ATP flux through creatine kinase in the normal, stressed, and failing human heart
ATP flux through creatine kinase in the normal, stressed, and failing human heart
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DOI：
10.1073/pnas.0408962102
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发表时间：
2005-01-18
影响因子：
11.1
通讯作者：
Bottomley, PA
中科院分区：
文献类型：
--
作者：
Weiss, RG;Gerstenblith, G;Bottomley, PA
心脏每克消耗的能量比任何其他器官都多，肌酸激酶（CK）反应是其主要的能量储备。由于心脏收缩和舒张功能需要化学能，因此衰竭的心脏是否“能量匮乏”的问题已经争论了几十年。尽管CK反应在心脏能量代谢中起着重要作用，但在跳动的人类心脏中直接测量CK通量以前是不可能的。使用图像引导的内源性ATP周转的分子评估，我们直接测量ATP流量通过CK在正常，紧张，和失败的人的心脏。我们表明，健康人的心脏CK通量比通过氧化磷酸化估计的要快，并且在多巴酚丁胺使心率-血压积加倍期间，CK通量不会增加。此外，轻中度心力衰竭患者通过CK的心脏ATP流量减少50%（1.6 +/- 0.6 vs. 3.2 +/- 0.9 mumol/g湿重/秒，P < 0.0005）。我们的结论是，磁共振策略，现在可以直接评估人类心肌CK能量通量。在衰竭心脏中由CK提供的ATP的缺乏是心脏特异性的，并且即使在ATP储存没有显著减少的情况下，也可能具有足够的幅度，以促成人类心力衰竭的病理生理学。这些发现支持寻求新的治疗方法，减少心力衰竭的能量需求和/或增加能量转移，并表明心脏磁共振可用于评估其有效性。
The heart consumes more energy per gram than any other organ, and the creatine kinase (CK) reaction serves as its prime energy reserve. Because chemical energy is required to fuel systolic and diastolic function, the question of whether the failing heart is "energy starved" has been debated for decades. Despite the central role of the CK reaction in cardiac energy metabolism, direct measures of CK flux in the beating human heart were not previously possible. Using an image-guided molecular assessment of endogenous ATP turnover, we directly measured ATP flux through CK in normal, stressed, and failing human hearts. We show that cardiac CK flux in healthy humans is faster than that estimated through oxidative phosphorylation and that CK flux does not increase during a doubling of the heart rate-blood pressure product by dobutamine. Furthermore, cardiac ATP flux through CK is reduced by 50% in mild-to-moderate human heart failure (1.6 +/- 0.6 vs. 3.2 +/- 0.9 mumol/g of wet weight per sec, P < 0.0005). We conclude that magnetic resonance strategies can now directly assess human myocardial CK energy flux. The deficit in ATP supplied by CK in the failing heart is cardiac-specific and potentially of sufficient magnitude, even in the absence of a significant reduction in ATP stores, to contribute to the pathophysiology of human heart failure. These findings support the pursuit of new therapies that reduce energy demand and/or augment energy transfer in heart failure and indicate that cardiac magnetic resonance can be used to assess their effectiveness.