Description:
Introduction: Heart failure with preserved ejection fraction (HFpEF) is present in ~50% of all heart failure (HF) patients. Left atrial (LA) dysfunction is common in HFpEF patients and associated with increased mortality. We hypothesized, that atrial dysfunction in-vivo is related to alterations of Ca2+ signaling in cardiomyocytes in-vitro. We investigated the role of neuro-humoral activation via angiotensin II (AT2) and paracrine activity of the fibroblast secretome as potential contributors to dysregulated Ca2+ signaling. Methods: 21- and 27 weeks- old ZSF-1 rats with a leptin receptor mutation and fed with a high caloric diet served as an HF model. Diseased rats showed a lean (heterozygous; hypertensive heart disease (HHD)) or obese (homozygous; HFpEF) phenotype. LA were imaged by echocardiography. LA myocytes were isolated using a novel Langendorff-based approach. Excitation-contraction-coupling (ECC) was assessed using Ca2+-sensitive fluorescent indicators, confocal imaging (cytosol, nucleus) and video edge detection. Myocardial fibrosis was quantified in histologic sections. Conditioned medium (CM) of primary cardiac fibroblasts was acquired after stretch. CM and LA tissue were screened for various cytokines with enzyme-linked immunosorbent assays. Results: HHD showed preserved LA size and ejection fraction (EF) vs. wild type (WT). In LA myocytes from HHD, amplitude of cytosolic calcium transients (CaT) was increased. Sarcoplasmic reticulum (SR) Ca2+ content was preserved while Ca2+ spark frequency and tetracaine-dependent SR Ca2+ leak were increased. In HFpEF, LA area was significantly increased and LA EF was impaired. However, atrial myocytes from HFpEF showed increased CaT amplitude and enhanced contractile performance in vitro. CaT kinetics and SR Ca2+ in HFpEF were not significantly different vs. WT, but SR Ca2+ leak remained increased. AT2 reduced cytosolic CaT amplitudes and enhanced nuclear Ca2+ release in HFpEF. No structural alterations of fibrosis could be detected in HHD or HFpEF. Upon ...