The Electrogenic Na+/K+ Pump Is a Key Determinant of Repolarization Abnormality Susceptibility in Human Ventricular Cardiomyocytes: A Population-Based Simulation Study

Figure 1. Action potential biomarkers. Peak membrane potential (Vm Peak); time of peak membrane potential (Vm Time); AP duration (APD) at 40/50/90% repolarization; triangulation and resting membrane potential (RMP). Each biomarker was calculated as defined in the Supplementary Material.

Figure 2. Examples of action potential traces. (A) Normal repolarization. (B) An early afterdepolarization. (C) Repolarization failure.

Figure 3. Population of human ventricular cell models. (A) APs obtained from control experimental recordings (red; n = 62 including three excluded outliers, two with long time to peak and one with long APD90); simulations using the models found to be within the experimental range (blue; n = 568); and the baseline ORd model (black), at 1 Hz pacing. (B) Distributions of each biomarker across the population of models. Dashed lines indicate the experimental range used to determine whether each model is accepted into the population. (C–J) Selected pairs of conductances across the population of models. Plots show scaling values relative to the value of each conductance in the baseline ORd model. Partial correlation coefficients (PCC) are shown for the six pairs of parameters with significant correlations (p < 0.05/36).

Figure 4. APD prolongation of ventricular preparations under 0.05 μM dofetilide (n = 16) compared to population of models under 65% IKr block, corresponding to the effects of 0.5 μM dofetilide using IC50 and Hill coefficient determined by Kramer et al. (2013). Models displaying repolarization abnormalities (7/568 models) were excluded from the figure. Black dots are experimental data points, gray dots are outliers (>1.5 times interquartile range from the nearest inner quartile).

Figure 5. Repolarization abnormality susceptibility across the population of models, in response to simulated drug block. (A–C) Percentage of models in the population that displayed repolarization abnormalities in response to combinations of different strength blocks of IKr, IKs, IK1, and ICaL. No model developed repolarization abnormalities in any of the simulations in which IKr was not blocked, therefore these simulations are not included in the plots. (D) Biomarker distributions for NS (black), MS (red), and HS (blue) models in the population. (E) Conductance distributions for NS (black), MS (red), and HS (blue) models in the population.

Figure 6. Magnitude of INa, ICaL, INaK, IKr, IKs, and IK1 during repolarization for HS models in control conditions and under 75% IKr block. Each current was averaged from the peak of the upstroke to APD40 (early) and from APD40 to APD90 (late), for each model.

Figure 7. Mechanisms of repolarization abnormality formation. (A): GCaL and GNaK values of models in the population classified by susceptibility to repolarization abnormalities. Black: NS. Red: MS. Blue crosses: HS. (B) Incidence of repolarization abnormalities in the HS sub-population (n = 41) at 75 and 90% IKr block compared to the same sub-population with GNaK = 1.0, and to the rest of the population of models. (C) Incidence of repolarization abnormalities in the HS sub-population under different conditions. Left to right: baseline IKr block; with intracellular Na+ fixed to 7 mM; with intracellular Na+ fixed to 20 mM and intracellular K+ fixed to 145 mM; and with the electrogenic effect of INaK on Vm removed. (D–G) Voltage and selected ionic current traces showing abnormality occurrence in a representative model with original value of GNaK scaling factor = 0.1675 (solid black) and with GNaK increased to a scaling factor of 1.0 (red dashes).

Figure 8. Incidence of repolarization abnormalities in the population of models under different levels of IKr block, following changes to extracellular potassium and intracellular calcium concentrations. (A) Control conditions ([K+]o = 5.4 mM, 1 Hz pacing). (B) Reduced extracellular potassium concentration ([K+]o = 4.0 mM). (C) Rapid pacing (2.5 Hz) to increase Ca2+ loading, followed by sudden decrease to 1 Hz.