Metabolomic Profiling Identifies Novel Circulating Biomarkers of Mitochondrial Dysfunction Differentially Elevated in Heart Failure With Preserved Versus Reduced Ejection Fraction: Evidence for Shared Metabolic Impairments in Clinical Heart Failure.
Metabolomic Profiling Identifies Novel Circulating Biomarkers of Mitochondrial Dysfunction Differentially Elevated in Heart Failure With Preserved Versus Reduced Ejection Fraction: Evidence for Shared Metabolic Impairments in Clinical Heart Failure.
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DOI：
10.1161/jaha.115.003190
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发表时间：
2016-07-29
影响因子：
5.4
通讯作者：
Shah SH
中科院分区：
文献类型：
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作者：
Hunter WG;Kelly JP;McGarrah RW 3rd;Khouri MG;Craig D;Haynes C;Ilkayeva O;Stevens RD;Bain JR;Muehlbauer MJ;Newgard CB;Felker GM;Hernandez AF;Velazquez EJ;Kraus WE;Shah SH
代谢障碍是心力衰竭（HF）发病机制和进展的重要因素。在射血分数正常的HF患者中，代谢途径失调的特征仍然不明显。我们试图确定HFpEF中的代谢异常，并确定HFpEF与射血分数降低的HF（HFrEF）中差异改变的途径。我们从接受心导管插入术的连续患者的CATHGEN研究中确定了HFpEF病例、HFrEF对照和无HF对照。HFpEF病例（N=282）定义为左心室射血分数（LVEF）≥ 45%，舒张功能不全分级≥1，HF病史; HFrEF对照组（N=279）定义相似，但LVEF <45%。无HF对照组（N=191）LVEF ≥ 45%，舒张功能正常，无HF诊断。靶向质谱法和酶测定法用于定量空腹血浆中的63种代谢物。主成分分析将63种代谢物减少为不相关因子，使用ANCOVA进行各组比较。在基本和完全校正模型中，各组间长链酰基肉毒碱因子水平差异显著（P<0.0001），HFrEF组高于HFpEF组（P=0.0004），两者均高于无HF对照组。我们在敏感性分析中使用更严格的入选标准、替代性LVEF阈值和胰岛素抵抗校正证实了这些结果。我们鉴定了反映脂肪酸氧化受损或失调的新型循环代谢物，这些代谢物与HF独立相关，并且在HFpEF和HFrEF中差异升高。这些结果阐明了HF中的特定代谢途径，并表明HF中沿着LVEF谱存在共同的代谢机制。
Metabolic impairment is an important contributor to heart failure (HF) pathogenesis and progression. Dysregulated metabolic pathways remain poorly characterized in patients with HF and preserved ejection fraction (HFpEF). We sought to determine metabolic abnormalities in HFpEF and identify pathways differentially altered in HFpEF versus HF with reduced ejection fraction (HFrEF). We identified HFpEF cases, HFrEF controls, and no‐HF controls from the CATHGEN study of sequential patients undergoing cardiac catheterization. HFpEF cases (N=282) were defined by left ventricular ejection fraction (LVEF) ≥45%, diastolic dysfunction grade ≥1, and history of HF; HFrEF controls (N=279) were defined similarly, except for having LVEF <45%. No‐HF controls (N=191) had LVEF ≥45%, normal diastolic function, and no HF diagnosis. Targeted mass spectrometry and enzymatic assays were used to quantify 63 metabolites in fasting plasma. Principal components analysis reduced the 63 metabolites to uncorrelated factors, which were compared across groups using ANCOVA. In basic and fully adjusted models, long‐chain acylcarnitine factor levels differed significantly across groups (P<0.0001) and were greater in HFrEF than HFpEF (P=0.0004), both of which were greater than no‐HF controls. We confirmed these findings in sensitivity analyses using stricter inclusion criteria, alternative LVEF thresholds, and adjustment for insulin resistance. We identified novel circulating metabolites reflecting impaired or dysregulated fatty acid oxidation that are independently associated with HF and differentially elevated in HFpEF and HFrEF. These results elucidate a specific metabolic pathway in HF and suggest a shared metabolic mechanism in HF along the LVEF spectrum.