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Modeling long QT syndrome using gene-edited pigs

ABSTRACT: To date, KCNH2 mutations identified in LQT2 patients have been heavily studied by heterologous expression systems, allowing for pathogenicity evaluation of a certain hERG mutation by overexpressing mutant channels. However, they fall short in mimicking the full spectrum of electrophysiological changes and ion channel remodeling that occur in cardiomyocytes under physiological conditions in the context of LQT. Due to the marked differences in the lifespan, size, anatomy and physiology from humans, current zebrafish and rodent models cannot fully mimic the abnormal QT interval diseases 2. For instance, rodents exhibit an extremely higher heart rate and a much shorter action potential duration (APD) compared to humans. IKr is the predominant repolarizing current in human ventricles while inhibition of IKr in rodents has no significant effect on ventricular repolarization, making it infeasible to study LQT2 by genetic mouse model 3. Hence, there is a crucial need to construct an animal model capable of mimicking human inherited arrhythmia conditions. To address the above scientific question, we chose to create a miniature pig model. Given many physiological similarities with humans, and breeding and genome editing advantages (when compared to non-human primates), To explore the mechanism underlying mutation of KCNH2 caused LQT, we compared the transcriptomes of KCNH2-mut pigs and WT controls

ORGANISM(S): Sus scrofa

PROVIDER: GSE288082 | GEO | 2025/02/03

REPOSITORIES: GEO

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Project description:This a model from the article: Regulation of Ca2+ and electrical alternans in cardiac myocytes: role of CAMKII and repolarizing currents. Livshitz LM, Rudy Y. Am J Physiol Heart Circ Physiol. 2007 Jun;292(6):H2854-66. 17277017 , Abstract: Alternans of cardiac repolarization is associated with arrhythmias and sudden death. At the cellular level, alternans involves beat-to-beat oscillation of the action potential (AP) and possibly Ca(2+) transient (CaT). Because of experimental difficulty in independently controlling the Ca(2+) and electrical subsystems, mathematical modeling provides additional insights into mechanisms and causality. Pacing protocols were conducted in a canine ventricular myocyte model with the following results: 1) CaT alternans results from refractoriness of the sarcoplasmic reticulum Ca(2+) release system; alternation of the L-type calcium current has a negligible effect; 2) CaT-AP coupling during late AP occurs through the sodium-calcium exchanger and underlies AP duration (APD) alternans; 3) increased Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) activity extends the range of CaT and APD alternans to slower frequencies and increases alternans magnitude; its decrease suppresses CaT and APD alternans, exerting an antiarrhythmic effect; and 4) increase of the rapid delayed rectifier current (I(Kr)) also suppresses APD alternans but without suppressing CaT alternans. Thus CaMKII inhibition eliminates APD alternans by eliminating its cause (CaT alternans) while I(Kr) enhancement does so by weakening CaT-APD coupling. The simulations identify combined CaMKII inhibition and I(Kr) enhancement as a possible antiarrhythmic intervention. This model was taken from the CellML repository and automatically converted to SBML. The original model was: Livshitz LM, Rudy Y. (2007) - version01 The original CellML model was created by: Noble, Penny, penny.noble@dpag.ox.ac.uk The University of Oxford This model originates from BioModels Database: A Database of Annotated Published Models (http://www.ebi.ac.uk/biomodels/). It is copyright (c) 2005-2011 The BioModels.net Team. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information. In summary, you are entitled to use this encoded model in absolutely any manner you deem suitable, verbatim, or with modification, alone or embedded it in a larger context, redistribute it, commercially or not, in a restricted way or not.. To cite BioModels Database, please use: Li C, Donizelli M, Rodriguez N, Dharuri H, Endler L, Chelliah V, Li L, He E, Henry A, Stefan MI, Snoep JL, Hucka M, Le Novère N, Laibe C (2010) BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. BMC Syst Biol., 4:92.

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Modeling long QT syndrome using gene-edited pigs

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