Evidence for Intramyocardial Disruption of Lipid Metabolism and Increased Myocardial Ketone Utilization in Advanced Human Heart Failure.
Evidence for Intramyocardial Disruption of Lipid Metabolism and Increased Myocardial Ketone Utilization in Advanced Human Heart Failure.
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DOI：
10.1161/circulationaha.115.017545
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发表时间：
2016-02-23
期刊：
影响因子：
37.8
通讯作者：
Rame JE
中科院分区：
文献类型：
--
作者：
Bedi KC Jr;Snyder NW;Brandimarto J;Aziz M;Mesaros C;Worth AJ;Wang LL;Javaheri A;Blair IA;Margulies KB;Rame JE
衰竭的人类心脏的特征是代谢异常，但这些缺陷仍然不完全清楚。在HF的动物模型中，存在从脂肪酸利用为主到更节省氧气的碳水化合物代谢的转变。最近的研究报道了心肌脂质含量的降低，但纳入糖尿病和非糖尿病患者模糊了对代谢紊乱的适应与对心力衰竭本身的适应的区别。我们在心脏移植或LVAD植入时，对非糖尿病、消瘦、主要为非缺血性晚期HF患者使用液相色谱-质谱法进行了无偏倚和有针对性的心肌脂质调查。我们确定了大部分心肌脂质中间体的浓度显着降低，包括长链酰基肉毒碱，线粒体脂肪酸氧化的主要能量脂质底物的子集。我们首次报告了纳入Krebs循环的中间体和回补酰基辅酶A物质的水平显著降低，而终末期心力衰竭的心肌乙酰辅酶A浓度显著增加。相反，我们观察到生酮β-羟基丁酰辅酶A的丰度增加，与β-羟基丁酸的心肌利用增加相关。我们观察到编码琥珀酰-CoA：3-氧代酸-CoA转移酶（SCOT）的基因表达显著增加，SCOT是心肌氧化βOHB和乙酰乙酸的限速酶。这些发现表明，在不依赖于糖尿病的严重衰竭的人类心脏中，酮利用增加，支持酮体作为替代燃料的作用，以及心肌酮氧化作为衰竭的人类心脏中的关键代谢适应。
The failing human heart is characterized by metabolic abnormalities, but these defects remains incompletely understood. In animal models of HF there is a switch from a predominance of fatty acid utilization to the more oxygen-sparing carbohydrate metabolism. Recent studies have reported decreases in myocardial lipid content, but inclusion of diabetics and nondiabetics obscures the distinction of adapations to metabolic derangements from adaptations to heart failure per se. We performed both unbiased and targeted myocardial lipid surveys using liquid chromatography-mass spectroscopy in non-diabetic, lean, predominantly non-ischemic advanced HF patients at the time of heart transplantation or LVAD implantation. We identified significantly decreased concentrations of the majority of myocardial lipid intermediates, including long-chain acylcarnitines, the primary subset of energetic lipid substrate for mitochondrial fatty acid oxidation. We report for the first time significantly reduced levels of intermediate and anaplerotic acyl-CoA species incorporated into Krebs cycle, while the myocardial concentration of acetyl-CoA was significantly increased in end-stage heart failure. In contrast, we observed an increased abundance of ketogenic β-hydroxybutyryl CoA, in association with increased myocardial utilization of β-hydroxybutyrate. We observed a significant increase in the expression of the gene encoding succinyl-CoA: 3oxoacid-CoA transferase (SCOT), the rate limiting enzyme for myocardial oxidation of βOHB and acetoacetate. These findings indicate increased ketone utilization in the severely failing human heart independent of diabetes, support the role of ketone bodies as an alternative fuel and myocardial ketone oxidation as a key metabolic adaptation in the failing human heart.