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Bio-Algorithms and Med-Systems

Editor-in-Chief: Roterman-Konieczna , Irena

CiteScore 2017: 0.43

SCImago Journal Rank (SJR) 2017: 0.160
Source Normalized Impact per Paper (SNIP) 2017: 0.223

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An analysis of cardiomyocytes’ electrophysiology in the presence of the hERG gene mutations

Anna Glinka
  • Corresponding author
  • Faculty of Pharmacy, Department of Social Pharmacy, Medical College, Jagiellonian University, Cracow, Poland
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  • Other articles by this author:
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/ Sebastian Polak
  • Faculty of Pharmacy, Department of Social Pharmacy, Medical College, Jagiellonian University, Cracow, Poland
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
Published Online: 2013-09-06 | DOI: https://doi.org/10.1515/bams-2013-0017


Mutations in the human ether-à-go-go-related gene are linked with cardiomyocyte repolarization impairment, which, in combination with other factors, can lead to life-threatening arrhythmias. The aim of the study was to demonstrate the effect of selected mutations associated with protein trafficking problems on the action potential of the ventricular cell. To perform the simulations, the O’Hara-Rudy dynamic model was used. The modification of membrane permeability to rapid delayed rectifier current was based on data obtained from in vitro studies with the human embryonic kidney (HEK293) cell line transfected with human genes: wild type and one of the seven mutations (F805C, G601S, D456Y, I31S, R823W, F640V, and A561V). Simulations were carried out for each mutation on epicardial, endocardial, and M-cells with RR interval values of 500, 750, 1000, and 1500 ms. A positive correlation between the APD90 length and the percentage of current reduction and between APD90 and RR interval lengths was observed.

Keywords: action potential; computational models; human ether-à-go-go-related gene (hERG); long QT syndrome; single nucleotide polymorphism (SNP) mutation; trafficking; wild type; rapid delayed rectifier current (IKr)


  • 1.

    El Harchi A, Melgari D, Zhang YH, Zhang H, Hancox JC. Action potential clamp and pharmacology of the variant 1 short QT syndrome T618I hERG K(+) channel. PLoS One 2012;7:1–15.Web of ScienceGoogle Scholar

  • 2.

    Splawski I, Shen J, Timothy KW, Lehmann MH, Priori S, Robinson JL, et al. Spectrum of mutations in long-QT syndrome genes. KVLQT1, HERG, SCN5A, KCNE1, and KCNE2. Circulation 2000;102:1178–85.Google Scholar

  • 3.

    Tester DJ, Will ML, Haglund CM, Ackerman MJ. Compendium of cardiac channel mutations in 541 consecutive unrelated patients referred for long QT syndrome genetic testing. Heart Rhythm 2005;2:507–17.PubMedCrossrefWeb of ScienceGoogle Scholar

  • 4.

    Kapa S, Tester DJ, Salisbury BA, Harris-Kerr C, Pungliya MS, Alders M, et al. Genetic testing for long-QT syndrome: distinguishing pathogenic mutations from benign variants. Circulation 2009;120:1752–60.CrossrefPubMedGoogle Scholar

  • 5.

    Männikkö R, Overend G, Perrey C, Gavaghan CL, Valentin JP, Morten J, et al. Pharmacological and electrophysiological characterization of nine, single nucleotide polymorphisms of the hERG-encoded potassium channel. Br J Pharmacol 2010;159:102–14.PubMedCrossrefGoogle Scholar

  • 6.

    Single Nucleotide Polymorphism Database. dbSNP short genetic variations. Available at: http://www.ncbi.nlm.nih.gov/projects/SNP. Accessed on 6, August 2013.

  • 7.

    Anderson CL, Delisle BP, Anson BD, Kilby JA, Will ML, Tester DJ, et al. Most LQT2 mutations reduce Kv11.1 (hERG) current by a class 2 (trafficking-deficient) mechanism. Circulation 2006;113:365–73.CrossrefGoogle Scholar

  • 8.

    Thomas D, Kiehn J, Katus HA, Karle CA. Defective protein trafficking in hERG-associated hereditary long QT syndrome (LQT2): molecular mechanisms and restoration of intracellular protein processing. Cardiovasc Res 2003;60:235–41.PubMedCrossrefGoogle Scholar

  • 9.

