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mRNA Expression Levels in Failing Human Hearts Predict Cellular Electrophysiological Remodeling: A Population-Based Simulation Study

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  • John Walmsley
  • Jose F Rodriguez
  • Gary R Mirams
  • Kevin Burrage
  • Igor R Efimov
  • Blanca Rodriguez

Abstract

Differences in mRNA expression levels have been observed in failing versus non-failing human hearts for several membrane channel proteins and accessory subunits. These differences may play a causal role in electrophysiological changes observed in human heart failure and atrial fibrillation, such as action potential (AP) prolongation, increased AP triangulation, decreased intracellular calcium transient (CaT) magnitude and decreased CaT triangulation. Our goal is to investigate whether the information contained in mRNA measurements can be used to predict cardiac electrophysiological remodeling in heart failure using computational modeling. Using mRNA data recently obtained from failing and non-failing human hearts, we construct failing and non-failing cell populations incorporating natural variability and up/down regulation of channel conductivities. Six biomarkers are calculated for each cell in each population, at cycle lengths between 1500 ms and 300 ms. Regression analysis is performed to determine which ion channels drive biomarker variability in failing versus non-failing cardiomyocytes. Our models suggest that reported mRNA expression changes are consistent with AP prolongation, increased AP triangulation, increased CaT duration, decreased CaT triangulation and amplitude, and increased delay between AP and CaT upstrokes in the failing population. Regression analysis reveals that changes in AP biomarkers are driven primarily by reduction in I, and changes in CaT biomarkers are driven predominantly by reduction in I and SERCA. In particular, the role of I is pacing rate dependent. Additionally, alternans developed at fast pacing rates for both failing and non-failing cardiomyocytes, but the underlying mechanisms are different in control and heart failure.

Suggested Citation

  • John Walmsley & Jose F Rodriguez & Gary R Mirams & Kevin Burrage & Igor R Efimov & Blanca Rodriguez, 2013. "mRNA Expression Levels in Failing Human Hearts Predict Cellular Electrophysiological Remodeling: A Population-Based Simulation Study," PLOS ONE, Public Library of Science, vol. 8(2), pages 1-11, February.
    • Handle: RePEc:plo:pone00:0056359
    DOI: 10.1371/journal.pone.0056359
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    1. Darwin Jeyaraj & Saptarsi M. Haldar & Xiaoping Wan & Mark D. McCauley & Jürgen A. Ripperger & Kun Hu & Yuan Lu & Betty L. Eapen & Nikunj Sharma & Eckhard Ficker & Michael J. Cutler & James Gulick & At, 2012. "Circadian rhythms govern cardiac repolarization and arrhythmogenesis," Nature, Nature, vol. 483(7387), pages 96-99, March.
    2. Amrita X Sarkar & Eric A Sobie, 2010. "Regression Analysis for Constraining Free Parameters in Electrophysiological Models of Cardiac Cells," PLOS Computational Biology, Public Library of Science, vol. 6(9), pages 1-11, September.
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    1. Maria T Mora & Juan F Gomez & Gregory Morley & Jose M Ferrero & Beatriz Trenor, 2019. "Mechanistic investigation of Ca2+ alternans in human heart failure and its modulation by fibroblasts," PLOS ONE, Public Library of Science, vol. 14(6), pages 1-19, June.
    2. Tanmay A Gokhale & Jong M Kim & Robert D Kirkton & Nenad Bursac & Craig S Henriquez, 2017. "Modeling an Excitable Biosynthetic Tissue with Inherent Variability for Paired Computational-Experimental Studies," PLOS Computational Biology, Public Library of Science, vol. 13(1), pages 1-26, January.

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