Previously published work established the correlation between hiPSC-CM APD90 to clinical concentrations of drugs associated with a + 10 ms change in QTc (Kilfoil et al., PMID 34678241). In this prior work, completed at 28 °C, the relationship (expressed in -Log [M] units) between free plasma exposure causing +10 ms QTc (X) and drug concentration causing threshold rate-corrected cAPD90 increase (Y) was described by the linear equation Y = 0.86× - 0.64 (Pearson r2 = 0.762). Here, we investigated the effect of temperature on hiPSC-CM action potential parameters and impact on in vitro to clinical translation. 14 compounds were retested at 37 °C to investigate the impact of physiological temperature on this relationship.1) Repolarization time (APD90 = 408 ± 20 vs 773 ± 69 ms, p < 0.0001) and spontaneous beat rate (61 ± 5 vs 25 ± 3 beats per min, p < 0.0001) were accelerated at 37 °C compared to 28 °C. When recorded at physiological temperature, these parameters are more physiologically relevant (APD90 200–400 ms, beat rate 50–70 per min). 2) Rate-corrected repolarization was also faster at 37 °C than at 28 °C (cAPD90 = 410 ± 21 vs. 512 ± 25 ms, p < 0.001), reflecting the inability to correct for different heart rates and temperature conditions with one eq. 3) Finally, the cAPD90-QTc relationship at 37 °C is described by the equation Y = 0.98× −0.37 (Pearson r2 = 0.8) which is greater than the relationship described by this same subset of compounds at 28 °C (Pearson r2 = 0.74).These results demonstrate that recording temperature has profound effects on the basal electrophysiological function of these cells, and that the correlation between drug effect on hiPSC-CM repolarization and clinical QTc outcome is enhanced at physiological temperature.
原文链接
分享
引用
