This editorial relates to the manuscript "Polyunsaturated fatty acid‐derived I_Ks channel activators shorten the QT interval ex‐vivo and in‐vivo" by Skarsfeldt, Liin, Larsson, and Bentzen.1

Despite our growing understanding of the patho‐physiological mechanisms underlying the different subtypes of long‐QT syndrome (LQTS), current treatment approaches in this disease target the pro‐arrhythmic sympathetic trigger (by beta‐blockade or left‐cardiac sympathetic denervation) or terminate ventricular arrhythmias once they occur (by implantable cardioverter defibrillators).

A mechanism‐based therapy has, thus far, only been developed in LQTS type 3—namely therapeutic sodium‐channel blockade—based on a thorough understanding of the biophysical consequences of the disease‐causing SCN5A mutations.2 Moreover, this approach has already entered the clinical guidelines as subtype‐specific add‐on therapy in LQT3. For the more frequent potassium‐channel‐based long‐QT subtypes 1 and 2, in contrast, no such subtype‐specific mechanism‐based therapy has entered clinical therapy to date—despite promising experimental work on potential drugs that may rescue trafficking‐deficient mutant channels or agents that may activate HERG/I_Kr channels or KCNQ1/KCNE1/I_Ks channels, thereby helping to restore normal cardiac repolarization.3-5

The authors of an interesting study in this issue on the potential use of polyunsaturated fatty acids to shorten/normalize cardiac repolarization in LQTS1 have a long‐standing interest in identifying and characterizing potassium channel activators that might close this gap. They have elucidated the molecular mechanisms, by which polyunsaturated fatty acids interact with alpha‐ and beta‐subunits to activate KCNQ1/KCNE1/I_Ks channels.5, 6

In their manuscript in this issue, they take these analyses a step further by investigating the effects of chemically distinct natural and modified polyunsaturated fatty acids (docosahexaenoic acid (DHA), docosahexaenoyl glycine (DHA‐GLY), linoleoyl glycine (Lin‐GLY) and N‐arachidonoyl‐taurine) on cardiac repolarization ex vivo in guinea pig hearts. Additionally, they investigated the effect of the apparently most efficient I_Ks activator among these PUFAs—DHA‐GLY—in vivo on QT interval duration in a guinea pig model of drug‐induced LQT type 2. The authors observed QT/APD‐shortening effects of all—natural and modified—polyunsaturated fatty acids (PUFAs) in guinea pig hearts treated with I_Kr blocker E4031 to induce drug‐induced LQT type 2. Interest to note, the extent of the QT/APD shortening, however, was different. Here, modified PUFAs seem to be even more efficient as natural PUFAs: DHA‐Gly tended to shorten APD more than natural DHA; and only DHA‐Gly and N‐arachidonoyl‐taurine could shorten the (E4031‐prolonged) QT interval back to baseline values and thus normalize the (drug‐induced) defective cardiac repolarization. These data add some important aspects to the ongoing discussion on potential beneficial cardiac effects of fish oil and its main components polyunsaturated fatty acids. The authors demonstrate that the modification of natural PUFAs may help to more specifically and more efficiently target the KCNQ1/KCNE1/I_Ks channels—and thus exert beneficial cardiac effects in different diseases with (genetically or remodelling‐induced) defective cardiac repolarization.

In addition, this study demonstrates very impressively species differences in cardiac ion channel biophysics and in their susceptibility to ion channel activators. Despite similar efficacy of DHA‐GLY and Lin‐GLY in activating human KCNQ1/KCNE1/I_Ks channels, the latter was not as effective in shortening QT interval in guinea pigs as DHA‐GLY. These species differences in the susceptibility to I_Ks activators were further confirmed, when the authors co‐expressed human KCNQ1 with guinea pig‐like KCNE1, and observed a reduced I_Ks‐activating effect by Lin‐GLY compared to DHA‐GLY. These findings highlight the need for a thorough assessment of potential novel drugs in different species—and also in human cells—prior to clinical translation.

In summary, this study by Skarsfeldt et al on I_Ks‐activator‐based APD/QT‐shortening effects of different PUFAs is of high clinical relevance as there is a clear need for novel, mechanism‐based QT/APD‐shortening drugs in long‐QT syndrome that restore the defective cardiac repolarization. The authors highlight that the modification of naturally occurring PUFAs might result in even more promising agents for novel treatment options in LQTS.

