A new hERG allosteric modulator rescues genetic and drug-induced Long-QT Syndrome phenotypes in cardiomyocytes from isogenic pairs of patient induced pluripotent stem cells (2016)
Figure 4

Figure 4. LUF7346 rescues drug-induced LQTS in both wild type and LQTS genetic backgrounds.

A) Representative MEA trace (left) showing the effect of 100 nM AST and increasing concentrations of LUF7346 in the presence of AST on FP contour, measured in LQT1R594Q-CMs. Average data (right) of the effect of AST and LUF7346 in the presence of AST on QT interval duration compared to baseline in CMs derived from all the hiPSC lines used in this study. * = p<0.05 vs respective baseline. ° = p<0.05 vs AST. Colour in the heatmap defines the magnitude of QT prolongation (red) and QT shortening (blue), respectively, after treatment with AST and with increasing concentrations of LUF7346 in the presence of AST. N: 5-10.

B) Representative AP from WT-, LQT1R594Q- and JLNSR594Q-CMs, paced at 1 Hz, under baseline conditions (black), after application of 100 nM AST (red), and after addition of increasing concentrations of LUF7346 in the presence of AST (colour-code is shown).

C) Effect of AST and LUF7346 in the presence of AST on APD90, APD70, and APD50 in WT- (grey), LQT1R594Q- (red) and JLNSR594Q-CMs (black) paced at 1 Hz. * = p<0.05 vs respective baseline; ° = p<0.05 vs AST. N: 11-16.

D) Effect of AST and LUF7346 in the presence of AST on APA and Ediast in WT- (grey), LQT1R594Q- (red) and JLNSR594Q-CMs (black) paced at 1 Hz. N: 11-16.

Data information: A: Repeated measures One-way ANOVA with Holm-Sidak’s multiple testing correction: LQT1R594Q: Baseline vs AST: 0.0038, Baseline vs AST+LUF7346 20µM: 0.0007. Baseline vs AST+LUF7346 30µM: 0.0022. AST vs AST+LUF7346 20µM: <0.0001; AST vs AST+LUF7346 30µM: < 0.0001. JLNSR594Q: Baseline vs AST: 0.0020; Baseline vs AST+LUF7346 20µM: 0.0195; Baseline vs AST+LUF7346 30µM: 0.0009; AST vs AST+LUF7346 20µM: 0.0002; AST vs AST+LUF7346 30µM: <0.0001. WT: Baseline vs AST: 0.0388; Baseline vs AST+LUF7346 20µM: 0.0430; Baseline vs AST+LUF7346 30µM: 0.0021; AST vs AST+LUF7346 20µM: 0.0282; AST vs AST+LUF7346 30µM: 0.0015. LQT2corr: Baseline vs AST: 0.0202; Baseline vs AST+LUF7346 30µM: <0.0001; AST vs AST+LUF7346 20µM: 0.0203; AST vs AST+LUF7346 30µM: 0.0013. LQT2N996I: Baseline vs AST: 0.0178; Baseline vs AST+LUF7346 20µM: 0.0058; Baseline vs AST+LUF7346 30µM: <0.0001; AST vs AST+LUF7346 20µM: 0.0001; AST vs AST+LUF7346 30µM: <0.0001. LQT1R190Q: Baseline vs AST: 0.0466; Baseline vs AST+LUF7346 20µM: 0.0268; Baseline vs AST+LUF7346 30µM: 0.0001; AST vs AST+LUF7346 20µM: 0.0160; AST vs AST+LUF7346 30µM: 0.0138. LQT1corr: Baseline vs AST: 0.0374; Baseline vs AST+LUF7346 20µM: 0.0493; Baseline vs AST+LUF7346 30µM: <0.0001; AST vs AST+LUF7346 20µM: 0.0012; AST vs AST+LUF7346 30µM: <0.0001.

B: Adjusted p-values respectively for JLNSR594Q; LQT1R594Q ; WT: APD90: Tyr vs AST: 0.0017; 0.0026; 0.0012. Tyr vs AST+LUF1µM: 0.0448; 0.0027; 0.0002. Tyr vs AST+LUF3µM: 0.0017; 0.3097; 0.1147. Tyr vs AST+LUF5µM: 0.9974; 0.2752; 0.0404. Tyr vs AST+LUF10µM: 0.0145; 0.0003 ; n/a. AST vs AST+LUF3µM: 0.0215; <0.0001; 0.0289. AST vs AST+LUF5µM: 0.0144; 0.0007; 0.0029. AST vs AST+LUF10µM: 0.0045; <0.0001 ; n/a. APD70: Tyr vs AST: 0.0078; 0.0041; 0.0294. Tyr vs AST+LUF1µM: 0.0488; 0.0266; 0.0452. Tyr vs AST+LUF3µM: 0.9527; 0.2919 ;0.4299. Tyr vs AST+LUF5µM: 0.3003; 0.0039; <0.0001. Tyr vs AST+LUF10µM: <0.0001; 0.0009; n/a. AST vs AST+LUF3µM: 0.0267; <0.0001 ; 0.0238. AST vs AST+LUF5µM: 0.0032; 0.0022; 0.0048. AST vs AST+LUF10µM: 0.0002; 0.0008; n/a. APD50: Tyr vs AST: 0.0385; 0.0472; 0.0055. Tyr vs AST+LUF1µM: 0.0429; 0.2383; 0.0210. Tyr vs AST+LUF3µM: 0.8840; 0.0650; 0.2113. Tyr vs AST+LUF5µM: 0.0470; 0.0023; 0.0020. Tyr vs AST+LUF10µM: 0.0012; 0.0002; n/a. AST vs AST+LUF3µM: 0.0191; <0.0001; 0.0027. AST vs AST+LUF5µM: 0.0241; 0.0014; 0.0006. AST vs AST+LUF10µM: 0.0028; 0.0002; n/a. Comparisons not indicated were not statistically significant.

D: One-way ANOVA with Holm-Sidak’s multiple testing correction. All comparisons were not significant.