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- W3089240669 abstract "Certain individuals have increased propensity to develop prolonged QT interval and consequent life-threatening ventricular arrhythmias in response to drugs that alter cardiac ion currents, notably IKr. We recently performed a transcriptomic profiling of induced pluripotent stem cells-derived cardiomyocytes (iPSC-CM) in patients with high risk to develop diLQTS and identified 5 molecules mechanistically connected to QT prolongation including 4 up-regulated (DLG2, KCNE4, PTRF, and HTR2 C) and 1 down-regulated (CAMKV) genes. To confirm the role the 5 identified candidates in modulating cardiac repolarization in response to drugs. We used iPSC-CM from 10 subjects with the highest sensitivity (S + ) to sotalol (ie, those with the highest increase in QT interval) and from 8 individuals with the lowest sensitivity to sotalol (S-) to perform molecular and electrophysiological investigations. In line with the recorded QT prolongation after Sotalol administration in patients, S+ iPSC-CM displayed 2 and 3 Fold increase of field potential duration after adding 30 and 100 μM of Sotalol respectively. Among the 5 candidate genes, we found that PTRF presented the highest transcriptomic level in human ventricular tissue in GTEx publicly available bank. PTRF mRNA and protein expression levels were increased by 40% in the S+ iPSC-CM as compared to the S- iPSC-CM. PTRF has been reported as a key regulator of calveolae. To assess the implication of PTRF in the exaggerated reaction to Sotalol, we aimed to induce PTRF overexpression in the S- iPSC-CM and to repress its translation in the S+ iPSC-CMs using shRNA. Electrophysiological tests will be then used to assess the changes in response to Sotalol after manipulation of PTRF expression. Altogether, this work identified PTRF as a candidate for diLQTS. Further understanding of its contribution may pave the way for personalized drug prescription to avoid undesirable cardiotoxicity." @default.
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- W3089240669 date "2020-10-01" @default.
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- W3089240669 title "Elucidating molecular regulators of drug-induced long QT syndrome (diLQTS)" @default.
- W3089240669 doi "https://doi.org/10.1016/j.acvdsp.2020.03.141" @default.
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