Evidence of Glycolysis Up-Regulation and Pyruvate Mitochondrial Oxidation Mismatch During Mechanical Unloading of the Failing Human Heart: Implications for Cardiac Reloading and Conditioning.
Evidence of Glycolysis Up-Regulation and Pyruvate Mitochondrial Oxidation Mismatch During Mechanical Unloading of the Failing Human Heart: Implications for Cardiac Reloading and Conditioning.
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DOI：
10.1016/j.jacbts.2016.06.009
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发表时间：
2016-10
期刊：
影响因子：
--
通讯作者：
Drakos SG
中科院分区：
文献类型：
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作者：
Diakos NA;Navankasattusas S;Abel ED;Rutter J;McCreath L;Ferrin P;McKellar SH;Miller DV;Park SY;Richardson RS;Deberardinis R;Cox JE;Kfoury AG;Selzman CH;Stehlik J;Fang JC;Li DY;Drakos SG
LVAD去负荷逆转心肌重塑的几个方面，但不是所有方面，通常导致晚期HF患者的心脏恢复不完全。我们进行了代谢组学分析和线粒体结构和功能的表征配对的人心肌组织采购自31例晚期HF患者在LVAD植入和心脏移植加上组织从11个正常供体。LVAD卸载诱导糖酵解上调，而葡萄糖氧化没有相应增加。LVAD后线粒体功能和体积密度缺乏改善可以解释糖酵解-葡萄糖氧化不匹配。已知可改善线粒体生物发生、结构和功能的治疗性干预（如心肌调节）可能会进一步改善心脏代谢和能量产生，从而通过LVAD诱导的卸载增强心脏恢复。本研究旨在研究机械卸载对心肌能量学和心力衰竭（HF）代谢紊乱的影响，以确定潜在的新的治疗靶点，可以提高卸载诱导的心脏恢复。作者前瞻性地检查了从31例左心室辅助装置（LVAD）植入和心脏移植的晚期HF患者中获得的配对人心肌组织以及11例正常供体的组织。他们发现LVAD后糖酵解代谢产物增加，而早期三羧酸（TCA）循环中间产物没有协调增加。增加的丙酮酸并不直接进入线粒体和TCA循环进行完全氧化，而是主要转化为细胞溶质乳酸。核苷酸浓度增加，可能表明通过磷酸戊糖途径的通量增加。线粒体功能和结构的评价显示LVAD后线粒体氧化功能能力、线粒体体积密度和脱氧核糖核酸含量缺乏改善。最后，LVAD卸载后，发现氨基酸水平增加，可能代表一种补偿机制和替代能源，可以通过回补为TCA循环提供燃料。总之，作者报告了LVAD卸载诱导糖酵解与丙酮酸线粒体氧化失配一致的证据，最有可能是持续性线粒体功能障碍的结果。这些研究结果表明，已知可以改善线粒体生物发生、结构和功能的干预措施，如受控的心脏再负荷和调节，需要进一步研究以增强卸载诱导的逆向重塑和心脏恢复。
LVAD unloading reverses several but not all aspects of myocardial remodeling and usually leads to incomplete cardiac recovery in a subset of patients with advanced HF. We performed metabolomic analysis and mitochondrial structural and functional characterization in paired human myocardial tissue procured from 31 patients with advanced HF at LVAD implant and at heart transplant plus tissue from 11 normal donors. LVAD unloading induces glycolysis up-regulation without a corresponding increase in glucose oxidation. Lack of post-LVAD improvement in mitochondrial function and volume density could explain the glycolysis-glucose oxidation mismatch. Therapeutic interventions, such as myocardial conditioning, that are known to improve mitochondrial biogenesis, structure, and function might further improve cardiac metabolism and energy production and thereby enhance cardiac recovery with LVAD-induced unloading. This study sought to investigate the effects of mechanical unloading on myocardial energetics and the metabolic perturbation of heart failure (HF) in an effort to identify potential new therapeutic targets that could enhance the unloading-induced cardiac recovery. The authors prospectively examined paired human myocardial tissue procured from 31 advanced HF patients at left ventricular assist device (LVAD) implant and at heart transplant plus tissue from 11 normal donors. They identified increased post-LVAD glycolytic metabolites without a coordinate increase in early, tricarboxylic acid (TCA) cycle intermediates. The increased pyruvate was not directed toward the mitochondria and the TCA cycle for complete oxidation, but instead, was mainly converted to cytosolic lactate. Increased nucleotide concentrations were present, potentially indicating increased flux through the pentose phosphate pathway. Evaluation of mitochondrial function and structure revealed a lack of post-LVAD improvement in mitochondrial oxidative functional capacity, mitochondrial volume density, and deoxyribonucleic acid content. Finally, post-LVAD unloading, amino acid levels were found to be increased and could represent a compensatory mechanism and an alternative energy source that could fuel the TCA cycle by anaplerosis. In summary, the authors report evidence that LVAD unloading induces glycolysis in concert with pyruvate mitochondrial oxidation mismatch, most likely as a result of persistent mitochondrial dysfunction. These findings suggest that interventions known to improve mitochondrial biogenesis, structure, and function, such as controlled cardiac reloading and conditioning, warrant further investigation to enhance unloading-induced reverse remodeling and cardiac recovery.