Louradour Julien, Hornyik Tibor, De la Cruz Alicia, Hiniesto-Iñigo Irene, Alerni Nicolò, Barbieri Miriam, Lopez Ruben, Perez-Feliz Stefanie, Matas Lluís, Nimani Saranda, Giammarino Lucilla, Koren Gideon, Zehender Manfred, Brunner Michael, Liin Sara I, Larsson H Peter, Odening Katja E
Translational Cardiology, Institute of Physiology and Department of Cardiology, University of Bern, Switzerland.
Department of Cardiology and Angiology I, University Heart Center Freiburg, Medical Faculty, Freiburg, Germany.
Europace. 2025 Aug 5. doi: 10.1093/europace/euaf168.
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.
KCNQ1和KCNH2（分别为缓慢延迟整流钾通道IKs和快速延迟整流钾通道IKr的α亚基）功能缺失突变分别导致1型长QT综合征（LQT1）和2型长QT综合征（LQT2）。这些通道病表现为动作电位时程（APD）延长以及心电图上QT间期延长，最终可导致致命性心律失常。在此，我们研究了多不饱和脂肪酸二十二碳六烯酰甘氨酸（DHA - gly）通过增加IKs来使LQT2的APD和QT间期恢复正常的治疗潜力。
在非洲爪蟾卵母细胞、野生型（WT）、LQT1（KCNQ1 - Y315S）和LQT2（KCNH2 - G628S）转基因兔模型以及人诱导多能干细胞衍生的心肌细胞（hiPSC - CMs）中评估DHA - gly对电和机械参数的影响。
DHA - gly以剂量依赖方式增加卵母细胞和WT心室心肌细胞（VCMs）中的IKs。因此，DHA - gly在体外缩短WT和LQT2兔的APD，在体内缩短其QT间期，但对LQT1无效。然而，DHA - gly无法减少LQT2中的心律失常形成。有益的APD/QT缩短效应伴随着所有基因型（包括LQT1）的细胞和心室收缩的有害减少，这可能是由于在VCMs和hiPSC - CMs中观察到的Ca2+瞬变持续时间缩短所致。
DHA - gly诱导的IKs增强在缩短LQT2兔的APD/QT方面显示出有前景的结果，而对LQT1（IKs受损）无效。然而，即使对LQT1，其对心脏收缩性的不良影响使其不适合用于治疗LQTS患者。我们的研究强调了在临床转化之前考虑潜在治疗化合物的电和机械效应的重要性。
