi: 10.1002/ehf2.13272. Epub 2021 Feb 20.
Heart failure with reduced ejection fraction (HFrEF) induces skeletal muscle mitochondrial abnormalities that contribute to exercise limitation; however, specific mitochondrial therapeutic targets remain poorly established. This study quantified the relationship and contribution of distinct mitochondrial respiratory states to prognostic whole-body measures of exercise limitation in HFrEF.
Male patients with HFrEF (n = 22) were prospectively enrolled and underwent ramp-incremental cycle ergometry cardiopulmonary exercise testing to determine exercise variables including peak pulmonary oxygen uptake (V̇O ), lactate threshold (V̇O ), the ventilatory equivalent for carbon dioxide (V̇ /V̇CO ), peak circulatory power (CircP ), and peak oxygen pulse. Pectoralis major was biopsied for assessment of in situ mitochondrial respiration. All mitochondrial states including complexes I, II, and IV and electron transport system (ETS) capacity correlated with V̇O (r = 0.40-0.64; P < 0.05), V̇O (r = 0.52-0.72; P < 0.05), and CircP (r = 0.42-0.60; P < 0.05). Multiple regression analysis revealed that combining age, haemoglobin, and left ventricular ejection fraction with ETS capacity could explain 52% of the variability in V̇O and 80% of the variability in V̇O , respectively, with ETS capacity (P = 0.04) and complex I (P = 0.01) the only significant contributors in the model.
Mitochondrial respiratory states from skeletal muscle biopsies of patients with HFrEF were independently correlated to established non-invasive prognostic cycle ergometry cardiopulmonary exercise testing indices including V̇O , V̇O , and CircP . When combined with baseline patient characteristics, over 50% of the variability in V̇O could be explained by the mitochondrial ETS capacity. These data provide optimized mitochondrial targets that may attenuate exercise limitations in HFrEF.
射血分数降低的心力衰竭（HFrEF）会导致骨骼肌线粒体异常，这是运动受限的原因之一；然而，具体的线粒体治疗靶点仍未明确。本研究量化了不同线粒体呼吸状态与HFrEF运动受限的预后全身测量指标之间的关系及贡献。
前瞻性纳入22例男性HFrEF患者，进行递增负荷运动心肺运动试验，以确定运动变量，包括峰值肺摄氧量（V̇O₂）、乳酸阈值（V̇O₂）、二氧化碳通气当量（V̇E/V̇CO₂）、峰值循环功率（CircP）和峰值氧脉搏。取胸大肌活检以评估原位线粒体呼吸。所有线粒体状态，包括复合体I、II和IV以及电子传递系统（ETS）能力，均与V̇O₂（r = 0.40 - 0.64；P < 0.05）、V̇O₂（r = 0.52 - 0.72；P < 0.05）和CircP（r = 0.42 - 0.60；P < 0.05）相关。多元回归分析显示，将年龄、血红蛋白、左心室射血分数与ETS能力相结合，分别可解释V̇O₂变异性的52%和V̇O₂变异性的80%，模型中唯一显著的贡献因素是ETS能力（P = 0.04）和复合体I（P = 0.01）。
HFrEF患者骨骼肌活检的线粒体呼吸状态与已确立的无创预后运动心肺运动试验指标，包括V̇O₂、V̇O₂和CircP独立相关。当与患者基线特征相结合时，线粒体ETS能力可解释V̇O₂变异性的50%以上。这些数据提供了优化的线粒体靶点，可能减轻HFrEF患者的运动受限。
