Short QT Syndrome Patients

Experimental models of Short QT Syndrome

Transgenic upregulation of IK1 in the mouse heart leads to multiple abnormalities of cardiac excitability. Li J, McLerie M, Lopatin AN. Am J Physiol Heart Circ Physiol 2004;287:H2790-H2802

The authors produced and characterized the first transgenic mouse model of _I_K1 upregulation. Two lines of animals were established with one showing a short QT interval

Amplified Transmural Dispersion of Repolarization as the Basis for Arrhythmogenesis in a Canine Ventricular-Wedge Model of Short-QT Syndrome. Extramiana F, Antzelevitch CCirculation 2004;110:3661-3666

The authors demonstrates that shortening of the QT interval in a canine wedge preparation by Pinacidil (a specific activator of the IK-ATP channel) is associated with an increased trasmural dispersion of repolarization and inducibility of VF by programmed stimulation.

This model of short QT syndrome is phenotypically different from the clinical short QT syndrome cases caused by a gain of function of either HERG or KCNQ1. In these two syndromes, the ECG of affected individuals often manifests tall, peaked, symmetrical T waves rather than inverted T waves as seen in the experimental model.

Modelling of short QT syndrome in a heterogeneous model of the human ventricular wall**.** Weiss DL, Seemann G, Sachse FB, Doessel O. Europace 2005;7:S105-S117

These authors have been able to create a computer model of human cardiomyocytes that incorporates modifications in _I_Kr as seen in some SQTS patients. They found a heterogeneous abbreviation of the action potential duration leading to a decreased dispersion of repolarization in heterogeneous tissue. Repolarisation was homogenized and the final repolarisation was shifted to epicardial sites.

The short QT syndrome as a paradigm to understand the role of potassium channels in ventricular fibrillation Cerrone M, Noujaim S, Jalife J.. J Int Med 2006;259:24-38

Review article where molecular and genetic features of SQTS is addressed. New knowledge on the mechanism of wavebreak, which is the hallmark of reentry initiation summarized.

The authors stat, that it is likely that the mechanisms that lead to electrical instability and eventually results in VF in patients carrying mutations in HERG or KvLQT1 would be different from those resulting from gain-of-function substitutions in Kir2.1

Arrhythmogenesis in the short QT syndrome associated with combined HERG channel gating defects: a simulation study**.** Itoh H, Horie M, Ito M, Imoto K. Circ J 2006;70(4):502-508

Conclusion: Although gain of function of the KCNH2 (HERG) channel shortens APD in the Short QT Syndrome, arrhythmogenesis may be associated not only with gain of function, but also with accelerated deactivation of KCNH2.

Over-expression of Kv1.5 in rat cardiomyocytes extremely shortens the duration of the action potential and causes rapid excitation. Tanabe Y, Hatada K, Naito N, Aizawa Y, Chinushi M, Nawa H, Aizawa Y Biochemical and Biophysical Research Communications 2006;345:1116-1121

The authors have been able to create a model based upon fetal rat cardiomyocytes with over-expression of Kv1.5 leading to shortening of the action potential. They have suggested that this model can be used to study the arrhythmogenic substrate in SQTS.

Deficient Zebrafish Ether-à-Go-Go-Related Gene Channel Gating Causes Short-QT Syndrome in Zebrafish Reggae Mutants Hassel D, Scholz EP, Trano N, Friedrich O, Just S. Meder B, Weiss DL, Zitron E, Marquart S, Vogel B, Karle CA, Seemann G, Fishman MC, Katus HA, Tootbauer W., Circulation 2008;117:866-875

Cellular basis for arrhythmogenesis in an experimental model of the SQT1 form of the short QT syndrome Patel C, Antzelevitch C. Heart Rhythm 2008;5:585-590

An experimental model of SQT1 was created using PD-118057 (Pinacidil) which is an _I_K-ATP agonist. Their results suggest that a combination of ERP abbreviation and TDR amplification underlie the development of pVT in SQT1 and that quinidine prevents pVT principally by prolonging ERP.

Celluler basis for atrial fibrillation in an experimental model of QT1: Implications for a pharmacological approach to therapy. Nof E, Burashnikov A, Antzelevitch C. Heart Rhythm 2010;7:251-257

Assessment of ECG interval and restitution parameters in the canine model of short QT syndrome.

Kijtawornrat A, Panyasing Y, del Rio C, Hamlin RL. J Pharmacological and Toxicological Methods 2010;61:231-237

Shortening of the QT was accomplished by _I_K-ATP agonists.

Computational analysis of the electromechanical consequences of short QT syndrome

Christoffer L.-H. Huang. Front Physiol 2015;6:590-591

In silico investigation of the short QT syndrome, using human ventricle models incorporating electromechanical coupling. Adeniran I, Hancox JC, Zhang H Frontiers in Physiology 2013;4:Article 166 (

The aim of this study was to utilize electromecanically coupled human ventricle models to explore electromechanical consequences of the SQTS. Previously validated K channel formulations for SQT variants 1 and 3 were incorporated.

Whilst there is little evidence of profoundly impaired cardiac contractile function in SQTS patients, the 3D simulations in this study correlate qualitatively with reported evidence for dissociation between ventricular repolarization and the end of mechanical systole.

Structural Interplay of Kv7.1 and KCNE1 is essential for normal repolarization and is compromised in Short QT syndrome 2 (Kv7-A287T)

Rothenberg I, Piccini I, Wrobel E, Stallmeyer B, Muller J, Greber B, Strutz-Seebohm, Schulze-Bahr E, Schmitt N, Seebohm. HeartRhythm Case rep 2016;.2(6):521-529

Atrial arrhythmogenicity of KCNJ2 mutation in short QT syndrome: Insights from virtual human atria.

