Baczkó István

Brunner Michael

Bősze Zsuzsanna

Castiglione Alessandro

Edler Iask

Giammarino Lucilla

Hornyik Tibor

Jowais Jessica J.

Larsson Hans Peter

Liin Sara

Odening Katja E.

Perez-Feliz Stefanie

Rieder Marina

Varró András

Wülfers Eike M.

English

University of Szeged

84 8th European Section Meeting of the International Academy of Cardiovascular Sciences (IACS); September 28 – October 1, 2022; Szeged, Hungary BENEFICIAL REPOLARISATION-NORMALIZING EFFECT OF A POLYUNSATURATED FATTY ACID, DHA IN TRANSGENIC LONG QT TYPE 2 RABBIT MODEL Tibor Hornyik1,3,4, Alessandro Castiglione3,4,5, Eike M. Wülfers6, Lucilla Giammarino4,5, Iask Edler7, Jessica J. Jowais8, Marina Rieder3,4,5, Stefanie Perez-Feliz3,6, Zsuzsanna Bősze9, András Varró1,2, Michael Brunner3,10, Sara I. Liin7, Hans Peter Larsson8, Katja E. Odening3,4,5 and István Baczkó11Department of Pharmacology and Pharmacotherapy, University of Szeged, Szeged, Hungary; 2ELKH-SZTE Research Group for Cardiovascular Pharmacology, Eötvös Loránd Research Network, Szeged, Hungary; 3Department of Cardiology and Angiology I, University Heart Center Freiburg, Medical Faculty, University of Freiburg, Freiburg, Germany;  4Department of Translational Cardiology/Electrophysiology,Institute of Physiology, University of Bern, Bern, Switzerland;  5Translational Cardiology, Department of Cardiology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland;  6Institute of Experimental Cardiovascular Medicine, University Heart Center Freiburg—Bad Krozingen, Medical Faculty, University of Freiburg, Freiburg, Germany;  7Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden; 8Department of Physiology and Biophysics, University of Miami, Miami, FL, USA;  9Animal Biotechnology Department, NARIC Agricultural Biotechnology Institute, Gödöllő, Hungary; and  10Department of Cardiology and Medical Intensive Care, St. Josefskrankenhaus, Freiburg, Germany Current therapies of congenital long QT syndrome (LQTS) fail to prevent arrhythmic events in up to 40% of the patients. Docosahexaenoic acid (DHA), a polyunsaturated fatty acid activates the repolarizing IKs current if both α- (KvLQT1) and β (KCNE1) –subunits to IKs are functionally intact.  The potential beneficial (repolarisation-normalizing) effects of DHA in transgenic LQT1 (KCNQ1-Y315S, loss of IKs), LQT2 (HERG-G628S, loss of IKr), LQT5 (KCNE1-G52R, decreased IKs) and LQT2-5 (loss of IKr/decreased IKs) rabbits were investigated.  In vivo telemetric ECG analyses in wild-type (WT), LQT1, LQT2, LQT5 and LQT2-5 rabbits were performed at baseline and after 10µM/kg DHA i.m. to assess changes in heart rate corrected QT (QTc) and short term variability of QT (STVQT). Ex vivo monophasic action potential measurements in Langendorff-perfused hearts were carried out to investigate DHA-induced (20µM) changes in action potential duration (APD75) and action potential (AP) triangulation (APD90-APD30).  Baseline QTc (ms±SEM) was significantly longer in LQT1, LQT2 and LQT2-5 than in WT (166±3.8, 165±3.7, and 167±12.1 vs. 144±14.3; p<0.05). Baseline STVQT (ms±SEM) was increased only in LQT2. In vivo, DHA shortened QTc through activation of IKs only in WT (-12.0±1.9, p<0.01) and in LQT2 (-20.7±1.7, p<0.01). Furthermore, in LQT2, DHA normalized STVQT. Similarly, ex vivo, DHA shortened APD75 (ms±SEM) only in WT and in LQT2 (-12.3±2.2 and -18.1±3.5, p<0.01). Moreover, AP triangulation was decreased by DHA in LQT2 (-5.8±1.8, p<0.01). Importantly, DHA didn’t increase the spatial dispersion of repolarisation (QT and APD75 dispersion).  DHA exerts a beneficial repolarisation-normalizing effect through activation of IKs in LQT2 with intact α- and β-subunits to IKs. DHA could thus represent a novel therapeutic tool in LQT2 syndrome. Keywords: long QT syndrome, impaired repolarization reserve, transgenic LQT rabbit models, polyunsaturated fatty acid, docosahexaenoic acid (DHA) 

Beneficial repolarisation-normalizing effect of a polyunsaturated fatty acid, DHA in transgenic long QT type 2 rabbit model : [abstract]

http://acta.bibl.u-szeged.hu/77545/1/iacs_es_2022_084.pdf

Beneficial repolarisation-normalizing effect of a polyunsaturated fatty acid, DHA in transgenic long QT type 2 rabbit model : [abstract]

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