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Heart failure (HF) is characterized by altered Ca 2+  cycling, resulting in cardiac contractile dysfunction. Failing myocytes undergo electrophysiological remodeling, which is known to be the main cause of abnormal Ca 2+  homeostasis. However, structural remodeling, specifically proliferating fibroblasts coupled to myocytes in the failing heart, could also contribute to Ca 2+  cycling impairment. The goal of the present study was to systematically analyze the mechanisms by which myocyte–fibroblast coupling could affect Ca 2+  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 [Ca 2+ ] waveforms. Variability in ion channels and pumps was imposed and populations of models were analyzed to determine effects on Ca 2+  dynamics. Our results suggest that both univariate and multivariate sensitivity analyses are valuable methodologies to shed light into the ionic mechanisms underlying Ca 2+  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 Ca 2+  dynamics. Coupling either healthy or failing myocytes to fibroblasts decreased Ca 2+  transients due to an indirect sink effect on action potential (AP) and thus on Ca 2+  related currents. Simulations that investigated restoration of normal physiology in failing myocytes showed that Ca 2+  cycling can be normalized by increasing SERCA and L-type Ca 2+  current activity while decreasing Na + –Ca 2+  exchange and SR Ca 2+  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 Ca 2+  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.

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