Dominic G. Whittaker, Haibo Ni, Aziza El Harchi, Jules C. Hancox, Henggui Zhang. PLoS Comput Biol 2017;16:69

Human Atrial Arrhythmogenesis and Sinus Bradycardia in _KCNQ1-_Linked Short QT Syndrome: Insights From Computational Modeling.

Dominic G Whittaker, Michael A. Colman, Haibo Ni, Jules C. Hancox, Henggui Zhang.

Front Physiol. 2018;9:1402

Modeling Short QT Syndrome Using Human-Induced Pluripotent Stem Cell-derived Cardiomyocytes.

Ibrahim El-Battrawy, Huan Lan, Lukas Cyganek, Xhihan Zhao, Xin Li, Fanis Buljubasic, Siegfred Lang, Gokhan Yucel, Katherine Sattler, Wolfram-Hbertus Zimmerman, Jochen Utikal, Thomas Wieland, Ursula Ravens, Martin Borggrefe, Xiao-Bo Zhou, Ibrahim Akin J Am Heart Assoc. 2018;7(7)

Correction: Atrial arrhythmogenicity of KCNJ2 mutations in short QT syndrome: Insights from virtual human atria.

The PLOS Computational Biology Staff. PLoS Comput Biol. 2019 Jun; 15(6)

Ranolazine and Vernakalant Prevent Ventricular Arrhythmias in an Experimental Whole-Heart Model of Short QT Syndrome Gerrit Frommeyer, Christian Ellerman, Dirk G. Dechering, Simon Kochhauser, Nils Bögeholz, Fatih Güner, Patrick Leitz, Christian Pott, Lars Eckardt J Cardiovasc Electrophysiol 2016;27(10):1214-1219

Modeling the effects of amiodarone on short QT syndrome variant 2 in the human ventricles Curjin Luo, Kuanquan Wang, Henggui Zhang  Annu Int Cont IEEE Eng Med Biol Soc 2017;2017:4273-4276

Atrial arrhythmogenicity of KCNJ2 mutations in short QT syndrome: Insights from virtual human atria Dominic G. Whittager, Holbo Ni, Aziza El Harchi, Jules C. Hancox, Henggui Zhang PLoS Comput Biol 13(6): e1005593 (2017)

In Silico investigation of a KCNQ1 mutation associated with short QT syndrome Ismail Adeniran, Dominic G. Whittaker, Aziza El Harchi. Jules C. Hancox & Henggui Zhang. Nature: Scientific Reports I 7:8469 I DOI.10.1038/s41598-017-08367-2 (2017) 

Computational Analysis of the Mode of Action of Disopyramide and Quinidine on hERG-Linked Short QT Syndrome in Human Ventricle Dominic G Whittaker, Haibo Ni, Alan P. Benson, Jules C. Hancox and Henggui Zhang PLOS Comput. Biol.  doi: 10.3389/fphys.2017.00759

Human Atrial Arrhythmogenesis and Sinus Bradycardia in KCNQ1-Linked Short QT Syndrome: Insights from Computational Modelling Dominic G. Whittaker, Michael A. Colman, Haibo Ni, Jules C. Hancox and Henggui Zhang Computational Modeling, Front. Physiol. 9:1402. doi: 10.3389/fphys.2018.01402

In silico Assessment of Pharmacotherapy for Human Atrial Patho-Electrophysiology Associated With hERG-Linked Short QT Syndrome Dominic G. Whittager, Jules C. Hancox and Henggui Zhang Front. Physiol. 9:1888. doi: 103389/fphys.2018.01888

Functional and pharmacological characterization of an S5 domain hERG mutation associated with short QT syndrome Andrew Butler, Yihong Zhang, A. Graham Stuart, Christopher E. Dempsey, Jules C. Hancox  Heliyon 5 (2019) e01429 doi: 10.1016/j.heliyon.2019

Modeling Reentry in the Short QT Syndrome With Human-Induced Pluripotent Stem Cell Derived Cardiac Cell Sheets Rami Shinnawi, Naim Shaheen, Irit Huber, Assad Shiti, Gil Arbel, Amira Gepstein, Nimer Ballan, Noga Setter, Anke J Tijsen, Martin Borggrefe, Lior Gepstein JACC 2019;73(18):2310-2324

Transgenic short-QT syndrome 1 rabbits mimic the human disease phenotype with QT/action potential duration shortening in the atria and ventricles and increased ventricular tachycardia/ventricular fibrillation inducibility. Katja E Odening, Ilona Bodi, Gerlind Franke, Raphaela Rieke, Anna Ryan de Medeiros, Stefanie Perez-Feliz, Hannah Fürniss, Lea Mettke, Konstantin Michaelides, Corinna N Lang, Johannes Steinfurt, Naga Deepa Pantulu, David Ziupa, Marius Menza, Manfred Zehender, Heiko Bugger, Remi Peyronnet, Jan C Behrends, Zoltan Doleschall, Axel Zur Hausen, Christoph Bode, Genevieve Joliver, Michael Brunner Eur Heart J 40(10):842-853:2019  

Computational prediction of drug response in short QT syndrome type 1 based on measurements of compound effect in stem cell-derived cardiomyocytes Karoline Horgmo Jæger, Samuel Wall, Asiak Tveito PLoS Comput Biol. doi: 10.1371/journal.pcbi. 1008089

Preclinical short QT syndrome models: studying the phenotype and drug-screening Xuehui Fan, Guoqiang Yang, Jacqueline Kowitz, First Duru, Ardan M Saguner, Ibrahim Akin, Xiaobo Zhou, Ibrahim El-Battrawy Europace 2021 (ahead of print) doi: 10.1093/europace/euab214