School of Imaging Sciences and Biomedical Engineering, King's College, London, UK (G.C.-E.).
King's College London British Heart Foundation Centre of Excellence, School of Cardiovascular Medicine and Sciences, James Black Centre, UK (N.A., N.C., T.M., M.M., A.M.S., D.O.O.).
Circulation. 2019 May 21;139(21):2386-2398. doi: 10.1161/CIRCULATIONAHA.118.038516.
Iron repletion augments exercise capacity in chronic heart failure (HF), but there is a lack of mechanistic data explaining how iron could augment exercise performance despite minimal changes in hemoglobin (Hb). Besides Hb, iron is an obligate component of mitochondrial enzymes that generate cellular energy in the form of adenosine triphosphate and phosphocreatine (PCr). Dynamic phosphorus magnetic resonance spectroscopy is a noninvasive tool that quantifies in vivo muscle energetics by measuring the kinetics of PCr recovery after exertion. We tested the hypothesis that intravenous iron repletion in chronic HF enhances skeletal muscle energetics as reflected by shorter PCr recovery half-times (PCr t) on phosphorus magnetic resonance spectroscopy.
We enrolled 40 patients (50% anemic) with chronic HF, New York Heart Association class ≥II, left ventricular ejection fraction ≤45%, and iron deficiency (ferritin<100 μg/L or 100-300 μg/L with transferrin saturation <20%). Subjects underwent stratified (anemic versus nonanemic) randomization (1:1) to a single, double-blinded, total dose infusion of iron isomaltoside or saline placebo with end points reassessed early at 2 weeks posttreatment to minimize confounding from exercise adaptation. The primary end point was PCr t at 2 weeks. Secondary end points included ADP recovery half-time (ADP t energetic marker), iron status, symptoms, Hb, exercise capacity, and safety.
In the total population, treatment groups were similar at baseline. At 2 weeks, iron isomaltoside improved PCr t (adjusted difference, -6.8 s; 95% CI, 11.5 to -2.1; P=0.006), ADP t (-5.3 s; 95% CI, -9.7 to -0.9; P=0.02), ferritin (304 ng/mL; 95% CI, 217-391; P<0.0001), transferrin saturation (6.8%; 95% CI, 2.7-10.8; P=0.002), New York Heart Association class (-0.23; 95% CI, -0.46 to -0.01; P=0.04), resting respiratory rate (-0.7 breaths/min; 95% CI, -1.2 to -0.2; P=0.009), and postexercise Borg dyspnea score (-2.0; 95% CI, -3.7 to -0.3; P=0.04), but not Hb (2.4 g/L; 95% CI, -3.5 to 8.4; P=0.41). Adverse events were similar between groups. In subgroup analyses, iron isomaltoside improved PCr t in anemic (-8.4 s; 95% CI, -16.7 to -0.2; P=0.04) and nonanemic (-5.2 s; 95% CI, -10.6 to 0.2; P=0.06) cohorts.
In patients with chronic HF and iron deficiency, a total repletion dose of iron isomaltoside given at a single sitting is well tolerated and associated with faster skeletal muscle PCr t at 2 weeks, implying better mitochondrial function. Augmented skeletal muscle energetics might therefore be an important mechanism via which iron repletion confers benefits in chronic HF despite minimal Hb changes.
URL: https://www.clinicaltrialsregister.eu/ctr-search/trial/2012-005592-13/GB . Unique identifier: EudraCT 2012-005592-13.
铁补充剂可增强慢性心力衰竭（HF）患者的运动能力，但缺乏机制数据来解释为什么尽管血红蛋白（Hb）变化不大，但铁仍能增强运动表现。除了 Hb 之外，铁还是生成细胞能量的线粒体酶的必需成分，这些能量以三磷酸腺苷（ATP）和磷酸肌酸（PCr）的形式存在。动态磷磁共振波谱是一种非侵入性工具，可通过测量运动后 PCr 恢复的动力学来定量测量肌肉内的能量代谢。我们检验了以下假设：在慢性 HF 中静脉补充铁可增强骨骼肌的能量代谢，表现为磷磁共振波谱上 PCr 恢复半衰期（PCr t）更短。
我们招募了 40 名（50%为贫血）慢性 HF 患者（纽约心脏协会[NYHA]心功能分级≥Ⅱ级，左心室射血分数≤45%，且存在铁缺乏症（铁蛋白<100μg/L 或 100-300μg/L 时转铁蛋白饱和度<20%））。根据贫血与非贫血情况，对患者进行分层（1:1），随机分配接受单次、双盲、总剂量的异麦芽糖铁或生理盐水安慰剂输注，在治疗后 2 周早期重新评估终点，以最大限度地减少运动适应的混杂因素。主要终点为 2 周时的 PCr t。次要终点包括 ADP 恢复半衰期（ADP t，能量标志物）、铁状态、症状、Hb、运动能力和安全性。
在总人群中，治疗组在基线时相似。在 2 周时，异麦芽糖铁可改善 PCr t（校正差异，-6.8s；95%置信区间，11.5 至-2.1；P=0.006）、ADP t（-5.3s；95%置信区间，-9.7 至-0.9；P=0.02）、铁蛋白（304ng/mL；95%置信区间，217-391；P<0.0001）、转铁蛋白饱和度（6.8%；95%置信区间，2.7-10.8；P=0.002）、NYHA 心功能分级（-0.23；95%置信区间，-0.46 至-0.01；P=0.04）、静息呼吸频率（-0.7 次/分钟；95%置信区间，-1.2 至-0.2；P=0.009）和运动后 Borg 呼吸困难评分（-2.0；95%置信区间，-3.7 至-0.3；P=0.04），但对 Hb 无影响（2.4g/L；95%置信区间，-3.5 至 8.4；P=0.41）。两组间不良事件相似。在亚组分析中，在贫血（-8.4s；95%置信区间，-16.7 至-0.2；P=0.04）和非贫血（-5.2s；95%置信区间，-10.6 至 0.2；P=0.06）患者中，异麦芽糖铁可改善 PCr t。
在慢性 HF 合并铁缺乏症的患者中，单次输注总铁补充剂量耐受性良好，与 2 周时骨骼肌 PCr t 更快有关，提示线粒体功能增强。因此，铁补充增强骨骼肌能量代谢可能是一个重要的机制，通过该机制，铁补充在慢性 HF 中尽管 Hb 变化不大，但仍能带来益处。
网址：https://www.clinicaltrialsregister.eu/ctr-search/trial/2012-005592-13/GB。独特标识符：EudraCT 2012-005592-13。
