Messenger RNA Expression Levels Predict Cellular Electrophysiologic Remodeling in Failing Human Hearts Using a Population-Based Simulation Study

Abstract

<h3>Background</h3> Alterations in mRNA expression levels are reported in human heart failure (HF). However, their potential causative link to changes in action potential (AP) and calcium transient (Ca_iT) measured in human HF is still unclear. Our aim is to investigate consequences of HF-related mRNA changes on cellular electrophysiology taking into account interindividual variability and uncertainty in membrane-level effect of changed mRNA expression of channel subunits. <h3>Methods</h3> HF and non-HF human cell model populations were constructed using Monte-Carlo sampling and recent mRNA expression data from HF and nondiseased human hearts. Six AP and Ca_iT biomarkers were calculated for each cell at cycle lengths between 1500 and 300 ms. Regression analysis was used to determine key ionic properties underlying biomarker changes. <h3>Results</h3> Simulations show that HF-related mRNA changes result in increase in AP duration, AP triangulation, Ca_iT duration, delay between AP and Ca_iT upstroke as well as decrease in Ca_iT triangulation and amplitude in HF cells. Changes in AP biomarkers in HF are correlated with reduction in I_Kr, whereas changes in Ca_iT biomarkers are correlated with reduction in I_CaL and SERCA. The role of I_CaL is pacing rate dependent. At fast pacing rates, both HF and non-HF cells develop alternans, but the underlying mechanisms differed. <h3>Conclusions</h3> A population-based simulation study reveals the functional consequences of HR-related mRNA changes on cellular electrophysiology, consistent with experimental measurements in human HF. Remodeling in I_Kr, I_CaL, and SERCA are identified as main determinants of AP and Ca_iT changes in HF. Sample AP traces at 1500ms BCL