In Silico Studies of Cardiac Inotropy using a New Model of Force Generation

Abstract

An improved model of force generation was incorporated into a complete mathematical description of action potential (AP), ionic currents and Ca2+ transient of the rabbit ventricular myocyte (LabHEART 5.0). This new model reproduces the main events involved in Excitation-Contraction Coupling, namely the AP (excitation), the shortening (contraction) and the Ca2+ transient as the link between them. LabHEART 5.0 was able to reproduce isotonic and isometric contractions and the classical curves of Force vs. Ca2+ and Force vs cell length. Cardiac inotropy was investigated by simulating the application of isoproterenol (ISO). This effect was achieved by altering L-type Ca2+ current, the slowly activating delayed rectifier K+ current, sarcoplasmic reticulum (SR) Ca2+ pump, SR Ca2+ leak, myofilament Ca-sensitivity and cross-bridge cycling. The latter modification was essential for replicating the ISO-induced increase in force generation/shortening development experimentally observed. AP duration (APD, for 90% of repolarization) adaptation to pacing frequencies was also examined. ISO shortened APD at all frequencies with respect to control and flattened the adaptation curve, thus allowing an APD compatible with short cycle length (up to 5 Hz). ISO also increased the Ca2+ transient dynamic range by keeping a low diastolic level while increasing the peak Ca2+ at all the simulated frequencies (0.5 to 9 Hz). This model provides a useful framework to study cardiac inotropy and constitutes a starting point to investigate the electro-mechanical feedback in cardiac performance. The new version LabHEART 5.0 is freely available online at www.labheart.org.