LR1 model for Long QT Syndrome Type 2 mutation in hERG channel

Summary

Type 2 long QT is a subtype of LQTS and it is a cardiac disorder typically associated with specific symptoms such as tachyarrhythmias and sudden death which is caused by mutations in HERG gene. The formation of the Kv 11.1 pore-forming α-subunit of the Ikr channel. Mutant Ikr channels can be subject to reduced functionality, including but not limited to abnormal gating and interrupted protein trafficking[1]. The repolarization phase of the action potential is heavily dependent on the proper functionality of the Ikr channel, and thus the length of the QT interval is affected. Abnormal functionality induces early afterdepolarization (EAD), which disrupts the heart’s rhythm, leading to arrhythmia [2].

Many individuals with LQTS do not show any apparent symptoms, often requiring ECG examination. Mutation in the HERG gene can lead to function loss of the channel protein and a prolonged repolarization in QT interval[3]. LQT2 makes up to 40% of all LQTS patients. There are no differences in risks for children to have LQT2, however, adult females with LQT2 have a higher risk of experiencing cardiac events when compared to males with LQT2 and almost half of deaths from LQT2 occur during sleep [4]. Most of the cardiac events in LQT2 patients are associated with emotional stress 43%, mainly auditory stimulation, and only 13% occur during exercise.[6]

As far as treatment goes, β-blockers are the golden standard, and are effective in preventing cardiac arrest in approximately 70% of patients. Propranolol, nadolol, atenolol and metoprolol are the most frequently used β-blockers.[5] In cases where β-blockers prove ineffective, implantation of a cardioverter defibrillator is another effective method in preventing cardiac arrest. In the therapeutic strategies, β-blockers are significantly less effective in LQT2 compare to the other subtypes. In our cohort of LQT2 patients, β-blockers decreased cardiac events from 58% to 23% after an average follow-up of 4.9 years on therapy[6]

[1] Matsa, Elena, et al. “Drug evaluation in cardiomyocytes derived from human induced pluripotent stem cells carrying a long QT syndrome type 2 mutation.”European heart journal 32.8 (2011): 952-962.

[2] Gepstein, Lior, and Rami Shinnawi. “IPCS Cell Modeling of Inherited Cardiac Arrhythmias.” Springer. Springer International Publishing AG, 1 July 2014. Web. 16 Apr. 2015. http://link.springer.com/article/10.1007/s11936-014-0331-4/fulltext.html

[3]  Zhu, R., et al., Abstract 15961: Syncytial Model of Type 2 Long QT Syndrome Derived From Human iPS Cells Can Be Paced and Responds to Ikr Block and Activation. Circulation, 2014. 130(Suppl 2): p. A15961.

[4] The Children’s Hospital of Philadelphia. Long QT syndrome knowledge base. http://www.research.chop.edu/programs/lqts/clinical.php. Web. 5 May 2015.

[5 ]Goldenberg I, Thottathil P, Lopes CM, et al. Trigger-specific ion-channel mechanisms, risk factors, and response to therapy in type 1 long QT syndrome. Heart Rhythm. Jan 2012;9(1):49-56.

[6]Ruan, Y., et al., Therapeutic strategies for long-QT syndrome: does the molecular substrate matter? Circ Arrhythm Electrophysiol, 2008. 1(4): p. 290-7.

MATLAB code

Click here to download the m-file matlab_code

Click here to download the m-file gui_code

Changes to Matlab code

In order to model LQT2, we implemented four inputs associated with Ikr channel, including scaling factor of conductance (g_krscale), voltage shift in activation gate (vshift_a) and inactivation gate (vshift_n), and scaling factor of deactivation gate (Bp). Literature shows that change/s in any of these parameters may lead to elongation of APD, and therefore LQT2. Based on the paper by Zeng et al., we split the Ik into Ikr and Iks. The equations associated with k in the original template were replaced by the equations associated with kr and ks from the Zeng’s paper. The parameters were then implemented in the corresponding equations.

GUI

   

Presentation

Click here to download the powerpoint LQT2 presentation

Click here to download the pdf LQT2 presentation

Members

Acknowledgments 

We would like to thank Professor Entcheva for her support and guidance and also thank the TAs.