Metabolic Rates of ATP Transfer Through Creatine Kinase (CK Flux) Predict Clinical Heart Failure Events and Death

Abstract

Morbidity and mortality from heart failure (HF) are high, and current risk stratification approaches for predicting HF progression are imperfect. Adenosine triphosphate (ATP) is required for normal cardiac contraction, and abnormalities in creatine kinase (CK) energy metabolism, the primary myocardial energy reserve reaction, have been observed in experimental and clinical HF. However, the prognostic value of abnormalities in ATP production rates through CK in human HF has not been investigated. Fifty-eight HF patients with nonischemic cardiomyopathy underwent 31P magnetic resonance spectroscopy (MRS) to quantify cardiac high-energy phosphates and the rate of ATP synthesis through CK (CK flux) and were prospectively followed for a median of 4.7 years. Multiple-event analysis (MEA) was performed for HF-related events including all-cause and cardiac death, HF hospitalization, cardiac transplantation, and ventricular-assist device placement. Among baseline demographic, clinical, and metabolic parameters, MEA identified four independent predictors of HF events: New York Heart Association (NYHA) class, left ventricular ejection fraction (LVEF), African-American race, and CK flux. Reduced myocardial CK flux was a significant predictor of HF outcomes, even after correction for NYHA class, LVEF, and race. For each increase in CK flux of 1 μmol g−1 s−1, risk of HF-related composite outcomes decreased by 32 to 39%. These findings suggest that reduced CK flux may be a potential HF treatment target. Newer imaging strategies, including noninvasive 31P MRS that detect altered ATP kinetics, could thus complement risk stratification in HF and add value in conditions involving other tissues with high energy demands, including skeletal muscle and brain.

Energy metabolism regulated by HDAC inhibitor attenuates cardiac injury in hemorrhagic rat model

“…Previous evidence suggests that supplemental energy production increases survival8910. Adenosine triphosphate (ATP), mainly synthesized in the mitochondria by the tricarboxylic acid (TCA) cycle, is an essential and direct source of energy for normal cardiac contraction, thus it is a promising indicator of heart failure and death11. We therefore sought to evaluate energy metabolism as a predictor of survival during hemorrhagic heart injury.…”

Metabolomics in epidemiology: from metabolite concentrations to integrative reaction networks

“…ATP and creatine phosphate concentrations as well as common clinical scores were used as predictors of heart failure over an 8.2 year follow-up period. Abnormal creatine kinase flux significantly outperformed patient age, gender and metabolite concentrations in predicting heart failure events and death, including hospitalization for heart failure, cardiac mortality, cardiac transplantation and ventricular-assist device placement, as well as all-cause mortality 85 , 86 . These results are in a relatively small patient cohort with a limited number of events, but they add weight to the argument for the development of reaction rate-based biomarkers in the study of disease.…”

“…Metabolic flux imaging techniques using hyperpolarized metabolites have shown promise in the diagnosis and localization of tumours in prostate cancer patients, 82 and a number of studies have investigated reaction fluxes in the cardiovascular systems of model organisms 83 , 84 . An epidemiological study of particular note is a prospective study in a set of 58 heart failure patients where the investigators measured the rate of ATP synthesis through cardiac creatine kinase flux in situ using 31 P magnetic resonance spectroscopy 85 . ATP and creatine phosphate concentrations as well as common clinical scores were used as predictors of heart failure over an 8.2 year follow-up period.…”

Identification of nondiabetic heart failure-associated genes by bioinformatics approaches in patients with dilated ischemic cardiomyopathy

“…HF with fairly high morbidity and mortality (21), is increasing in prevalence with the aging of the worldwide population (22). In order to improve the understanding on the underlying mechanisms and identify molecular markers of HF, particularly in dilated ischemic cardiomyopathy-associated HF, the present study screened the DEGs between control and ND-HF patients.…”