title: Diet-induced pre-diabetes slows cardiac conductance and promotes arrhythmogenesis.
abstract: BACKGROUND
  Type 2 diabetes is associated with abnormal electrical conduction and sudden cardiac death, but the pathogenic mechanism remains unknown. This study describes electrophysiological alterations in a diet-induced pre-diabetic rat model and examines the underlying mechanism.
  
  
  METHODS
  Sprague-Dawley rats were fed either high-fat diet and fructose water or normal chow and water for 6 weeks. The electrophysiological properties of the whole heart was analyzed by in vivo surface ECG recordings, as wells as ex vivo in Langendorff perfused hearts during baseline, ischemia and reperfussion. Conduction velocity was examined in isolated tissue strips. Ion channel and gap junction conductances were analyzed by patch-clamp studies in isolated cardiomyocytes. Fibrosis was examined by Masson's Trichrome staining and thin-layer chromatography was used to analyze cardiac lipid content. Connexin43 (Cx43) expression and distribution was examined by western blotting and immunofluorescence respectively.
  
  
  RESULTS
  Following 6 weeks of feeding, fructose-fat fed rats (FFFRs) showed QRS prolongation compared to controls (16.1 ± 0.51 (n = 6) vs. 14.7 ± 0.32 ms (n = 4), p < 0.05). Conduction velocity was slowed in FFFRs vs. controls (0.62 ± 0.02 (n = 13) vs. 0.79 ± 0.06 m/s (n = 11), p < 0.05) and Langendorff perfused FFFR hearts were more prone to ventricular fibrillation during reperfusion following ischemia (p < 0.05). The patch-clamp studies revealed no changes in Na(+) or K(+) currents, cell capacitance or gap junctional coupling. Cx43 expression was also unaltered in FFFRs, but immunofluorescence demonstrated an increased fraction of Cx43 localized at the intercalated discs in FFFRs compared to controls (78 ± 3.3 (n = 5) vs. 60 ± 4.2 % (n = 6), p < 0.01). No fibrosis was detected but FFFRs showed a significant increase in cardiac triglyceride content (1.93 ± 0.19 (n = 12) vs. 0.77 ± 0.13 nmol/mg (n = 12), p < 0.0001).
  
  
  CONCLUSIONS
  Six weeks on a high fructose-fat diet cause electrophysiological changes, which leads to QRS prolongation, decreased conduction velocity and increased arrhythmogenesis during reperfusion. These alterations are not explained by altered gap junctional coupling, Na(+), or K(+) currents, differences in cell size or fibrosis.
authors.affiliation: Department of Biomedical Sciences, Faculty of Health and Medical Sciences, The Danish National Research Foundation Centre for Cardiac Arrhythmia, University of Copenhagen, Blegdamsvej 3B, Copenhagen, N DK-2200, Denmark. lax@sund.ku.dk.
authors.forename: Lene Nygaard
authors.initials: LN
authors.lastname: Axelsen
authors.affiliation: Department of Veterinary Clinical and Animal Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Kirstine
authors.initials: K
authors.lastname: Calloe
authors.affiliation: Department of Biomedical Sciences, Faculty of Health and Medical Sciences, Core Facility for Integrated Microscopy, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Thomas Hartig
authors.initials: TH
authors.lastname: Braunstein
authors.affiliation: Department of Biomedical Sciences, Faculty of Health and Medical Sciences, The Danish National Research Foundation Centre for Cardiac Arrhythmia, University of Copenhagen, Blegdamsvej 3B, Copenhagen, N DK-2200, Denmark.
authors.forename: Mads
authors.initials: M
authors.lastname: Riemann
authors.affiliation: Department of Biomedical Sciences, Faculty of Health and Medical Sciences, The Danish National Research Foundation Centre for Cardiac Arrhythmia, University of Copenhagen, Blegdamsvej 3B, Copenhagen, N DK-2200, Denmark.
authors.forename: Johannes Pauli
authors.initials: JP
authors.lastname: Hofgaard
authors.affiliation: Department of Biomedical Sciences, Faculty of Health and Medical Sciences, The Danish National Research Foundation Centre for Cardiac Arrhythmia, University of Copenhagen, Blegdamsvej 3B, Copenhagen, N DK-2200, Denmark.
authors.forename: Bo
authors.initials: B
authors.lastname: Liang
authors.affiliation: Department of Biomedical Sciences, Faculty of Health and Medical Sciences, The Danish National Research Foundation Centre for Cardiac Arrhythmia, University of Copenhagen, Blegdamsvej 3B, Copenhagen, N DK-2200, Denmark.
authors.forename: Christa Funch
authors.initials: CF
authors.lastname: Jensen
authors.affiliation: Department of Forensic Medicine, Section of Forensic Pathology, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Kristine Boisen
authors.initials: KB
authors.lastname: Olsen
authors.affiliation: Department of Clinical Biochemistry, Rigshospitalet, Copenhagen, Denmark.
authors.forename: Emil D
authors.initials: ED
authors.lastname: Bartels
authors.affiliation: Centre for Clinical Research, Vendsyssel Hospital/Department of Clinical Medicine, Aalborg University, Aalborg, Denmark.
authors.forename: Ulrik
authors.initials: U
authors.lastname: Baandrup
authors.affiliation: Department of Biomedical Sciences, Faculty of Health and Medical Sciences, The Danish National Research Foundation Centre for Cardiac Arrhythmia, University of Copenhagen, Blegdamsvej 3B, Copenhagen, N DK-2200, Denmark.
authors.forename: Thomas
authors.initials: T
authors.lastname: Jespersen
authors.affiliation: Department of Biomedical Sciences, Faculty of Health and Medical Sciences, The Danish National Research Foundation Centre for Cardiac Arrhythmia, University of Copenhagen, Blegdamsvej 3B, Copenhagen, N DK-2200, Denmark.|Department of Clinical Biochemistry, Rigshospitalet, Copenhagen, Denmark.
authors.forename: Lars Bo
authors.initials: LB
authors.lastname: Nielsen
authors.affiliation: Department of Biomedical Sciences, Faculty of Health and Medical Sciences, The Danish National Research Foundation Centre for Cardiac Arrhythmia, University of Copenhagen, Blegdamsvej 3B, Copenhagen, N DK-2200, Denmark.
authors.forename: Niels-Henrik
authors.initials: NH
authors.lastname: Holstein-Rathlou
authors.affiliation: Department of Biomedical Sciences, Faculty of Health and Medical Sciences, The Danish National Research Foundation Centre for Cardiac Arrhythmia, University of Copenhagen, Blegdamsvej 3B, Copenhagen, N DK-2200, Denmark.
authors.forename: Morten Schak
authors.initials: MS
authors.lastname: Nielsen
mesh_terms: D000818:Animals; D001145:Arrhythmias, Cardiac / Q000503:physiopathology*; D018031:Connexin 43 / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000503:physiopathology; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D004562:Electrocardiography; D005632:Fructose; D017629:Gap Junctions / Q000378:metabolism; D006329:Heart Conduction System / Q000503:physiopathology*; D008297:Male; D009200:Myocardial Contraction; D017202:Myocardial Ischemia / Q000503:physiopathology*; D015425:Myocardial Reperfusion; D009206:Myocardium / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D015221:Potassium Channels / Q000378:metabolism; D011236:Prediabetic State / Q000503:physiopathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015222:Sodium Channels / Q000378:metabolism; D014280:Triglycerides / Q000378:metabolism
chemical_list: D018031:Connexin 43; C580592:Gja1 protein, rat; D015221:Potassium Channels; D015222:Sodium Channels; D014280:Triglycerides; D005632:Fructose