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- Castiglione, Alessandro, et al.
(författare)
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Docosahexaenoic acid normalizes QT interval in long QT type 2 transgenic rabbit models in a genotype-specific fashion
- 2022
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Ingår i: Europace. - : OXFORD UNIV PRESS. - 1099-5129 .- 1532-2092. ; 24:3, s. 511-522
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Tidskriftsartikel (refereegranskat)abstract
- Aim Long QT syndrome (LQTS) is a cardiac channelopathy predisposing to ventricular arrhythmias and sudden cardiac death. Since current therapies often fail to prevent arrhythmic events in certain LQTS subtypes, new therapeutic strategies are needed. Docosahexaenoic acid (DHA) is a polyunsaturated fatty acid, which enhances the repolarizing I-Ks current. Methods and results We investigated the effects of DHA in wild type (WT) and transgenic long QT Type 1 (LQT1; loss of I-Ks), LQT2 (loss of I-Kr), LQT5 (reduction of I-Ks), and LQT2-5 (loss of I-Kr and reduction of I-Ks) rabbits. In vivo ECGs were recorded at baseline and after 10 mu M/kg DHA to assess changes in heart-rate corrected QT (QTc) and short-term variability of QT (STVQT). Ex vivo monophasic action potentials were recorded in Langendorff-perfused rabbit hearts, and action potential duration (APD(75)) and triangulation were assessed. Docosahexaenoic acid significantly shortened QTc in vivo only in WT and LQT2 rabbits, in which both alpha- and beta-subunits of I-K(s)-conducting channels are functionally intact. In LQT2, this led to a normalization of QTc and of its short-term variability. Docosahexaenoic acid had no effect on QTc in LQT1, LQT5, and LQT2-5. Similarly, ex vivo, DHA shortened APD(75) in WT and normalized it in LQT2, and additionally decreased AP triangulation in LQT2. Conclusions Docosahexaenoic acid exerts a genotype-specific beneficial shortening/normalizing effect on QTc and APD(75) and reduces pro-arrhythmia markers STVQT and AP triangulation through activation of I-Ks in LQT2 rabbits but has no effects if either alpha- or beta-subunits to I-Ks are functionally impaired. Docosahexaenoic acid could represent a new genotype-specific therapy in LQT2.
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| 2. |
- De la Cruz, Alicia, et al.
(författare)
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Pharmacological Screening of Kv7.1 and Kv7.1/KCNE1 Activators as Potential Antiarrhythmic Drugs in the Zebrafish Heart
- 2023
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Ingår i: International Journal of Molecular Sciences. - : MDPI. - 1661-6596 .- 1422-0067. ; 24:15
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Tidskriftsartikel (refereegranskat)abstract
- Long QT syndrome (LQTS) can lead to ventricular arrhythmia and sudden cardiac death. The most common congenital cause of LQTS is mutations in the channel subunits generating the cardiac potassium current I-Ks. Zebrafish (Danio rerio) have been proposed as a powerful system to model human cardiac diseases due to the similar electrical properties of the zebrafish heart and the human heart. We used high-resolution all-optical electrophysiology on ex vivo zebrafish hearts to assess the effects of I-Ks analogues on the cardiac action potential. We found that chromanol 293B (an I-Ks inhibitor) prolonged the action potential duration (APD) in the presence of E4031 (an I-Kr inhibitor applied to drug-induced LQT2), and to a lesser extent, in the absence of E4031. Moreover, we showed that PUFA analogues slightly shortened the APD of the zebrafish heart. However, PUFA analogues failed to reverse the APD prolongation in drug-induced LQT2. However, a more potent I-Ks activator, ML-277, partially reversed the APD prolongation in drug-induced LQT2 zebrafish hearts. Our results suggest that I-Ks plays a limited role in ventricular repolarizations in the zebrafish heart under resting conditions, although it plays a more important role when the I-Kr is compromised, as if the I-Ks in zebrafish serves as a repolarization reserve as in human hearts. This study shows that potent I-Ks activators can restore the action potential duration in drug-induced LQT2 in the zebrafish heart.
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