bioRxiv2020
The ventricular action potential (AP) is subserved by an interdependent system of voltage-gated ion channels and pumps that both alter and respond (directly or indirectly) to the dynamic transmembrane potential ({Delta}{psi}m(t)) via voltage-dependent state transitions governing inward and outward ion currents. The native dynamic inward-outward current balance is subject to disruption caused by acquired or inherited loss or gain of function in one or more ion channels or pumps. Building on our previous work, we used a modified version of the OHara-Rudy (ORd) model of the undiseased human ventricular cardiomyocyte to study the pro-arrhythmic effects of three types of arrhythmia-inducing perturbations in midmyocytes (M cells): O_LIBlockade of the human ether-a-go-go related gene (hERG) K+ channel introduced via a Markov state binding model. C_LIO_LIMutation-induced voltage shifts in hERG channel gating, resulting in faster inactivation or slowed recovery of both phosphorylated and non-phosphorylated forms of the channel (known as LQT2 syndrome). C_LIO_LIMutation-induced voltage shifts in Nav1.5 gating, resulting in slowed late inactivation of the phosphorylated and non-phosphorylated forms of the channel (known as LQT3 syndrome). C_LI We studied the relationships between ion current anomalies and AP morphology as a function of cycle length (CL) and perturbation type/level. The results are summarized as follows: O_LIAP duration (APD) is governed directly by Kir2.1 activation (IK1), which is delayed when repolarization is slowed by abnormal net inward tipping of the dynamic inward-outward current balance (reflected in decreased d({Delta}{psi}m(t))/dt during the late AP repolarization phase). In the case of hERG blockade by non-trappable compounds, the perturbation level consists of the dynamic fractional occupancy of the channel, which is governed by blocker kon relative to the rate of channel opening, pharmacokinetic exposure, and koff (in that order). C_LIO_LIArrhythmia progresses from prolonged paced APs [->] atypical APs (spontaneous and paced) [->] self-sustaining oscillations. Abrupt transitions between these regimes occur at CL- and perturbation-specific thresholds (denoted as T1, T2, and T3, respectively), whereas intra-regime progression proceeds in a graded fashion toward the subsequent threshold. APD and d({Delta}{psi}m(t))/dt during the late repolarization phase varied significantly across the 200 APs of our simulations near the T1 threshold at CL = 1/35 min, reflecting increasing instability of the AP generation system. C_LIO_LIArrhythmic APs exhibit highly variable cycle-to-cycle morphologies, depending on the perturbation level, type, and phasing between the underlying ion channel states and pacing cycle. C_LIO_LIAtypical APs may be triggered by typical or atypical depolarizations prior to the T3 threshold, depending on perturbation type/level and phasing relative to CL: O_LIAPD/CL resides outside of the Goldilocks zone: O_LIAPD/CL [->] 1 at shorter CL and/or longer APD, resulting in pro-arrhythmic "collisions" between successive paced APs (APi and APj) within a given cardiomyocyte. We studied this scenario at 60 and 80 beats per minute (BPM), equating to CL = 1/60 and 1/80 min. C_LIO_LIAPD/CL < 1 at longer CL results in spontaneous atypical depolarizations within prolonged paced APs at elevated takeoff {Delta}{psi}m(t) and increased channel phosphorylation levels. We studied this scenario at CL = 1/35 min. C_LI C_LIO_LIAPD and d({Delta}{psi}m(t))/dt during the late repolarization phase become increasingly variable over successive APs on approach to the T1 threshold, which is the possible source of short-long-short sequences observed in the ECG preceding torsades de pointes arrhythmia (TdP). C_LI C_LIO_LIAll atypical depolarizations are solely Cav1.2 (ICa,L)-driven ({Delta}{psi}m(t) falls within the Nav1.5 inactivation window), whereas typical depolarizations are Nav1.5 (INa) + ICa,L-driven. Atypical depolarization versus typical repolarization occurrences are determined by the faster of Cav1.2 and Kir2.1 (IK1) activation (where IK1 becomes increasingly dampened as the minimum {Delta}{psi}m(t) drifts above the Kir2.1 activation window). C_LIO_LICav1.2 inactivation gates reset to the open position (accompanied by recovery) synchronously with channel closing under control conditions, generating a small ICa,L window current in the process. This current grows toward a depolarizing spike when the lag time between recovery and closing grows above a threshold level. C_LIO_LIAPs undergo damped oscillatory Cav1.2 recovery/re-inactivation cycles above the T3 threshold, which are refreshed by subsequent pacing signals (nodal or reentrant in origin). C_LI