Journal of Medical and Biological Engineering

, Volume 37, Issue 5, pp 780–789 | Cite as

Pro-arrhythmogenic Effects of the V141M KCNQ1 Mutation in Short QT Syndrome and Its Potential Therapeutic Targets: Insights from Modeling

  • Hsiang-Chun Lee
  • Yoram Rudy
  • Hongwu Liang
  • Chih-Chieh Chen
  • Ching-Hsing Luo
  • Sheng-Hsiung Sheu
  • Jianmin Cui
Original Article


Gain-of-function mutations in the pore-forming subunit of IKs channels, KCNQ1, lead to short QT syndrome (SQTS) and lethal arrhythmias. However, how mutant IKs channels cause SQTS and the possibility of IKs-specific pharmacological treatment remain unclear. V141M KCNQ1 is a SQTS associated mutation. We studied its effect on IKs gating properties and changes in the action potentials (AP) of human ventricular myocytes. Xenopus oocytes were used to study the gating mechanisms of expressed V141M KCNQ1/KCNE1 channels. Computational models were used to simulate human APs in endocardial, mid-myocardial, and epicardial ventricular myocytes with and without β-adrenergic stimulation. V141M KCNQ1 caused a gain-of-function in IKs characterized by increased current density, faster activation, and slower deactivation leading to IKs accumulation. V141M KCNQ1 also caused a leftward shift of the conductance-voltage curve compared to wild type (WT) IKs (V1/2 = 33.6 ± 4.0 mV for WT, and 24.0 ± 1.3 mV for heterozygous V141M). A Markov model of heterozygous V141M mutant IKs was developed and incorporated into the O’Hara–Rudy model. Compared to the WT, AP simulations demonstrated marked rate-dependent shortening of AP duration (APD) for V141M, predicting a SQTS phenotype. Transmural electrical heterogeneity was enhanced in heterozygous V141M AP simulations, especially under β-adrenergic stimulation. Computational simulations identified specific IK1 blockade as a beneficial pharmacologic target for reducing the transmural APD heterogeneity associated with V141M KCNQ1 mutation. V141M KCNQ1 mutation shortens ventricular APs and enhances transmural APD heterogeneity under β-adrenergic stimulation. Computational simulations identified IK1 blockers as a potential antiarrhythmic drug of choice for SQTS.


Arrhythmia Anti-arrhythmic IKs KCNQ1 Short QT syndrome 



We thank Dr. Jingyi Shi and Kelli Delaloye for KCNQ1 and KCNE1 subcloning. We thank Dr. Guohui Zhang for technical help with data analysis. We also thank Dr. Po-Yuan Chen for technical help with the computational simulation. The authors also thank the Statistical Analysis Laboratory, Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung Medical University. This study was funded by Taiwan National Science Council Grant NSC 102-2314-B-037 -041 and KMUH97-7G31 (to HC Lee), NIH–NHLBI Grants R01-HL-049054 and R01-HL-033343 (to Y. Rudy), and NIH Grants R01-HL70393 and R01-NS060706 (to J. Cui).

Compliance with Ethical Standards

Conflict of interest


Supplementary material

40846_2017_257_MOESM1_ESM.pdf (123 kb)
Supplementary material 1 (PDF 123 kb)


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Copyright information

© Taiwanese Society of Biomedical Engineering 2017

Authors and Affiliations

  • Hsiang-Chun Lee
    • 1
    • 2
    • 3
    • 4
    • 5
    • 6
  • Yoram Rudy
    • 1
  • Hongwu Liang
    • 1
  • Chih-Chieh Chen
    • 6
  • Ching-Hsing Luo
    • 7
  • Sheng-Hsiung Sheu
    • 2
    • 3
    • 4
  • Jianmin Cui
    • 1
  1. 1.Cardiac Bioelectricity and Arrhythmia CenterWashington University in St. LouisSt. LouisUSA
  2. 2.Division of Cardiology, Department of Internal MedicineKaohsiung Medical University Hospital, Kaohsiung Medical UniversityKaohsiungTaiwan
  3. 3.Faculty of Medicine, College of MedicineKaohsiung Medical UniversityKaohsiungTaiwan
  4. 4.Center for Lipid BiosciencesKaohsiung Medical University Hospital, Kaohsiung Medical UniversityKaohsiungTaiwan
  5. 5.Lipid Science and Aging Research CenterKaohsiung Medical UniversityKaohsiungTaiwan
  6. 6.Institute of Medical Science and Technology National Sun Yat-sen UniversityKaohsiungTaiwan
  7. 7.Department of Electric EngineeringNational Cheng Kung UniversityTainanTaiwan

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