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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 IKs 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 IKs channel activating effect to better restore QT interval suggests that modifying PUFAs to target the IKs channel is a means to improve the QT‐shortening effect. [ABSTRACT FROM AUTHOR]