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Mechanism‐based QT/APD‐shortening therapy for potassium‐channel‐based long‐QT syndromes?

2020; Wiley; Volume: 229; Issue: 4 Linguagem: Inglês

10.1111/apha.13481

1748-1716

Katja E. Odening,

ECG Monitoring and Analysis

This editorial relates to the manuscript "Polyunsaturated fatty acid-derived IKs 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/IKr channels or KCNQ1/KCNE1/IKs 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/IKs 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 IKs 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 IKr 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/IKs 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/IKs channels, the latter was not as effective in shortening QT interval in guinea pigs as DHA-GLY. These species differences in the susceptibility to IKs activators were further confirmed, when the authors co-expressed human KCNQ1 with guinea pig-like KCNE1, and observed a reduced IKs-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 IKs-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 The author declares no conflict of interest.