title: Hyperleptinemia Exacerbates High-Fat Diet-Mediated Atrial Fibrosis and Fibrillation.
abstract: BACKGROUND
  Obesity including metabolic syndrome is an independent risk factor of atrial fibrillation (AF). Although hyperleptinemia is usually a characteristic of obese subjects, the relationship with atrial fibrosis and AF is unknown. We tested the hypothesis that high-fat diet (HFD)-induced hyperleptinemia exacerbates atrial fibrosis and AF.
  
  
  RESULTS
  Eight-week-old male C57BL/6 (WT) and leptin-deficient ob/ob (Ob) mice were treated with a normal-fat diet (NFD) or 60% HFD. After 8 weeks, transesophageal burst pacing and electrophysiological study using isolated perfused hearts were performed and left atrial (LA) tissues were collected for histological analysis, hydroxyproline assay, and reverse transcription-polymerase chain reaction. HFD treatment increased body weight in both WT and Ob mice compared with NFD (both P < 0.01). In WT-HFD mice, hyperleptinemia was observed as expected. While transesophageal burst pacing invariably induced AF (8/8, 100%) in WT-HFD mice, AF was induced less frequently (1/8, 12.5%) in Ob-HFD mice (P < 0.01). In isolated perfused hearts, the interatrial conduction time was prolonged in WT-HFD mice, but not in Ob-HFD mice (P < 0.05). Masson's trichrome staining and the hydroxyproline assay revealed interstitial LA fibrosis in WT-HFD mice, which was not observed in Ob-HFD mice (P < 0.05). Upregulation of collagen1, collagen3, α-smooth muscle actin, tumor necrosis factor-α, and monocyte chemoattractant protein-1 mRNA levels was noted in WT-HFD mice LA, but attenuated in Ob-HFD mice LA.
  
  
  CONCLUSIONS
  Our findings suggest that hyperleptinemia exacerbates HFD-mediated atrial fibrosis and AF. Inhibition of leptin signaling may become a novel therapeutic target to prevent obesity-related AF.
authors.affiliation: Department of Cardiology and Clinical Examination, Oita University Faculty of Medicine, Oita, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Fukui
authors.affiliation: Department of Cardiology and Clinical Examination, Oita University Faculty of Medicine, Oita, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Ikebe-Ebata
authors.affiliation: Department of Cardiology and Clinical Examination, Oita University Faculty of Medicine, Oita, Japan.
authors.forename: Hidekazu
authors.initials: H
authors.lastname: Kondo
authors.affiliation: Department of Cardiology and Clinical Examination, Oita University Faculty of Medicine, Oita, Japan.
authors.forename: Shotaro
authors.initials: S
authors.lastname: Saito
authors.affiliation: Department of Endocrinology, Metabolism, Rheumatology and Nephrology, Oita University Faculty of Medicine, Oita, Japan.
authors.forename: Kohei
authors.initials: K
authors.lastname: Aoki
authors.affiliation: Department of Endocrinology, Metabolism, Rheumatology and Nephrology, Oita University Faculty of Medicine, Oita, Japan.
authors.forename: Naoya
authors.initials: N
authors.lastname: Fukunaga
authors.affiliation: Department of Cardiology and Clinical Examination, Oita University Faculty of Medicine, Oita, Japan.
authors.forename: Tetsuji
authors.initials: T
authors.lastname: Shinohara
authors.affiliation: Department of Endocrinology, Metabolism, Rheumatology and Nephrology, Oita University Faculty of Medicine, Oita, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Masaki
authors.affiliation: Department of Cardiology and Clinical Examination, Oita University Faculty of Medicine, Oita, Japan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Teshima
authors.affiliation: Department of Cardiology and Clinical Examination, Oita University Faculty of Medicine, Oita, Japan.
authors.forename: Naohiko
authors.initials: N
authors.lastname: Takahashi
mesh_terms: D000199:Actins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001281:Atrial Fibrillation / Q000097:blood / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology; D015415:Biomarkers / Q000097:blood; D002304:Cardiac Pacing, Artificial; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D003094:Collagen / Q000235:genetics / Q000378:metabolism; D059305:Diet, High-Fat / Q000009:adverse effects*; D004195:Disease Models, Animal; D005355:Fibrosis; D006325:Heart Atria / Q000473:pathology / Q000503:physiopathology; D006339:Heart Rate; D006909:Hydroxyproline / Q000378:metabolism; D000067268:Isolated Heart Preparation; D020738:Leptin / Q000097:blood*; D008297:Male; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D009765:Obesity / Q000097:blood / Q000150:complications*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D000199:Actins; D015415:Biomarkers; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D020738:Leptin; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; C544013:alpha-smooth muscle actin, mouse; D003094:Collagen; D006909:Hydroxyproline
keywords: atrial fibrillation; atrial fibrosis; inflammation; leptin; obesity