Overexpression of mitochondrial creatine kinase preserves cardiac energetics without ameliorating murine chronic heart failure

• DOI: 10.1007/s00395-020-0777-3
• Publication Date: 2020-01-10T09:03:25Z
• Authors: Fang Cao; Mahon L. Maguire; Debra J. McAndrew; Hannah A. Lake; Stefan Neubauer; Sevasti Zervou; Jürgen E. Schneider; Craig A. Lygate
• Keywords: Heart Failure; Male; 0303 health sciences; Ventricular Remodeling; Creatine Kinase, Mitochondrial Form; Mice, Transgenic; Original Contribution; Mitochondria, Heart; Ventricular Function, Left; 3. Good health; Mice, Inbred C57BL; Disease Models, Animal; Ventricular Dysfunction, Left; 03 medical and health sciences; Chronic Disease; Animals; Hypertrophy, Left Ventricular; Myocytes, Cardiac; Energy Metabolism; Signal Transduction

AbstractMitochondrial creatine kinase (Mt-CK) is a major determinant of cardiac energetic status and is down-regulated in chronic heart failure, which may contribute to disease progression. We hypothesised that cardiomyocyte-specific overexpression of Mt-CK would mitigate against these changes and thereby preserve cardiac function. Male Mt-CK overexpressing mice (OE) and WT littermates were subjected to transverse aortic constriction (TAC) or sham surgery and assessed by echocardiography at 0, 3 and 6 weeks alongside a final LV haemodynamic assessment. Regardless of genotype, TAC mice developed progressive LV hypertrophy, dilatation and contractile dysfunction commensurate with pressure overload-induced chronic heart failure. There was a trend for improved survival in OE-TAC mice (90% vs 73%, P = 0.08), however, OE-TAC mice exhibited greater LV dilatation compared to WT and no functional parameters were significantly different under baseline conditions or during dobutamine stress test. CK activity was 37% higher in OE-sham versus WT-sham hearts and reduced in both TAC groups, but was maintained above normal values in the OE-TAC hearts. A separate cohort of mice received in vivo cardiac 31P-MRS to measure high-energy phosphates. There was no difference in the ratio of phosphocreatine-to-ATP in the sham mice, however, PCr/ATP was reduced in WT-TAC but preserved in OE-TAC (1.04 ± 0.10 vs 2.04 ± 0.22; P = 0.007). In conclusion, overexpression of Mt-CK activity prevented the changes in cardiac energetics that are considered hallmarks of a failing heart. This had a positive effect on early survival but was not associated with improved LV remodelling or function during the development of chronic heart failure.