    Etheridge SP, Compton SJ, Tristani-Firouzi M, Mason JW. A new oral therapy for long QT syndrome: long-term oral potassium improves repolarization in patients with HERG mutations. J Am Coll Cardiol 2003;42:1777–82.CrossrefPubMedGoogle Scholar

  • 10.

    Fodstad H. Genetic and functional studies of severe ventricular arrhythmias, academic dissertation. Helsinki, Finland: University of Helsinki, 2005.Google Scholar

  • 11.

    Grilo LS, Schläpfer J, Fellmann F, Abriel H. Patient with syncope and LQTS carrying a mutation in the PAS domain of the hERG1 channel. Ann Noninvasive Electrocardiol 2011;16:213–8.Web of ScienceCrossrefGoogle Scholar

  • 12.

    Itoh T, Tanaka T, Nagai R, Kamiya T, Sawayama T, Nakayama T, et al. Genomic organization and mutational analysis of HERG, a gene responsible for familial long QT syndrome. Hum Genet 1998;102:435–9.PubMedCrossrefGoogle Scholar

  • 13.

    Tester DJ, Ackerman MJ. Sudden infant death syndrome: how significant are the cardiac channelopathies? Cardiovasc Res 2005;67:388–96.CrossrefPubMedGoogle Scholar

  • 14.

    Fijorek K, Patel N, Klima Ł, Stolarz-Skrzypek K, Kawecka-Jaszcz K, Polak S. Age and gender dependent heart rate circadian model development and performance verification on the proarrhythmic drug case study. Theor Biol Med Model 2013;10:1–11.Web of ScienceGoogle Scholar

  • 15.

    Furlan R, Guzzetti S, Crivellaro W, Dassi S, Tinelli M, Baselli G, et al. Continuous 24-hour assessment of the neural regulation of systemic arterial pressure and RR variabilities in ambulant subjects. Circulation 1990;81:537–47.CrossrefGoogle Scholar

  • 16.

    Malpas SC, Purdie GL. Circadian variation of heart rate variability. Cardiovasc Res 1990;24:210–3.CrossrefPubMedGoogle Scholar

  • 17.

    Tsuji H, Larson MG, Venditti FJ Jr, Manders ES, Evans JC, Feldman CL, et al. Impact of reduced heart rate variability on risk for cardiac events. The Framingham Heart Study. Circulation 1996;94:2850–5.CrossrefPubMedGoogle Scholar

  • 18.

    O’Hara T, Virág L, Varró A, Rudy Y. Simulation of the undiseased human cardiac ventricular action potential: model formulation and experimental validation. PLoS Comput Biol 2011;7:1–29.Web of ScienceGoogle Scholar

  • 19.

    Glukhov AV, Fedorov VV, Lou Q, Ravikumar VK, Kalish PW, Schuessler RB, et al. Transmural dispersion of repolarization in failing and nonfailing human ventricle. Circ Res 2010;106:981–91.Web of ScienceCrossrefPubMedGoogle Scholar

  • 20.

    Keating MT, Sanguinetti MC. Molecular and cellular mechanisms of cardiac arrhythmias. Cell 2001;104:569–80.PubMedCrossrefGoogle Scholar

  • 21.

    O’Hara T, Rudy Y. Arrhythmia formation in subclinical (“silent”) long QT syndrome requires multiple insults: quantitative mechanistic study using the KCNQ1 mutation Q357R as example. Heart Rhythm 2012;9:275–82.Web of ScienceGoogle Scholar

  • 22.

    Polak S, Fijorek K, Glinka A, Wisniowska B, Mendyk A. Virtual population generator for human cardiomyocytes parameters: in silico drug cardiotoxicity assessment. Toxicol Mech Methods 2012;22:31–40.PubMedWeb of ScienceCrossrefGoogle Scholar

About the article

Corresponding author: Anna Glinka, Faculty of Pharmacy, Department of Social Pharmacy, Medical College, Jagiellonian University, Medyczna 9 St., 30-688 Cracow, Poland

Received: 2013-06-25

Accepted: 2013-08-07

Published Online: 2013-09-06

Published in Print: 2013-09-01

Citation Information: Bio-Algorithms and Med-Systems, Volume 9, Issue 3, Pages 135–140, ISSN (Online) 1896-530X, ISSN (Print) 1895-9091, DOI: https://doi.org/10.1515/bams-2013-0017.

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