Fig 1.
Illustration of the AP and Ca2+ transient biomarkers utilized in the cost function employed to identify optimal drug concentrations.
From the AP, we consider the resting membrane potential (RMP), the AP amplitude (APA), the maximal upstroke velocity (dvdt) and the AP duration at different percentages of repolarization (APD10, APD50, …, APD90). From the cytosolic Ca2+ transient, we consider the resting Ca2+ concentration (CaR), the Ca2+ transient amplitude (CaA), the maximal upstroke velocity (dcdt) and the calcium transient durations CaD30, CaD50, and CaD80.
Table 1.
Drug characteristics.
Fig 2.
Action potentials, Ca2+ transients and IKr currents generated using our models for wild type and SQT1 hiPSC-CMs, rabbit ventricular CMs and adult human ventricular CMs.
Each panel in the upper row shows the action potentials in the wild type and SQT1 cases, and the middle row shows the Ca2+ transients. In the lower row, the IKr current from each action potential simulation is plotted as a function of the membrane potential during the entire AP waveform. Here, the filled circles mark the solution at t = 0 and the arrows indicate the direction with time. Data used in this figure can be found in S1 Data.
Fig 3.
Optimal cost function values obtained by applying our computational procedure to combinations of two drugs, selected for their potential to repair the SQT1 mutation in hiPSC-CMs, rabbit ventricular CMs and adult human ventricular CMs.
The numbers in the upper left to lower right diagonal report the cost function values found in searches for the optimal dose of a single drug. In addition, the pink circles indicate the lowest cost function value obtained in each case.
Fig 4.
AP and Ca2+ transient for hiPSC-CMs, rabbit ventricular CMs and adult human ventricular CMs in the wild type case (solid green), in the SQT1 case (solid red), and in the SQT1 case with the optimal combination of two drugs from Fig 3 applied (dotted yellow).
Data used in this figure can be found in S1 Data.
Fig 5.
AP and Ca2+ transient for adult human ventricular myocytes in the wild type case, in the SQT1 case, and in the SQT1 case with the optimal dose of each of the drugs of Table 1 applied.
The selected drugs are ordered from the smallest to the highest obtained cost function values. The applied doses are specified in Table 3. Data used in this figure can be found in S1 Data.
Table 2.
Biomarkers and cost function values.
Table 3.
Optimal doses and effect on the ion currents.
Fig 6.
Optimal cost function values obtained when our computational procedure is applied to combinations of an increasing number of drugs applied simultaneously with the goal of repairing the SQT1 mutation in hiPSC-CMs, rabbit ventricular CMs and adult human ventricular CMs.
These computations were done applying the restrictions D ≤ min(EC50)/2 (pink) and D ≤ min(EC50) (red) for the drug doses. Data used in this figure can be found in S1 Data.
Fig 7.
AP and Ca2+ transient waveforms for hiPSC-CMs, rabbit ventricular CMs and adult human ventricular CMs in the wild type case (solid green), in the SQT1 case (solid red), and in the SQT1 case with the optimal combination of five drugs with the restriction D ≤ min(EC50)/2 from Fig 6 applied (dotted yellow).
Data used in this figure can be found in S1 Data.
Table 4.
Biomarkers for WT, SQT1 and SQT1 with drug.
Table 5.
Optimal doses of five drug combinations.