Abstract
Metabolic syndrome-mediated heart failure with preserved ejection fraction (HFpEF) is commonly accompanied by left atrial (LA) cardiomyopathy, significantly affecting morbidity and mortality. We evaluate the role of reactive oxygen species (ROS) and intrinsic inflammation (TNF-α, IL-10) related to dysfunctional Ca2+ homeostasis of LA cardiomyocytes in a rat model of metabolic HFpEF. ZFS-1 obese rats showed features of HFpEF and atrial cardiomyopathy in vivo: increased left ventricular (LV) mass, E/e’ and LA size and preserved LV ejection fraction. In vitro, LA cardiomyocytes exhibited more mitochondrial-fission (MitoTracker) and ROS-production (H2DCF). In wildtype (WT), pro-inflammatory TNF-α impaired cellular Ca2+ homeostasis, while anti-inflammatory IL-10 had no notable effect (confocal microscopy; Fluo-4). In HFpEF, TNF-α had no effect on Ca2+ homeostasis associated with decreased TNF-α receptor expression (western blot). In addition, IL-10 substantially improved Ca2+ release and reuptake, while IL-10 receptor-1 expression was unaltered. Oxidative stress in metabolic syndrome mediated LA cardiomyopathy was increased and anti-inflammatory treatment positively affected dysfunctional Ca2+ homeostasis. Our data indicates, that patients with HFpEF-related LA dysfunction might profit from IL-10 targeted therapy, which should be further explored in preclinical trials.
Highlights
In heart failure (HF) with preserved ejection fraction (HFpEF), patients suffer from typical HF symptoms, while presenting normal left ventricular ejection fraction (>50%)
We have previously identified neurohumoral activation and paracrine activation through the fibroblast secretome as pivotal disruptors of Ca2+ handling in metabolic heart failure with preserved ejection fraction (HFpEF)-related left atrial cardiomyopathy [19,20]
We investigate the role of myocardial inflammation through TNF-α/interleukin-10 (IL-10) signaling for dysfunctional Ca2+ cycling of cardiomyocytes in a rat model of metabolic
Summary
In heart failure (HF) with preserved ejection fraction (HFpEF), patients suffer from typical HF symptoms (i.e., dyspnea, reduced exercise capacity), while presenting normal left ventricular ejection fraction (>50%). HFpEF is increasingly prevalent and currently accounts for approximately half of all HF patients [1]. The prevalence of co-morbidities which are marked by endothelial dysfunction and systemic inflammation, such as obesity, diabetes mellitus type 2, arterial hypertension, dyslipidemia and renal dysfunction, is strikingly high amongst HFpEF patients [5]. Mechanical stress and systemic inflammation have been shown stimulate the production of reactive oxygen species (ROS) of cardiac endothelial cells in HFpEF with detrimental effects on adverse myocardial remodeling and cardiac contractility [6,7,8]
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