Loss of Metabolic Flexibility in the Failing Heart.
Loss of Metabolic Flexibility in the Failing Heart.
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DOI：
10.3389/fcvm.2018.00068
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发表时间：
2018
影响因子：
3.6
通讯作者：
Lopaschuk GD
中科院分区：
文献类型：
--
作者：
Karwi QG;Uddin GM;Ho KL;Lopaschuk GD
为了保持其高能量需求，心脏配备了一种高度复杂和高效的酶机械，使用多种能量底物来协调ATP的产生，即脂肪酸、碳水化合物(葡萄糖和乳酸)、酮和氨基酸。这些单独的底物对ATP生产的贡献可能会发生巨大的变化，这取决于底物的可用性、激素状况和能量需求等变量。这种“新陈代谢的灵活性”是心脏的一个显著优点，它允许以不同的速率利用不同的能量底物来维持收缩功能。在心力衰竭时，心功能降低，伴随着明显的能量代谢紊乱和代谢灵活性受损。虽然人们普遍认为，衰竭的心脏整体线粒体ATP的产生受到了损害，但对于能量底物偏好的实际转换发生了什么，还没有达成一致。衰竭的心脏转向更多地依赖糖酵解和酮体氧化作为能量来源，葡萄糖氧化对线粒体氧化代谢的贡献减少。心脏也会对胰岛素产生抵抗。然而，对于心力衰竭时脂肪酸氧化会发生什么，还没有达成一致意见。虽然普遍认为脂肪酸氧化减少，但一些临床和实验研究表明，在心力衰竭中，脂肪酸氧化要么没有改变，要么增加了。重要的是，任何确实发生的代谢变化都有可能加剧心功能障碍和心力衰竭的进展。越来越多的证据表明，增加心脏ATP产量和/或调节心脏能量底物偏好与心功能呈正相关，并可导致更好的结果。这包括增加葡萄糖和酮的氧化，减少脂肪酸的氧化。在这篇综述中，我们介绍了心脏能量代谢途径的生理学以及这些途径在心力衰竭中发生的变化。我们还关注旨在操纵心肌代谢途径以实现更有效的底物利用的干预措施，这最终将改善心脏性能。
To maintain its high energy demand the heart is equipped with a highly complex and efficient enzymatic machinery that orchestrates ATP production using multiple energy substrates, namely fatty acids, carbohydrates (glucose and lactate), ketones and amino acids. The contribution of these individual substrates to ATP production can dramatically change, depending on such variables as substrate availability, hormonal status and energy demand. This “metabolic flexibility” is a remarkable virtue of the heart, which allows utilization of different energy substrates at different rates to maintain contractile function. In heart failure, cardiac function is reduced, which is accompanied by discernible energy metabolism perturbations and impaired metabolic flexibility. While it is generally agreed that overall mitochondrial ATP production is impaired in the failing heart, there is less consensus as to what actual switches in energy substrate preference occur. The failing heart shift toward a greater reliance on glycolysis and ketone body oxidation as a source of energy, with a decrease in the contribution of glucose oxidation to mitochondrial oxidative metabolism. The heart also becomes insulin resistant. However, there is less consensus as to what happens to fatty acid oxidation in heart failure. While it is generally believed that fatty acid oxidation decreases, a number of clinical and experimental studies suggest that fatty acid oxidation is either not changed or is increased in heart failure. Of importance, is that any metabolic shift that does occur has the potential to aggravate cardiac dysfunction and the progression of the heart failure. An increasing body of evidence shows that increasing cardiac ATP production and/or modulating cardiac energy substrate preference positively correlates with heart function and can lead to better outcomes. This includes increasing glucose and ketone oxidation and decreasing fatty acid oxidation. In this review we present the physiology of the energy metabolism pathways in the heart and the changes that occur in these pathways in heart failure. We also look at the interventions which are aimed at manipulating the myocardial metabolic pathways toward more efficient substrate utilization which will eventually improve cardiac performance.
影响因子：
3.7
作者：
Jameel MN;Hu Q;Zhang J
通讯作者：
Zhang J