Inter-individual variability and modeling of electrical activity: a possible new approach to explore cardiac safety?

Figure 1. Effects of molecules from subgroup A1 (dofetilide and sotalol), subgroup A2 (terfenadine, thioridazine and quinidine), group B (moxifloxacin, verapamil, risperidone), and group C (Phenytoin, propranolol, nicardipine) on IKR, IKS, IK1, INa and ICaL currents (taken from ref. 14). The inhibition of IK1 is expressed in % on the right scale while for the other currents, the IC50 (as given by pD2 = (−Log(IC50)) is represented on the left scale.

Figure 2. Decision tree proposed to classify molecules using TdPScreen ranking26.

Figure 3. Typical effects of drugs on the AP recorded from isolated dog Purkinje fibers. APs were triggered by field stimulation at 0.33 Hz in Tyrode (red line) and during drug application at the concentration indicated (black line). Drugs of subgroup A1 cause an exacerbated (>40%) increase in AP duration. Molecules of subgroup A2 cause a triangulation of the delayed phase of repolarization without shortening AP. Compounds of group B either induce (moxifloxacin) or don’t induce AP prolongation (verapamil) and are associated with arrhythmias at a very low frequency (≤2 cases). Group C molecules do not trigger AP prolongation.

Figure 4. Simulations of human ventricular action potentials under control conditions (red line) and in the presence of the drugs indicated above (black line). To calculate the conductances of ICaL, INa, IK1, IKS and IKR, the conductance block equation (1) given in the Methods section was applied, using the concentrations and IC50 (or % of IK1 blockade) given in Fig. 1.

Figure 5. Simulations of ventricular action potentials in the presence of intracellular spermine (SPM) as shown above the graphs and using the GCaL given at left. Simulations were performed under control conditions (red line) and after 90% blockade of GKR.

Figure 6. Simulations of human Purkinje cell action potentials in control (red line) and in the putative presence of the drugs indicated above (black line). To calculate the conductances of ICaL, INa, IK1, IKS and IKR, the conductance block equation described in the Methods section was applied, using the concentrations and IC50 (or % of IK1 blockade) given in Fig. 1.

Figure 7. Simulations of the effects of drugs from different TdPScreen® groups (as indicated on the left) after increasing the intracellular concentration of SPM from 3 to 5 μM. Cells were stimulated at 0.5 Hz for 3 min at each SPM concentration. For sotalol, moxifloxacine, phenytoin and propranolol, no arrhythmia occurred during the 6 min-simulation, whatever the [SPM]. For quinidine, an arrhythmia occurred during the transition from 3 μM to 5 μM [SPM]. For thioridazine and verapamil, the transition to 3 μM to 5 μM [SPM] took place 80 s and 20 s respectively before the model triggered arrhythmia. AP was not shown under 3 μM [SPM].

Figure 8. The distribution of circulating spermine concentrations in different people before and after a two-month polyamine-rich soybean diet (taken from ref. 11) are plotted on the same graph to assess the variability of this parameter. Stars in white are in the mean ± SD range (as shown on the right), stars in grey are in the mean ± SEM range (as shown on the left), stars in black are outside the previous ranges. The upper limit of mean + 3SD is indicated, and corresponds to a probability of measuring a similar or lower SPM concentration in 99.8% of the general population.

Figure 9. Putative Gaussian distribution of electrophysiological and metabolic parameters. (A) idealized distribution of a parameter influencing AP parameters and the position of the three values to be used in simulations. (B) proposed simulations using the three values from n parameters.