Impaired Myocardial Energetics Causes Mechanical Dysfunction in Decompensated Failing Hearts.
Impaired Myocardial Energetics Causes Mechanical Dysfunction in Decompensated Failing Hearts.
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DOI：
10.1093/function/zqaa018
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发表时间：
2020
期刊：
影响因子：
--
通讯作者：
Beard DA
中科院分区：
文献类型：
--
作者：
Lopez R;Marzban B;Gao X;Lauinger E;Van den Bergh F;Whitesall SE;Converso-Baran K;Burant CF;Michele DE;Beard DA
心脏机械功能由ATP水解支持，ATP水解提供化学自由能以驱动心脏泵送的分子过程。心肌ATP消耗的生理速率要求心脏每分钟重新合成其整个ATP库数次。在衰竭的心脏中，心肌细胞代谢功能障碍导致ATP合成能力和驱动细胞过程的相关自由能降低。然而，目前尚不清楚心力衰竭期间发生的代谢/能量功能障碍是否以及如何影响心脏的机械功能。我们假设与失代偿和心力衰竭相关的磷酸盐代谢物浓度（ATP、ADP、无机磷酸盐）的变化在阻碍心力衰竭心肌收缩功能方面具有直接作用，从而导致全身表型。为了检验这一假设，使用压力超负荷、肥大和失代偿的横向主动脉缩窄（TAC）大鼠模型来评估全器官泵功能和心肌能量状态的度量之间的关系。心脏机械能耦合的多尺度计算模型用于识别和量化代谢功能障碍对观察到的机械功能障碍的贡献。结果显示，与假手术对照组相比，TAC动物心肌中由脂肪酸或碳水化合物底物提供燃料的氧化ATP合成能力总体降低，以及腺嘌呤核苷酸和肌酸总水平降低。TAC大鼠中磷酸盐代谢物水平的变化与机械功能受损相关，与总体假设一致。此外，心肌代谢和收缩动力学的计算分析预测，与对照动物相比，TAC中无机磷酸盐水平的增加在动力学上损害失代偿性肥大/心力衰竭中的肌球蛋白ATP酶过桥循环。
Cardiac mechanical function is supported by ATP hydrolysis, which provides the chemical-free energy to drive the molecular processes underlying cardiac pumping. Physiological rates of myocardial ATP consumption require the heart to resynthesize its entire ATP pool several times per minute. In the failing heart, cardiomyocyte metabolic dysfunction leads to a reduction in the capacity for ATP synthesis and associated free energy to drive cellular processes. Yet it remains unclear if and how metabolic/energetic dysfunction that occurs during heart failure affects mechanical function of the heart. We hypothesize that changes in phosphate metabolite concentrations (ATP, ADP, inorganic phosphate) that are associated with decompensation and failure have direct roles in impeding contractile function of the myocardium in heart failure, contributing to the whole-body phenotype. To test this hypothesis, a transverse aortic constriction (TAC) rat model of pressure overload, hypertrophy, and decompensation was used to assess relationships between metrics of whole-organ pump function and myocardial energetic state. A multiscale computational model of cardiac mechanoenergetic coupling was used to identify and quantify the contribution of metabolic dysfunction to observed mechanical dysfunction. Results show an overall reduction in capacity for oxidative ATP synthesis fueled by either fatty acid or carbohydrate substrates as well as a reduction in total levels of adenine nucleotides and creatine in myocardium from TAC animals compared to sham-operated controls. Changes in phosphate metabolite levels in the TAC rats are correlated with impaired mechanical function, consistent with the overall hypothesis. Furthermore, computational analysis of myocardial metabolism and contractile dynamics predicts that increased levels of inorganic phosphate in TAC compared to control animals kinetically impair the myosin ATPase crossbridge cycle in decompensated hypertrophy/heart failure.
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影响因子：
20.1
作者：
Doenst T;Nguyen TD;Abel ED
通讯作者：
Abel ED
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GERTZ, EW;WISNESKI, JA;NEESE, RA
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NEESE, RA
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