Key result
The K897T polymorphism of the hERG gene significantly prolonged the simulated mean action potential duration (APD90) by 14.87 ms compared to the wild type gene.
Why the study?
Does the K897T polymorphism of the hERG gene prolong APD90 in simulated midmyocardial cells of Caucasians?
Does the K897T polymorphism of the hERG gene prolong APD90 in simulated midmyocardial cells of Caucasians?
Mean Difference: 14.87 (95% CI 4.38–25.37)
Absolute Event Rate: 363.95% vs 349.08%
p-value: p=0.006995
Computational modeling suggests the K897T polymorphism of the hERG gene significantly prolongs action potential duration, which may predispose individuals to drug-induced QT prolongation.
May predispose K897T carriers to drug-induced QT prolongation; leaves open human validation of this simulated effect.
The presented study aims to assess the possibility of simulating changes in cardiac cell electrophysiology due to K897T polymorphism in the Caucasian population. In the first part of the experiment, the parameters of the equations describing channel gating were fitted to the experimental data. Then, the action potentials of midmyocardial cells of 100 individuals were simulated in the in vitro - in vivo extrapolation system - ToxComp. Mean APD90 for the entire simulated population is 352.05 ms (SD = 21.69 ms). Mean APD90 for the 80 individuals with the WT version of the hERG gene and for the 20 K897T homo- and heterozygotes is respectively 349.08 ms (SD = 21.09 ms) and 363.95ms (SD = 20.41 ms). The ToxComp system can be useful in predicting the impact of genetic variability on drug triggered cardiac cell electrophysiology interference.
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Glinka et al. (2012) studied Healthy (n=100). K897T polymorphism of the hERG gene vs. Wild type (WT) hERG gene was evaluated on Mean Action Potential Duration at 90% repolarization (APD90) (MD 14.87, 95% CI 4.38-25.37, p=0.006995). The K897T polymorphism of the hERG gene significantly prolonged the simulated mean action potential duration (APD90) by 14.87 ms compared to the wild type gene.
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