CARDIOKIN1: Computational Assessment of Myocardial Metabolic Capability in Healthy Controls and Patients With Valve Diseases.

Background: Many heart diseases can develop a reduced pumping capacity of the heart muscle. A mismatch between ATP demand and ATP production of cardiomyocytes is one of the possible causes. Assessment of the relation between the myocardial ATP production (MVATP) and cardiac workload is important for better understanding disease development and choice of nutritional or pharmacological treatment strategies. As there is currently no method for the measurement of MVATP in vivo, the use of physiology-based metabolic models in conjunction with protein abundance data is an attractive approach. Methods: We developed a comprehensive kinetic model of the cardiac energy metabolism (CARDIOKIN1), which recapitulates numerous experimental findings on cardiac metabolism obtained with isolated cardiomyocytes, perfused animal hearts and in vivo studies with humans. We used the model to assess the energy status of the left ventricle (LV) of healthy subjects and patients with aortic stenosis (AS) and mitral valve insufficiency (MI). Maximal enzyme activities were individually scaled by means of protein abundances in LV tissue samples. The energy status of the LV was quantified by the ATP consumption at rest (MVATP (rest)), at maximal workload (MVATP (max)), and by the myocardial ATP production reserve (MAPR) representing the span between MVATP (rest) and MVATP (max). Results: Compared with controls, in both groups of patients, MVATP (rest) was increased and MVATP (max) was decreased resulting in a decreased MAPR, although all patients had preserved ejection fraction. Notably, the variance of the energetic status was high ranging from decreased to normal values. In both patient groups, the energetic status was tightly associated with mechanic energy demand. Moreover, a decrease of MVATP (max) was associated with a decrease of the cardiac output indicating that cardiac functionality and energetic performance of the ventricle are closely coupled. Conclusions: Our analysis suggests that the ATP producing capacity of the LV of patients with valvular dysfunction is generally diminished and correlates positively with mechanic energy demand and cardiac output. However, large differences exist in the energetic state of the myocardium even in patients with similar clinical or image-based markers of hypertrophy and pump function.