Quantification of the ionic current contributions to alterations in the action potential repolarization by means of piecewise-linear approximation

At cellular level, changes in the cardiac action potential (AP) duration (APD) are relevant proarrhythmic markers. The assessment of single current contributions to APD changes allows the investigation of the complex interplay of ionic mechanisms underlying such repolarization changes. In this paper, we present a new method to quantify the contributions of each membrane current to AP D changes due to a perturbation from the basal to a different condition. To achieve our goal, we used a piecewise-linear approximation of the AP. We tested our method on the O´Hara-Rudy model in case of rate adaptation: from the basal condition (pacing at 60 bpm), two different pacing rates are used as perturbations: 30 bpm, which prolongs APD by 21 ms, and 120 bpm, which shortens APD by -37 ms. At steady state, the most significant current contributions (30 bpm/120 bpm) are: I_NaK (68/-73 ms), l_CaL (-58/51 ms), I_NaCa (-10/25 ms), I_Ks (13/-7 ms) and I_NaL (7/-23 ms). Our method allows also quantifying the dynamic adaptation to rate changes from the perturbation until the steady state. In conclusion, our method enables the quantification of the adaptive and compensatory mechanisms implemented by the (in silico model of) cell in response to a perturbation, such as the pacing rate change.