Prior to clinical translation of these interesting and promising findings, however, it will be mandatory to investigate at first in genetic LQTS animal models and ultimately in pilot research in human patients with LQTS, whether these PUFAs may also exert anti‐arrhythmic effects—in addition to their QT/APD‐shortening/normalizing effects. Here it will also be important to investigate potential regional heterogeneities in their APD‐shortening capacity. This is particularly important to guarantee the safety of this approach; as it has been previously shown that due to regionally heterogeneous expression of various potassium channels, the activation of one specific potassium channel may exert pro‐arrhythmic effects by increasing dispersion of repolarization or by causing excessive APD‐shortening effects.4

这篇社论与Skarsfeldt，Liin，Larsson和Bentzen撰写的手稿“多不饱和脂肪酸衍生的I _Ks通道激活剂缩短了QT间期和离体时间”。1个

尽管我们对长QT综合征（LQTS）的不同亚型的病理生理机制的理解日益加深，但该疾病的当前治疗方法还是针对心律失常性原发性触发（通过β受体阻滞或左心交感神经失神经）或终止一旦发生心律失常（通过植入式心脏复律除颤器）。

迄今为止，基于机制的疗法仅基于对引起疾病的SCN5A突变的生物物理后果的全面了解，才在LQTS 3型中得到开发，即钠通道阻断治疗。2此外，这种方法已作为LQT3中亚型特异性附加疗法进入临床指南。相比之下，对于钾通道较长的长QT亚型1和2，迄今为止，尚无此类基于亚型的机制机制疗法进入临床治疗，尽管有前途的有希望的实验研究可能挽救了贩运缺陷型突变体的潜在药物通道或可能激活HERG / I _Kr通道或KCNQ1 / KCNE1 / I _Ks通道的药物，从而有助于恢复正常的心脏复极。3-5

关于这个问题的有趣研究的作者，关于在LQTS 1中使用多不饱和脂肪酸缩短/正常化心脏复极的潜在兴趣，长期以来一直对鉴定和表征可能弥合这一差距的钾通道活化剂感兴趣。他们阐明了多不饱和脂肪酸与α和β亚基相互作用以激活KCNQ1 / KCNE1 / I _Ks通道的分子机制。5、6

在本期的手稿中，他们通过研究化学上独特的天然和改性多不饱和脂肪酸（二十二碳六烯酸（DHA），二十二碳六烯酰基甘氨酸（DHA-GLY），亚油酰甘氨酸（Lin-GLY）和N-花生四烯酸-牛磺酸对豚鼠心脏离体心脏复极化的影响。此外，他们在药物诱导的2型LQT豚鼠模型中研究了这些PUFA中最有效的I _Ks活化剂（DHA-GLY）在体内对QT间隔持续时间的影响。作者观察到QT / APD缩短的作用I _Kr治疗的豚鼠心脏中的所有天然和改性多不饱和脂肪酸（PUFA）阻断剂E4031诱导2型药物诱导的LQT。值得注意的是，QT / APD缩短的程度不同。在这里，改性的PUFA似乎比天然的PUFA更有效：DHA-Gly的APD比天然DHA缩短的更多；只有DHA-Gly和N-花生四烯酰基-牛磺酸可以将（延长的E4031）QT间隔恢复到基线值，从而使（药物诱发的）心脏复极功能失常。这些数据为有关鱼油及其主要成分多不饱和脂肪酸的潜在有益心脏作用的持续讨论增加了一些重要方面。作者证明，天然PUFA的修饰可能有助于更具体，更有效地靶向KCNQ1 / KCNE1 / I _Ks通道-从而在具有（遗传性或重塑性）缺陷的心脏复极化的不同疾病中发挥有益的心脏作用。

此外，这项研究表明，在心脏离子通道生物物理学及其对离子通道激活剂的敏感性方面，物种差异非常显着。尽管DHA-GLY和Lin-GLY在激活人KCNQ1 / KCNE1 / I _Ks通道方面具有相似的功效，但后者在缩短豚鼠QT间隔方面不如DHA-GLY有效。当作者将人类KCNQ1与豚鼠样KCNE1共表达，并观察到与DHA-GLY相比，Lin-GLY降低了I _Ks激活作用，这进一步证实了这些对I _Ks激活剂敏感性的差异。这些发现强调了在临床翻译之前，需要对不同物种以及人类细胞中潜在的新药进行全面评估。

总之，Skarsfeldt等人针对不同PUFA的基于I _Ks激活剂的APD / QT缩短作用的研究具有高度的临床意义，因为长期以来显然需要新型的基于机制的QT / APD缩短药物-QT综合征，可恢复有缺陷的心脏复极。作者强调，天然存在的PUFA的修饰可能会为LQTS中的新治疗方法带来更有希望的药物。

然而，在对这些有趣且有希望的发现进行临床翻译之前，必须首先在遗传LQTS动物模型中进行研究，并最终在对LQTS的人类患者进行先导研究中进行研究，以确定这些PUFA是否还会发挥抗心律失常作用-此外其QT / APD缩短/标准化效果。在这里，研究潜在的区域异质性及其APD缩短能力也很重要。这对于保证这种方法的安全性尤其重要。如先前所示，由于各种钾离子通道的区域异质表达，一个特定钾离子通道的激活可能通过增加复极化的分散或引起过度的APD缩短效应而发挥心律失常作用。4