Date Published: February 20, 2013
Publisher: Public Library of Science
Author(s): John Walmsley, Jose F. Rodriguez, Gary R. Mirams, Kevin Burrage, Igor R. Efimov, Blanca Rodriguez, Xander HT. Wehrens. http://doi.org/10.1371/journal.pone.0056359
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.
A growing number of studies examine cardiac tissue mRNA expression levels in an attempt to characterize electrophysiological remodeling associated with disease conditions such as heart failure and atrial fibrillation –. Recent studies have shown alterations in expression of mRNA transcripts in human failing hearts compared to non-failing hearts , . Furthermore, recent optical mapping measurements have also demonstrated differences in action potential (AP) and calcium transients (CaT) between failing and non-failing human hearts –, with potentially pro-arrhythmic implications –.
In this study we have developed a population-based approach to investigate the potential of mRNA expression levels measured in failing human hearts to predict electrophysiological remodeling in AP and CaT, as measured experimentally. Our population-based approach takes into consideration natural variability that may arise from a variety of sources, as well as uncertainty associated with the extent to which mRNA expression affects functional channel conductance at the cell membrane, and uncertainty in electrophysiological measurements. This is in contrast to the traditional approach of considering unique values of ionic conductances in cardiac models of non-diseased and failing human cardiomyocytes , , . Our main findings are: