Diet-induced pre-diabetes slows cardiac conductance and promotes arrhythmogenesis

Cardiovascular Diabetology

Morten Schak Nielsen⁶  Niels-Henrik Holstein-Rathlou⁶  Lars Bo Nielsen⁴  Thomas Jespersen⁶  Ulrik Baandrup⁵  Emil D. Bartels⁴  Kristine Boisen Olsen³  Christa Funch Jensen⁶  Bo Liang⁶  Johannes Pauli Hofgaard⁶  Mads Riemann⁶  Thomas Hartig Braunstein²  Kirstine Calloe¹  Lene Nygaard Axelsen⁶ 

[1] Department of Veterinary Clinical and Animal Sciences, University of Copenhagen, Copenhagen, Denmark;Department of Biomedical Sciences, Faculty of Health and Medical Sciences, Core Facility for Integrated Microscopy, University of Copenhagen, Copenhagen, Denmark;Department of Forensic Medicine, Section of Forensic Pathology, University of Copenhagen, Copenhagen, Denmark;Department of Clinical Biochemistry, Rigshospitalet, Copenhagen, Denmark;Centre for Clinical Research, Vendsyssel Hospital/Department of Clinical Medicine, Aalborg University, Aalborg, Denmark;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

关键词: Conduction velocity;    Gap junctions;    Arrhythmias;    Electrophysiology;    Diabetes;   

Others  :  1219967
DOI  :  10.1186/s12933-015-0246-8

 received in 2015-02-20, accepted in 2015-06-11,  发布年份 2015

【 摘 要 】

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 re-perfussion. 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).

Conclusion

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.

【 授权许可】

   
2015 Axelsen et al.

【 图 表 】

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