Duke Molecular Physiology Institute, Duke University Medical Center, Durham, NC, 27710, USA.
Department of Medicine, Division of Cardiology, Duke University School of Medicine, Durham, NC, USA.
Cardiovasc Diabetol. 2021 Aug 3;20(1):161. doi: 10.1186/s12933-021-01353-z.
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, and were differentially associated in participants with and without DM (beta 1.58, p = 8 × 10 vs. 0.67, p = 9 × 10, 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), and were more strongly linked to outcomes in diabetic participants (HR 0.64, p = 3.21 × 10 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.
心力衰竭（HF）伴或不伴糖尿病（DM）患者的循环长链酰基辅酶 A（LCAC）是否存在差异，以及这些生物标志物是否能反映运动能力和临床结局，目前仍不清楚。本研究旨在利用代谢组学分析鉴定可报告 HF 患者运动能力、临床结局以及对运动反应差异的生物标志物，无论患者是否患有 DM。
使用靶向质谱法检测心力衰竭：一项评估运动训练结果的对照试验（HF-ACTION 试验）参与者的血浆代谢物。使用主成分分析确定 12 个不相关的因素。评估代谢物因子、糖尿病状态、运动能力与全因死亡率或全因住院的主要临床结局之间的关系。
共纳入 664 名参与者：359 名（54%）患有 DM。LCAC 因子水平与最大摄氧量（β 0.86，p = 2×10）所测的基线运动能力相关，且在 DM 患者与非 DM 患者中的相关性存在差异（β 1.58，p = 8×10 与 0.67，p = 9×10，p 值为交互作用=0.012）。DM 患者运动后 LCAC 水平的变化幅度较小（平均差异 0.09，p = 0.24），而非 DM 患者的变化幅度较大（平均差异 0.16，p = 0.08）。在单变量和多变量模型中，LCAC 因子水平与主要结局的时间相关（多变量 HR 0.80，p = 2.74×10），并且与糖尿病患者的结局相关性更强（HR 0.64，p = 3.21×10 与 HR 0.90，p = 0.104，p 值为交互作用=0.001）。当在个体代谢物水平上进行分析时，C16、C16：1、C18 和 C18：1 与运动能力和结局的相关性最大，水平较高与结局较差相关。在 CATHeterization GENetics（CATHGEN）研究中无 HF 的患者对照组中，未发现与主要临床结局时间的相似相关性。
LCAC 生物标志物与 HF 伴或不伴 DM 患者的运动状态和临床结局差异相关。骨骼肌和心肌中脂肪酸底物利用受损和线粒体功能障碍可能解释了 HF 伴 DM 患者运动能力下降、对运动训练反应减弱和临床结局不佳的原因。
临床试验.gov 标识符：NCT00047437。
