Linking Cellular Energetics to Local Flow Regulation in the Heart

Abstract

A mathematical model has been developed to explain the metabolic and energetic responses induced by abnormal routes of cardiac excitation. For example, in left bundle branch block (LBBB), both glucose uptake and flow are reduced in the septal region, similar to the situation in dogs paced at the right ventricular outflow tract. In these conditions the septum is activated early, the sarcomere lengths shorten rapidly against low left ventricular (LV) pressure, and the blood flow to the interventricular septum diminishes. In contrast, the work load and the blood flow increases in the later-activated LV free wall. To provide a logical, quantitatively appropriate representation, the model links: (1) the processes of excitation-contraction coupling; (2) regional ATP utilization for force development at the cross-bridge, for ion pumping, and for cell maintenance; (3) the regulation of demands on local fatty acid and glucose metabolism for ATP generation by glycolysis and oxidative phosphorylation; and (4) feedback regulation of blood flow to supply substrate and oxygen. The heart is considered as a cylinder composed of two parts: an early-activated region and a late-activated region in tandem, but activated separately with the time delay representing the time for excitation to spread from septum to free wall. The same model equations and parameter sets are used for the two regions. The contraction of the early-activated region stretches the other region, with the result that the early-stimulated region has diminished oxygen requirements compared to those found with simultaneous stimulation. The late-activated region has increased work and increased oxygen consumption, as seen in the intact heart. Integrating the modeling of cardiac energy metabolism with local blood flow regulation and capillary-tissue substrate exchange provides a quantitative description, an hypothesis formulated to stimulate further experimentation to test its validity. The hypothesis "explains" observations of contraction and metabolism in LBBB, but whether this concept can be extended to explain the normal flow heterogeneity in the heart remains unknown.