Whether differences in circulating long chain acylcarnitines (LCAC) are seen in heart failure (HF) patients with and without diabetes mellitus (DM), and whether these biomarkers report on exercise capacity and clinical outcomes, remains unknown. The objective of the current study was to use metabolomic profiling to identify biomarkers that report on exercise capacity, clinical outcomes, and differential response to exercise in HF patients with and without DM. Targeted mass spectrometry was used to quantify metabolites in plasma from participants in the heart failure: a controlled trial investigating outcomes of exercise training (HF-ACTION) trial. Principal components analysis was used to identify 12 uncorrelated factors. The association between metabolite factors, diabetes status, exercise capacity, and time to the primary clinical outcome of all-cause mortality or all-cause hospitalization was assessed. A total of 664 participants were included: 359 (54%) with DM. LCAC factor levels were associated with baseline exercise capacity as measured by peak oxygen consumption (beta 0.86, p = 2 × 10−7, and were differentially associated in participants with and without DM (beta 1.58, p = 8 × 10−8 vs. 0.67, p = 9 × 10−4, respectively; p value for interaction = 0.012). LCAC levels changed to a lesser extent in participants with DM after exercise (mean ∆ 0.09, p = 0.24) than in those without DM (mean ∆ 0.16, p = 0.08). In univariate and multivariate modeling, LCAC factor levels were associated with time to the primary outcome (multivariate HR 0.80, p = 2.74 × 10−8), and were more strongly linked to outcomes in diabetic participants (HR 0.64, p = 3.21 × 10−9 v. HR 0.90, p = 0.104, p value for interaction = 0.001). When analysis was performed at the level of individual metabolites, C16, C16:1, C18, and C18:1 had the greatest associations with both exercise capacity and outcomes, with higher levels associated with worse outcomes. Similar associations with time to the primary clinical outcome were not found in a control group of patients without HF from the CATHeterization GENetics (CATHGEN) study. LCAC biomarkers are associated with exercise status and clinical outcomes differentially in HF patients with and without DM. Impaired fatty acid substrate utilization and mitochondrial dysfunction both at the level of the skeletal muscle and the myocardium may explain the decreased exercise capacity, attenuated response to exercise training, and poor clinical outcomes seen in patients with HF and DM. Trial Registration clinicaltrials.gov Identifier: NCT00047437.

中文翻译：

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循环长链酰基肉碱和糖尿病心力衰竭的结果：HF-ACTION 临床试验子研究

在患有和不患有糖尿病 (DM) 的心力衰竭 (HF) 患者中是否观察到循环长链酰基肉碱 (LCAC) 的差异，以及这些生物标志物是否报告运动能力和临床结果，仍然未知。当前研究的目的是使用代谢组学分析来确定生物标志物，这些生物标志物可以报告有和没有 DM 的 HF 患者的运动能力、临床结果和对运动的不同反应。靶向质谱法用于量化心力衰竭参与者血浆中的代谢物：一项调查运动训练 (HF-ACTION) 试验结果的对照试验。主成分分析用于识别 12 个不相关的因素。代谢物因素、糖尿病状态、运动能力、评估了达到全因死亡率或全因住院的主要临床结果的时间。总共包括 664 名参与者：359 名 (54%) 患有 DM。LCAC 因子水平与通过峰值耗氧量衡量的基线运动能力相关（β 0.86，p = 2 × 10-7，并且在患有和不患有 DM 的参与者中存在差异（β 1.58，p = 8 × 10-8 vs. 0.67，分别为 p = 9 × 10−4；交互作用的 p 值 = 0.012。运动后糖尿病患者的 LCAC 水平变化（平均 Δ 0.09，p = 0.24）比没有糖尿病的参与者（平均 Δ 0.16, p = 0.08). 在单变量和多变量模型中，LCAC 因子水平与达到主要结果的时间相关（多变量 HR 0.80，p = 2.74 × 10−8），并且与糖尿病参与者的结果（HR 0.64，p = 3。21 × 10−9 v. HR 0.90，p = 0.104，交互作用的 p 值 = 0.001）。当在个体代谢物水平上进行分析时，C16、C16:1、C18 和 C18:1 与运动能力和结果的相关性最大，较高的水平与较差的结果相关。在来自 CATHeterization GENetics (CATHGEN) 研究的非 HF 患者对照组中未发现与时间与主要临床结果的类似关联。LCAC 生物标志物与患有和不患有 DM 的 HF 患者的运动状态和临床结果存在差异。骨骼肌和心肌水平的脂肪酸底物利用受损和线粒体功能障碍可能解释了 HF 和 DM 患者的运动能力下降、对运动训练的反应减弱以及临床结果不佳。