title: Alogliptin, a dipeptidyl peptidase-4 inhibitor, regulates the atrial arrhythmogenic substrate in rabbits.
abstract: BACKGROUND
  Dipeptidyl peptidase-4 (DPP-4) inhibitors were recently reported to have cardioprotective effects via amelioration of ventricular function. However, the role of DPP-4 inhibition in atrial remodeling, especially of the arrhythmogenic substrate, remains unclear.
  
  
  OBJECTIVE
  We investigated the effects of a DPP-4 inhibitor, alogliptin, on atrial fibrillation (AF) in a rabbit model of heart failure caused by ventricular tachypacing (VTP).
  
  
  METHODS
  Rabbits subjected to VTP at 380 bpm for 1 or 3 weeks, with or without alogliptin treatment, were assessed using echocardiography, electrophysiology, histology, and immunoblotting and compared with nonpaced animals.
  
  
  RESULTS
  VTP rabbits exhibited increased duration of atrial burst pacing-induced AF, whereas administration of alogliptin shortened this duration by 73%. The extent of atrial fibrosis after VTP was reduced by 39% in the alogliptin-treated group. VTP rabbits treated with alogliptin displayed a 1.6-fold increase in left atrial myocardial capillary density compared with nontreated rabbits. A 2-fold increase in endothelial nitric oxide synthase (eNOS) phosphorylation was observed in the left atrium of alogliptin-treated rabbits compared with nontreated rabbits. Moreover, a nitric oxide synthase inhibitor (N(ω)-nitro-l-arginine methyl ester) blocked the beneficial effects of alogliptin on AF duration, fibrosis, and capillary density.
  
  
  CONCLUSIONS
  Alogliptin shortened the duration of AF caused by VTP-induced fibrotic atrial tissue by augmenting atrial angiogenesis and activating eNOS. Our findings suggest that DPP-4 inhibitors may be useful in the prevention of heart failure-induced AF.
authors.affiliation: Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Yamamoto
authors.affiliation: Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan; Nagoya First Red Cross Hospital, Nagoya, Japan. Electronic address: mshimano@med.nagoya-u.ac.jp.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Shimano
authors.affiliation: Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Yasuya
authors.initials: Y
authors.lastname: Inden
authors.affiliation: Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Mikito
authors.initials: M
authors.lastname: Takefuji
authors.affiliation: Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Yanagisawa
authors.affiliation: Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Yoshida
authors.affiliation: Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
authors.forename: Yukiomi
authors.initials: Y
authors.lastname: Tsuji
authors.affiliation: Nagoya University Graduate School of Health Science, Nagoya, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Hirai
authors.affiliation: Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Toyoaki
authors.initials: T
authors.lastname: Murohara
mesh_terms: D000818:Animals; D001281:Atrial Fibrillation / Q000503:physiopathology / Q000517:prevention & control*; D015153:Blotting, Western; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / Q000037:antagonists & inhibitors*; D004452:Echocardiography; D004594:Electrophysiology; D004727:Endothelium / Q000201:enzymology; D004797:Enzyme-Linked Immunosorbent Assay; D005355:Fibrosis / Q000473:pathology; D005455:Fluorescent Antibody Technique; D006325:Heart Atria / Q000201:enzymology / Q000473:pathology; D006333:Heart Failure / Q000517:prevention & control; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D018919:Neovascularization, Physiologic / Q000187:drug effects; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D010766:Phosphorylation; D010880:Piperidines / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D011817:Rabbits; D017180:Tachycardia, Ventricular / Q000150:complications; D014498:Uracil / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000494:pharmacology
chemical_list: D010880:Piperidines; D014498:Uracil; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; C520853:alogliptin; D019331:NG-Nitroarginine Methyl Ester
keywords: Atrial arrhythmogenic substrate; Atrial fibrillation; Atrial fibrosis; Atrial neovascularization; DPP-4 inhibitor