Key result
Modified polyunsaturated fatty acids like DHA-GLY shorten guinea pig QT intervals via IKs channel activation.
Why the study?
The study aimed to assess the ability of natural and modified polyunsaturated fatty acids to shorten the QT interval in ex-vivo and in-vivo guinea pig hearts.
Do natural and modified PUFAs shorten the QT interval in guinea pig models of long QT?
Do natural and modified PUFAs shorten the QT interval in guinea pig models of long QT?
Modified PUFAs that target and activate the IKs channel, such as DHA-GLY, effectively shorten the QT interval in preclinical models, highlighting a potential therapeutic strategy for long QT syndrome.
May support IKs activation as a QT-shortening strategy in long QT models; leaves open translation to human therapy.
Aim We aimed to assess the ability of natural and modified polyunsaturated fatty acids (PUFAs) to shorten QT interval in ex‐vivo and in‐vivo guinea pig hearts. Methods The effect of one natural (docosahexaenoic acid [DHA]) and three modified (linoleoyl glycine [Lin‐GLY], docosahexaenoyl glycine [DHA‐GLY], N‐arachidonoyl taurine [N‐AT]) PUFAs on ventricular action potential duration (APD) and QT interval was studied in a E4031 drug‐induced long QT2 model of ex‐vivo guinea pig hearts. The effect of DHA‐GLY on QT interval was also studied in in‐vivo guinea pig hearts upon intravenous administration. The effect of modified PUFAs on I Ks was studied using Xenopus laevis oocytes expressing human KCNQ1 and KCNE1. Results All tested PUFAs shortened ADP and QT interval in ex‐vivo guinea pig hearts, however, with different ability in restoring baseline APD/QT interval with specific modified PUFAs being most efficacious. Despite comparable ability in activating the human KCNQ1/KCNE1 channel, Lin‐GLY was not as effective in shortening APD/QT interval as DHA‐GLY in ex‐vivo hearts. By constructing a guinea pig‐like KCNE1, we found Lin‐GLY to induce less activating effect compared with DHA‐GLY on human KCNQ1 co‐expressed with guinea pig‐like KCNE1. Docosahexaenoyl glycine was studied in more detail and was found to shorten QT interval in in‐vivo guinea pig hearts. Conclusion Our results show that specific PUFAs shorten QT interval in guinea pig hearts. The tendency of modified PUFAs with pronounced I Ks channel activating effect to better restore QT interval suggests that modifying PUFAs to target the I Ks channel is a means to improve the QT‐shortening effect.
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Skarsfeldt et al. (2020) studied Drug-induced long QT2 model. Natural and modified polyunsaturated fatty acids (DHA, Lin-GLY, DHA-GLY, N-AT) vs. Baseline (E4031 drug-induced long QT2 model) was evaluated on Ventricular action potential duration (APD) and QT interval. Specific polyunsaturated fatty acids, particularly modified ones like DHA-GLY, shortened the QT interval in ex-vivo and in-vivo guinea pig hearts by activating the IKs channel.
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