Genotype-specific beneficial QT-shortening effects of docosahexaenoic acid in transgenic LQT1, LQT2, LQT5 and LQT2-5 rabbit models

Abstract: Introduction:
Congenital long QT syndrome is a rare, but potentially lethal disease, which predisposes to ventricular arrhythmias and sudden cardiac death. Current standard therapies in LQTS may fail in up to 32% to prevent arrhythmic events. New efficient therapeutic strategies are therefore needed.
Docosahexaenoic acid (DHA) is a polyunsaturated fatty acid, which enhances the repolarizing IKs current. Such effects on IKs seem to depend on the functionality of both α-subunit KvLQT1 and β-subunit KCNE1.
Purpose: We aimed at investigating genotype-specific beneficial effects of DHA in transgenic LQT1, LQT2, LQT5, and LQT2-5 rabbit models.

Methods:
In wild type (WT), transgenic LQT1 (loss of IKs), LQT2 (loss of IKr), LQT5 (reduction of IKs), and LQT2-5 (loss of IKr and reduction of IKs) rabbits, telemetric ECG analyses were performed in vivo at baseline and after 10µM/kg DHA i.m. to assess changes in heart rate corrected QT (QTc). In Langendorff-perfused hearts of the same WT, LQT1, LQT2, LQT5 and LQT2-5 rabbits, ex vivo monophasic action potentials were recorded. DHA-induced changes in action potential duration (APD75) and in action potential triangulation (APD90 - APD30) were measured.

Results:
The IKs-activator DHA significantly shortened QTc in vivo only in rabbits with functional α- and β-subunits of IKs channels, i.e., in WT and in LQT2 rabbits. In contrast, DHA had no effect on QTc in LQT1, in LQT5 and LQT2-5 rabbits. Similarly, ex vivo, DHA significantly shortened APD75 in WT and in LQT2 rabbits, but had no effect on APD75 in LQT1, LQT5, and LQT2-5 rabbits. Moreover, DHA significantly decreased APD triangulation in LQT2 and in WT rabbit hearts.
Conclusion: Docosahexaenoic acid exerts a genotype-specific beneficial shortening effect of QTc, APD and AP triangulation through activation of IKs in LQT2 rabbits but has no effects if either α- or β-subunits to IKs are functionally impaired. DHA could thus represent a new therapeutic tool in LQT2 syndrome

Object Details

• Location: Deutsche Nationalbibliothek Frankfurt am Main
• Extent: Online-Ressource
• Language: Englisch
• Notes: Universität Freiburg, Dissertation, 2018

Classification and Topics

• Keyword: Docosahexaenoic acid ; Q-T-Verlängerung ; Kaninchen ; Ionenkanal ; Docosahexaensäure

Contributors, Places and Time

• Event: Veröffentlichung
• (where): Freiburg
• (who): Universität
• (when): 2020
• Creator: Castiglione, Alessandro
• Contributor: Odening, Katja Elisabeth ; Albert-Ludwigs-Universität Freiburg. Medizinische Fakultät

Further information

• DOI: 10.6094/UNIFR/166906
• URN: urn:nbn:de:bsz:25-freidok-1669064
• Rights: Der Zugriff auf das Objekt ist unbeschränkt möglich.
• Last update: 25.03.2025, 1:56 PM CET