mRNA Expression Levels in Failing Human Hearts Predict Cellular Electrophysiological Remodeling: A Population-Based Simulation Study
Open Access
- 20 February 2013
- journal article
- research article
- Published by Public Library of Science (PLoS) in PLOS ONE
- Vol. 8 (2), e56359
- https://doi.org/10.1371/journal.pone.0056359
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.This publication has 40 references indexed in Scilit:
- Gender Differences in Electrophysiological Gene Expression in Failing and Non-Failing Human HeartsPLOS ONE, 2013
- Conduction Remodeling in Human End-Stage Nonischemic Left Ventricular CardiomyopathyCirculation, 2012
- Transmural Heterogeneity and Remodeling of Ventricular Excitation-Contraction Coupling in Human Heart FailureCirculation, 2011
- Cardiac electrical remodeling in health and diseaseTrends in Pharmacological Sciences, 2011
- Gender-related differences in ion-channel and transporter subunit expression in non-diseased human heartsJournal of Molecular and Cellular Cardiology, 2010
- Transmural Dispersion of Repolarization in Failing and Nonfailing Human VentricleCirculation Research, 2010
- Transmural expression of ion channels and transporters in human nondiseased and end-stage failing heartsPflügers Archiv - European Journal of Physiology, 2009
- Arrhythmogenic Ion-Channel Remodeling in the Heart: Heart Failure, Myocardial Infarction, and Atrial FibrillationPhysiological Reviews, 2007
- What Causes Sudden Death in Heart Failure?Circulation Research, 2004
- Electrophysiological remodeling in hypertrophy and heart failureCardiovascular Research, 1999