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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.

SUBMITTER: Mora MT

PROVIDER: S-EPMC6116328 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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

Mora Maria T MT Ferrero Jose M JM Gomez Juan F JF Sobie Eric A EA Trenor Beatriz B

Frontiers in physiology 20180823

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 mechanism ...[more]

PMID: 30190684

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Project description:Ventricular arrhythmias can cause death in heart failure (HF). A trigger is the occurrence of Ca2+ waves which activate a Na+ -Ca2+ exchange (NCX) current, leading to delayed after-depolarisations and triggered action potentials. Waves arise when sarcoplasmic reticulum (SR) Ca2+ content reaches a threshold and are commonly induced experimentally by raising external Ca2+ , although the mechanism by which this causes waves is unclear and was the focus of this study. Intracellular Ca2+ was measured in voltage-clamped ventricular myocytes from both control sheep and those subjected to rapid pacing to produce HF. Threshold SR Ca2+ content was determined by applying caffeine (10 mM) following a wave and integrating wave and caffeine-induced NCX currents. Raising external Ca2+ induced waves in a greater proportion of HF cells than control. The associated increase of SR Ca2+ content was smaller in HF due to a lower threshold. Raising external Ca2+ had no effect on total influx via the L-type Ca2+ current, ICa-L , and increased efflux on NCX. Analysis of sarcolemmal fluxes revealed substantial background Ca2+ entry which sustains Ca2+ efflux during waves in the steady state. Wave frequency and background Ca2+ entry were decreased by Gd3+ or the TRPC6 inhibitor BI 749327. These agents also blocked Mn2+ entry. Inhibiting connexin hemi-channels, TRPC1/4/5, L-type channels or NCX had no effect on background entry. In conclusion, raising external Ca2+ induces waves via a background Ca2+ influx through TRPC6 channels. The greater propensity to waves in HF results from increased background entry and decreased threshold SR content. KEY POINTS: Heart failure is a pro-arrhythmic state and arrhythmias are a major cause of death. At the cellular level, Ca2+ waves resulting in delayed after-depolarisations are a key trigger of arrhythmias. Ca2+ waves arise when the sarcoplasmic reticulum (SR) becomes overloaded with Ca2+ . We investigate the mechanism by which raising external Ca2+ causes waves, and how this is modified in heart failure. We demonstrate that a novel sarcolemmal background Ca2+ influx via the TRPC6 channel is responsible for SR Ca2+ overload and Ca2+ waves. The increased propensity for Ca2+ waves in heart failure results from an increase of background influx, and a lower threshold SR content. The results of the present study highlight a novel mechanism by which Ca2+ waves may arise in heart failure, providing a basis for future work and novel therapeutic targets.

Project description:Aim: Dysfunction of the cardiac ryanodine receptor (RyR2) is an almost ubiquitous finding in animal models of heart failure (HF) and results in abnormal Ca2+ release in cardiomyocytes that contributes to contractile impairment and arrhythmias. We tested whether exercise training (ET), as recommended by current guidelines, had the potential to stabilize RyR2-dependent Ca2+ release in rats with post-myocardial infarction HF. Materials and Methods: We subjected male Wistar rats to left coronary artery ligation or sham operations. After 1 week, animals were characterized by echocardiography and randomized to high-intensity interval ET on treadmills or to sedentary behavior (SED). Running speed was adjusted based on a weekly VO2max test. We repeated echocardiography after 5 weeks of ET and harvested left ventricular cardiomyocytes for analysis of RyR2-dependent systolic and spontaneous Ca2+ release. Phosphoproteins were analyzed by Western blotting, and beta-adrenoceptor density was quantified by radioligand binding. Results: ET increased VO2max in HF-ET rats to 127% of HF-SED (P < 0.05). This coincided with attenuated spontaneous SR Ca2+ release in left ventricular cardiomyocytes from HF-ET but also reduced Ca2+ transient amplitude and slowed Ca2+ reuptake during adrenoceptor activation. However, ventricular diameter and fractional shortening were unaffected by ET. Analysis of Ca2+ homeostasis and major proteins involved in the regulation of SR Ca2+ release and reuptake could not explain the attenuated spontaneous SR Ca2+ release or reduced Ca2+ transient amplitude. Importantly, measurements of beta-adrenoceptors showed a normalization of beta1-adrenoceptor density and beta1:beta2-adrenoceptor ratio in HF-ET. Conclusion: ET increased aerobic capacity in post-myocardial infarction HF rats and stabilized RyR2-dependent Ca2+ release. Our data show that these effects of ET can be gained without major alterations in SR Ca2+ regulatory proteins and indicate that future studies should include upstream parts of the sympathetic signaling pathway.

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

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Ca<sup>2+</sup> Cycling Impairment in Heart Failure Is Exacerbated by Fibrosis: Insights Gained From Mechanistic Simulations.

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