FEED FORWARD MODELING: A NOVEL APPROACH TO MODELING THE EFFECTS OF β-ADRENERGIC STIMULATION ON VENTRICULAR MYOCYTES.

The relationship between force and frequency in the cardiac muscle is mediated by β1-adrenergic stimulation. Changes in heart rate at the sinoatrial node lead to alterations in ventricular cells, increasing contractile force and reducing relaxation time to accommodate more beats in less time. Mathematical models lacking this characteristic provide incomplete descriptions of physiological changes and compromise the interpretation of "in silico" results. To overcome this limitation, a new proposal for mathematical modeling of the ventricular myocyte, called "Feed Forward Modeling" (FFM), is introduced. FFM adapts model parameters according to the stimulation frequency, replacing fixed values used for activation, channel conductance, and Ca2+ pump affinity with empirical curves. Simulations with FFM demonstrate more physiologically coherent results, with increased inotropic and lusitropic effects, indicating better adaptation to different frequencies. Compared to the conventional model, FFM reduces the repolarization time (APD90) from 206 ms at 1 Hz to 173 ms at 4 Hz, while the conventional model increases to 208.3 ms at 4 Hz, impairing the heart's ability to cope with higher frequencies. The peak force increases from 8.5 mN/mm2 at 1 Hz to 11.9 mN/mm2 at 4 Hz with FFM, whereas the conventional model only shows an increase to 7.8 mN/mm2 at 4 Hz. FFM proves to be more efficient than including all beta-adrenergic pathways, making it suitable for large-scale simulations. It is suggested that experiments involving changes in stimulation frequency should be conducted with fractional dosages of isoproterenol (ISO) concentration to better mimic the heart's natural environment.