An Integrated Model of Human Beta-Adrenergic Signaling and Ventricular Electrophysiology Reveals Contributors to Positive Inotropy

Adrenergic regulation is well recognized as an important player in cardiac functions and contributes to pathology underlying arrhythmia and heart failure. Mathematical models of beta-adrenergic signaling have been developed and adrenergic effects on cardiac electrophysiology have been analyzed in animal cells. However, key contributors of these effects in human myocytes remain largely unknown. We have integrated detailed beta-adrenergic signaling cascade with human ventricular electrophysiology based on published models of these two systems. PKA targets in human ventricular electrophysiology: fast sodium channel, slow delayed rectifier potassium channel, sodium potassium ATPase, L-type calcium channel, ryanodine receptor, phospholamban and troponin-I, are simulated to incorporate both baseline and phosphorylation-modified behaviors. Responses to different concentrations of adrenergic agonist isoproteronol are also monitored and adjusted. The model was validated by ensuring these behaviors matched published voltage-clamp data before and after phosphorylation. Simulations to analyze sensitivity of each PKA target were performed with blocking the phosphorylation of a single target one at a time. These simulations showed that phosphorylation of L-type calcium channel and phospholamban were by far the largest contributors to the positive inotropic response observed at 1 Hz with beta-adrenergic stimulation. Further analysis of this integrated model would dissect contribution from parameters in the adrenergic signaling cascade to human ventricular electrophysiology. These results will greatly facilitate understanding of human adrenergic regulation on cardiac functions and diseases.