Multiscale modeling of cardiac cellular energetics

Inducing abnormal routes of cardiac excitation results in predictable changes in regional blood flows and metabolism. In LBBB, glucose uptake and flow are both reduced in the septal region, similar to the situation in dogs paced at the right ventricular outflow tract, when the septum is activated early, shorten rapidly against low left ventricular (LV) pressure, and blood flow to the interventricular septum diminishes, while flow increases in the later-activated LV free wall. A mathematical model has been developed to explain this set of phenomena, attempting to minimize the model in order to identify the key characteristics governing the observed responses. The specific objective is to provide a logical, quantitatively appropriate representation of the linked events: (1) local blood flow and substrate and oxygen supply, (2) local fatty acid and glucose metabolism, (3) ATP generation by glycolysis and oxidative phosphorylation, (4) ATP utilization by hydrolysis at the cross bridge, by ion pumps, and for cell maintenance, (5) the processes of excitation-contraction coupling, and (6) feedback regulation of blood flow. We attempt to explain the observations in a simplified representation of these events using a common parameter set for two regions linked in tandem, but activating them separately with a time delay representing the time for excitation to spread from septum to free wall. The early activation of one cell stretches the other, so that the first cell has diminished oxygen requirements and the second, increased, as seen in the intact heart. Integrative modeling of cardiac energy metabolism, capillary-tissue substrate exchange, and local blood flow regulation provides an overall representation of the data in a quantitative fashion, an approach in accord with the goals for physiome projects. KEYWORDS: Myocardial blood flow heterogeneity, cardiac pacing, excitation-contraction coupling, cellular energetics, cardiac cell model, bundle branch block, shortening deactivation, ionic regulation.