Beneficial APD-shortening effects, but deleterious negative inotropism of IKs-activator Docosahexaenoyl glycine (DHA-gly) in long QT syndrome type 2

Loss-of-function mutations in KCNQ1 and KCNH2 (α-subunits of the slow delayed IKs and rapid delayed IKr-conducting repolarising K+ channels) lead to long QT syndrome type 1 (LQT1) and 2 (LQT2), respectively. These channelopathies present with longer action potential duration (APD) and prolonged QT interval on ECG, which can ultimately lead to deadly arrhythmias. Here we investigated the therapeutic potential of the polyunsaturated fatty acid docosahexaenoyl glycine (DHA-gly) in normalizing APD and QT interval in LQT2 by increasing IKs. The effects of DHA-gly on electrical and mechanical parameters were assessed in Xenopus laevis oocytes, wild-type (WT), LQT1 (KCNQ1-Y315S) and LQT2 (KCNH2-G628S) transgenic rabbit models, and human induced pluripotent stem cells-derived cardiomyocytes (hiPSC-CMs). DHA-gly increased IKs in oocytes and WT ventricular cardiomyocytes (VCMs) in a dose-dependent manner. Consequently, DHA-gly shortened APD in vitro and QT interval ex vivo in WT and LQT2 rabbits, but not in LQT1. However, DHA-gly was unable to reduce arrhythmia formation in LQT2. Beneficial APD/QT shortening effects were accompanied by a detrimental decrease in both cellular and ventricular contraction across all genotypes, including LQT1, which could be due to a shortening in Ca2+ transient duration observed in VCMs and hiPSC-CMs. DHA-gly-induced IKs enhancement shows promising results in shortening APD/QT in LQT2 rabbits, while having no effect on LQT1 (impaired IKs). However, its adverse effect on cardiac contractility, even in LQT1, makes it unsuitable to treat LQTS patients. Our study highlights the importance of considering both electrical and mechanical effects of potential therapeutic compounds prior to clinical translation.