A Novel Method for Quantifying the Contribution of Different Intracellular Mechanisms to Mechanically Induced Changes in Action Potential Characteristics

We introduce the Difference-Current Integral (DCI) method as a tool for quantitative assessment of contributions by individual model components to dynamic responses at the system's level. Using a detailed model of cardiac electrophysiology and mechanics, we assess the relative effects of mechano-sensitive ion channels and intracellular calcium handling to stretch-induced changes in action potential (AP) characteristics. DCI supports the hypothesis that some of the experimentally observed variability in cardiac AP responses to mechanical stimulation may be caused by differences in activation of underlying mechanisms, rather than solely species or technical differences. In particular, the model suggests that systems with a pronounced reverse mode Na+- Ca2+ exchange during the AP will respond to mechanical interventions that affect primarily cellular Ca2+ handling with AP shortening, whereas a predominant contribution of mechano-sensitive ion channels, in particular cation non-selective ones, may cause late AP prolongation and cross-over of repolarisation.