Myocardial Energetics in Obesity: Enhanced ATP Delivery Through Creatine Kinase with Blunted Stress Response.

Background: Obesity is strongly associated with exercise intolerance and development of heart failure. While myocardial energetics and diastolic function are impaired in obesity, systolic function is usually preserved. This suggests that the rate of ATP delivery is maintained, but this has never been explored in human obesity. We hypothesised that ATP transfer rate through creatine kinase (CK) (k_f^CKrest) would be increased, compensating for depleted energy stores (PCr/ATP), but potentially limiting greater ATP delivery during increased workload. We hypothesised these changes would normalise with weight loss. Methods: We recruited 80 volunteers (35 controls (BMI 24±3kg/m²), 45 obese (BMI 35±5m/kg²)) without co-existing cardiovascular disease. Participants underwent body composition analysis, MRI of abdominal, liver and myocardial fat content, left ventricular function and ³¹P-magnetic resonance spectroscopy to assess PCr/ATP and CK kinetics, at rest and during dobutamine stress. Obese volunteers were assigned to a dietary weight loss intervention, before re-examination. Results: At rest, although myocardial PCr/ATP was 14% lower in obesity (1.9±0.3 vs 2.2±0.2, p<0.001), k_f^CKrest was 33% higher (0.23±0.07s^-1 vs 0.16±0.08s^-1, p=0.002), yielding no difference in overall resting ATP delivery (obese 2.5±0.9µmol/g/sec vs control 2.2±1.1µmol/g/sec, p=0.232). In controls, increasing cardiac workload led to an increase in both k_f^CK (+86%, p<0.001) and ATP delivery (+80%, p<0.001). However, in obesity, similar stress led to no significant increase in either k_f^CK (p=0.117), or ATP delivery (p=0.608). This was accompanied by reduced systolic augmentation (absolute increase in LVEF obese +16±7% vs control +21±4%, p=0.031). Successful weight loss (-11±5% body weight) was associated with improvement of these energetic changes such that there was no significant difference compared to controls. Conclusions: In the obese resting heart, the myocardial CK reaction rate is increased, maintaining ATP delivery despite reduced PCr/ATP. During increased workload, whilst the non-obese heart increases ATP delivery through CK, the obese heart does not; this is associated with reduced systolic augmentation and exercise tolerance. Weight loss reverses these energetic changes. This highlights myocardial energy delivery via CK as a potential therapeutic target to improve symptoms in obesity-related heart disease, as well as a fascinating modifiable pathway involved in the progression to heart failure.