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

Reduced rates of adenosine triphosphate synthesis through myocardial creatine kinase (CK flux) predict adverse clinical events in patients with heart failure. Measuring Metabolic Changes in Heart Failure Predicting whether a patient’s heart will fail could help with tailoring therapeutic intervention. Current clinical predictors, such as New York Heart Association (NYHA) class and left ventricular ejection fraction (LVEF), are nonspecific and imperfect. Because energy metabolism is impaired in the diseased heart, Bottomley et al. hypothesized that it would be an independent and more accurate predictor of heart failure (HF). Adenosine triphosphate (ATP) is the energy source of cells. Creatine kinase (CK) is an enzyme that interacts with ATP to keep the energy supply constant in the beating heart. Thus, the authors sought to measure the rate of ATP synthesis through CK, or what they termed “CK flux,” using a naturally abundant form of phosphorus, 31P, which can be detected using magnetic resonance spectroscopic imaging. CK flux was measured in patients with nonischemic cardiomyopathy over time to see whether myocardial metabolism correlated with clinical HF events or mortality. Indeed, CK flux was significantly lower in HF patients than in healthy controls. Other independent predictors of HF events and mortality, as determined by multiple-event analysis, are African-American race, NYHA class ≥3, and LVEF. Measuring ATP and CK flux in a larger patient cohort will be needed for validation. Nevertheless, this metabolic imaging method could be used in combination with other clinical parameters in devising a more complete prediction of HF events and death, thus helping doctors to better plan treatment courses for their patients. 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.