Ca2+ Cycling Impairment in Heart Failure Is Exacerbated by Fibrosis: Insights Gained From Mechanistic Simulations

Abstract

Heart failure (HF) is characterized by altered Ca2+ cycling, resulting in cardiac contractile dysfunction. Failing myocytes undergo electrophysiological remodeling, which is known to be the main cause of abnormal Ca2+ homeostasis. However, structural remodeling, specifically proliferating fibroblasts coupled to myocytes in the failing heart, could also contribute to Ca2+ cycling impairment. The goal of the present study was to systematically analyze the mechanisms by which myocyte–fibroblast coupling could affect Ca2+ dynamics in normal conditions and in HF. Simulations of healthy and failing human myocytes were performed using established mathematical models, and cells were either isolated or coupled to fibroblasts. Univariate and multivariate sensitivity analyses were performed to quantify effects of ion transport pathways on biomarkers computed from intracellular [Ca2+] waveforms. Variability in ion channels and pumps was imposed and populations of models were analyzed to determine effects on Ca2+ dynamics. Our results suggest that both univariate and multivariate sensitivity analyses are valuable methodologies to shed light into the ionic mechanisms underlying Ca2+ impairment in HF, although differences between the two methodologies are observed at high parameter variability. These can result from either the fact that multivariate analyses take into account ion channels or non-linear effects of ion transport pathways on Ca2+ dynamics. Coupling either healthy or failing myocytes to fibroblasts decreased Ca2+ transients due to an indirect sink effect on action potential (AP) and thus on Ca2+ related currents. Simulations that investigated restoration of normal physiology in failing myocytes showed that Ca2+ cycling can be normalized by increasing SERCA and L-type Ca2+ current activity while decreasing Na+–Ca2+ exchange and SR Ca2+ leak. Changes required to normalize APs in failing myocytes depended on whether myocytes were coupled to fibroblasts. In conclusion, univariate and multivariate sensitivity analyses are helpful tools to understand how Ca2+ cycling is impaired in HF and how this can be exacerbated by coupling of myocytes to fibroblasts. The design of pharmacological actions to restore normal activity should take into account the degree of fibrosis in the failing heart.

The Effects of Fibrotic Cell Type and Its Density on Atrial Fibrillation Dynamics: An In Silico Study

“…We assessed the effect of the fibrosis configurations on the APD and conduction velocity. Our results suggest that the presence of fibrosis produces a slight APD reduction, in agreement with Trenor et al [80] and Morgan et al [81]. A significant reduction in the conduction velocity was observed in all fibrosis configuration, with a larger effect observed at high fibrosis density.…”

Impact of oxidative posttranslational modifications of SERCA2 on heart failure exacerbation in young patients with non-ischemic cardiomyopathy: A pilot study

“…This association between OPTM of SERCA2 and myocardial fibrosis is consistent with the results of a previous study showing that myocardial fibrosis was mitigated by upregulation of SERCA2 in mice [33]. Further, a recent study reported that fibroblasts exacerbate [Ca 2+ ] c dysregulation in failing myocytes by reducing SR Ca 2+ content [34]. Thus, [Ca 2+ ] c dysregulation by fibroblast-myocyte coupling might further aggravate [Ca 2+ ] c dysregulation by OPTM of SERCA2.…”

In silico Cell Therapy Model Restores Failing Human Myocyte Electrophysiology and Calcium Cycling in Fibrotic Myocardium

“…hCICs were permitted to be coupled to cardiomyocytes or other hCICs; hMSCs were permitted to be coupled to cardiomyocytes or other hMSCs); G gap,k is the gap junctional conductance between a given cell and its k th neighbor; and V k is the membrane voltage of the k th neighbor. Adapted from Mora et al (2018), for the FHF-hCM model, 5 CFs were coupled to one HF-hCM with a gap junctional conductance of 1 nS. When incorporating the hMSC paracrine signaling variable and its anti-fibrotic effects (see section "Modeling Paracrine Signaling Effects" below for details), the corrected number of coupled CFs was rounded to the nearest integer.…”

“…To identify non-excitable cell ion channels responsible for influencing the action potential waveform, calcium transient, and net ionic channel charge of coupled HF-hCMs, we examined the model parameter sensitivity using an established multivariable regression analysis (Mayourian et al, 2016(Mayourian et al, , 2017Mora et al, 2018). More specifically, the prescribed hCIC, hMSC, and CF ion channel parameters of interest were randomly varied for 300 trials by a normally distributed pseudorandom scale factor with a coefficient of variation of 20%.…”