Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD (G.K., A.G., J.S., J.A., M.L., B.O., G.G., N.P., R.G.W.).
Department of Diagnostic and Interventional Imaging, The University of Texas Health Science Center at Houston (UTHealth) (R.G.).
Circ Res. 2022 Mar 4;130(5):741-759. doi: 10.1161/CIRCRESAHA.121.319648. Epub 2022 Feb 3.
Abnormalities in cardiac energy metabolism occur in heart failure (HF) and contribute to contractile dysfunction, but their role, if any, in HF-related pathologic remodeling is much less established. CK (creatine kinase), the primary muscle energy reserve reaction which rapidly provides ATP at the myofibrils and regenerates mitochondrial ADP, is down-regulated in experimental and human HF. We tested the hypotheses that pathologic remodeling in human HF is related to impaired cardiac CK energy metabolism and that rescuing CK attenuates maladaptive hypertrophy in experimental HF.
First, in 27 HF patients and 14 healthy subjects, we measured cardiac energetics and left ventricular remodeling using noninvasive magnetic resonance P spectroscopy and magnetic resonance imaging, respectively. Second, we tested the impact of metabolic rescue with cardiac-specific overexpression of either Ckmyofib (myofibrillar CK) or Ckmito (mitochondrial CK) on HF-related maladaptive hypertrophy in mice.
In people, pathologic left ventricular hypertrophy and dilatation correlate closely with reduced myocardial ATP levels and rates of ATP synthesis through CK. In mice, transverse aortic constriction-induced left ventricular hypertrophy and dilatation are attenuated by overexpression of CKmito, but not by overexpression of CKmyofib. CKmito overexpression also attenuates hypertrophy after chronic isoproterenol stimulation. CKmito lowers mitochondrial reactive oxygen species, tissue reactive oxygen species levels, and upregulates antioxidants and their promoters. When the CK capacity of CKmito-overexpressing mice is limited by creatine substrate depletion, the protection against pathologic remodeling is lost, suggesting the ADP regenerating capacity of the CKmito reaction rather than CK protein per se is critical in limiting adverse HF remodeling.
In the failing human heart, pathologic hypertrophy and adverse remodeling are closely related to deficits in ATP levels and in the CK energy reserve reaction. CKmito, sitting at the intersection of cardiac energetics and redox balance, plays a crucial role in attenuating pathologic remodeling in HF. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT00181259.
心脏能量代谢异常发生在心力衰竭（HF）中，并导致收缩功能障碍，但它们在 HF 相关病理性重塑中的作用（如果有的话）则远未确定。CK（肌酸激酶）是主要的肌肉能量储备反应，可在肌原纤维中迅速提供 ATP，并使线粒体 ADP 再生，在实验性和人类 HF 中均下调。我们检验了以下假设：人类 HF 中的病理性重塑与心脏 CK 能量代谢受损有关，并且恢复 CK 可减轻实验性 HF 中的适应性肥大。
首先，在 27 例 HF 患者和 14 例健康受试者中，我们分别使用非侵入性磁共振 P 谱和磁共振成像测量了心脏能量代谢和左心室重塑。其次，我们通过心脏特异性过表达肌球蛋白 CK（myofibrillar CK）或线粒体 CK（mitochondrial CK）来检验代谢恢复对 HF 相关适应性肥大的影响。
在人类中，病理性左心室肥大和扩张与心肌 ATP 水平降低以及 CK 介导的 ATP 合成速率密切相关。在小鼠中，过表达 CKmito 可减轻主动脉缩窄引起的左心室肥大和扩张，但过表达 CKmyofib 则不能。CKmito 过表达还可减轻慢性异丙肾上腺素刺激后的肥大。CKmito 降低线粒体活性氧、组织活性氧水平，并上调抗氧化剂及其启动子。当 CKmito 过表达小鼠的 CK 容量受到肌酸底物耗尽的限制时，对病理性重塑的保护作用丧失，这表明 CKmito 反应的 ADP 再生能力而不是 CK 蛋白本身对于限制不良 HF 重塑至关重要。
在衰竭的人心肌中，病理性肥大和不良重塑与 ATP 水平和 CK 能量储备反应的缺陷密切相关。CKmito 位于心脏能量代谢和氧化还原平衡的交点，在 HF 病理性重塑中起着至关重要的作用。
