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Modeling incomplete penetrance in long QT syndrome type 3 (LQT3) through ion channel heterogeneity

Miller, Jacob Andrew
http://orcid.org/0000-0001-6640-169X
http://rave.ohiolink.edu/etdc/view?acc_num=osu1670015305148325

Abstract Details

2022, Master of Science, Ohio State University, Biomedical Engineering.
Many cardiac diseases are characterized by an increased late sodium current, including heart failure, hypertrophic cardiomyopathy, and inherited long QT syndrome type 3 (LQT3). The late sodium current in LQT3 is caused by a gain-of- function mutation in the voltage-gated sodium channel Nav1.5. Despite a well- defined genetic cause of LQT3, treatment remains inconsistent due to incomplete penetrance of the mutation and variability of anti-arrhythmic efficacy. Here, we investigate the relationship between LQT3-associated mutation incomplete penetrance and variability in ion channel expression, simulating a population of 1,000 “individuals” using the O’Hara-Rudy model of the human ventricular myocyte. We first simulate healthy electrical activity (i.e., in the absence of a mutation), then in- corporate heterozygous expression for three LQT3-associated mutations (Y1795C, I1768V, and ∆KPQ), to directly compare the effects of each mutation on individuals across a diverse population. For all mutations, we find that susceptibility, defined either by the presence of an early afterdepolarization (EAD) or prolonged action potential duration (APD), primarily depends on the balance between the conductance of IKr and INa, for which individuals with a higher IKr-INa ratio are less susceptible. Further, we find distinct differences across the population, observing ii individuals susceptible to zero, one, two, or all three mutations. Individuals tend to be less susceptible with an appropriate balance of repolarizing currents, typically via increased IKs or IK1. Interestingly, the more critical repolarizing current is mutation-specific. We conclude that balance between key currents plays a significant role in mutant-specific presentation of the disease phenotype in LQT3.
Seth Weinberg (Advisor)
Rengasayee Veeraraghavan (Committee Member)
105 p.
Biology; Biomedical Engineering; Biomedical Research; Biophysics; Physiology
LQT3; ion channel; INaL; gain-of-function; arrhythmia; sudden cardiac death; SIDS

Recommended Citations

Citations

  • Miller, J. A. (2022). Modeling incomplete penetrance in long QT syndrome type 3 (LQT3) through ion channel heterogeneity [Master's thesis, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1670015305148325

    APA Style (7th edition)

  • Miller, Jacob. Modeling incomplete penetrance in long QT syndrome type 3 (LQT3) through ion channel heterogeneity . 2022. Ohio State University, Master's thesis. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1670015305148325.

    MLA Style (8th edition)

  • Miller, Jacob. "Modeling incomplete penetrance in long QT syndrome type 3 (LQT3) through ion channel heterogeneity ." Master's thesis, Ohio State University, 2022. http://rave.ohiolink.edu/etdc/view?acc_num=osu1670015305148325

    Chicago Manual of Style (17th edition)

osu1670015305148325
104
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This open access ETD is published by The Ohio State University and OhioLINK.