Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, United Kingdom.
Clin Sci (Lond). 2024 Apr 24;138(8):491-514. doi: 10.1042/CS20230616.
The non-stop provision of chemical energy is of critical importance to normal cardiac function, requiring the rapid turnover of ATP to power both relaxation and contraction. Central to this is the creatine kinase (CK) phosphagen system, which buffers local ATP levels to optimise the energy available from ATP hydrolysis, to stimulate energy production via the mitochondria and to smooth out mismatches between energy supply and demand. In this review, we discuss the changes that occur in high-energy phosphate metabolism (i.e., in ATP and phosphocreatine) during ischaemia and reperfusion, which represents an acute crisis of energy provision. Evidence is presented from preclinical models that augmentation of the CK system can reduce ischaemia-reperfusion injury and improve functional recovery. Energetic impairment is also a hallmark of chronic heart failure, in particular, down-regulation of the CK system and loss of adenine nucleotides, which may contribute to pathophysiology by limiting ATP supply. Herein, we discuss the evidence for this hypothesis based on preclinical studies and in patients using magnetic resonance spectroscopy. We conclude that the correlative evidence linking impaired energetics to cardiac dysfunction is compelling; however, causal evidence from loss-of-function models remains equivocal. Nevertheless, proof-of-principle studies suggest that augmentation of CK activity is a therapeutic target to improve cardiac function and remodelling in the failing heart. Further work is necessary to translate these findings to the clinic, in particular, a better understanding of the mechanisms by which the CK system is regulated in disease.
不断提供化学能对心脏正常功能至关重要，需要迅速转化 ATP 以提供松弛和收缩所需的动力。肌酸激酶（CK）磷酸原系统是这一过程的核心，它缓冲局部 ATP 水平，优化 ATP 水解产生的能量，通过线粒体刺激能量产生，并解决能量供应和需求之间的不匹配问题。在这篇综述中，我们讨论了高能磷酸盐代谢（即 ATP 和磷酸肌酸）在缺血和再灌注过程中发生的变化，这代表了能量供应的急性危机。来自临床前模型的证据表明，增强 CK 系统可以减少缺血再灌注损伤并改善功能恢复。能量损伤也是慢性心力衰竭的一个标志，特别是 CK 系统的下调和腺嘌呤核苷酸的丧失，通过限制 ATP 供应，可能对病理生理学产生影响。在此，我们根据临床前研究和使用磁共振波谱技术的患者讨论了这一假说的证据。我们得出的结论是，将能量代谢受损与心脏功能障碍联系起来的相关证据是令人信服的；然而，来自功能丧失模型的因果证据仍然存在争议。然而，初步研究表明，增强 CK 活性是改善心力衰竭心脏功能和重塑的治疗靶点。有必要进一步开展工作将这些发现转化为临床实践，特别是更好地理解 CK 系统在疾病中的调节机制。
