Abstract
Very-low-density lipoproteins (VLDL) is a hallmark of metabolic syndrome (MetS) and each manifestation of MetS is related to atrial fibrillation (AF) risks. Slowed atrial conduction is a mechanism of AF in MetS. We hypothesized that VLDL can modulate and reduce atrial gap junctions. VLDLs were separated from normal (Normal-VLDL) and MetS (MetS-VLDL) individuals. VLDLs (15 µg/g) and equivalent volumes of saline (CTL) were injected respectively to C57BL/6 mice for 6 weeks. Electrocardiograms demonstrated that MetS-VLDL induced prolongation of P wave (P = 0.041), PR intervals (P = 0.014), QRS duration and QTc interval (both P = 0.003), but Normal-VLDL did not. Optical mapping of perfused hearts confirmed slowed conduction on atria and ventricles of MetS-VLDL mice. Slowed cardiac conduction was associated with significant atrial and ventricular remodeling, along with systolic dysfunction and comparable intra-cardiac fibrosis. MetS-VLDL induced downregulation of Cx40 and Cx43 at transcriptional, translational and tissue levels, and it also enhanced O-GlcNAcylation of Cx40 and Cx43. Protein structure analyses predicted O-GlcNAcylation at serine 18 of Cx40 and Cx43 which may impair stability of gap junctions. In conclusion, MetS-VLDL modulates gap junctions and delays both atrial and ventricular conduction. VLDL may contribute to the pathophysiology of atrial fibrillation and ventricular arrhythmias in MetS.
Highlights
Electrical conduction occurring along atria from the sinus node to the ventricles can be reflected by the PR interval in electrocardiography
In vivo metabolic syndrome (MetS)-Very-low-density lipoproteins (VLDL) resulted in prolonged P waves, PR intervals, QRS width, and QT intervals
In MetS-VLDL injection (msVLDL) mice (n = 10), P wave was significantly wider than nVLDL (n = 10) and control mice (n = 10) (Control 19.4 ± 6.4 vs nVLDL 19.3 ± 5.6 vs msVLDL 27.8 ± 12.3 msec, ANOVA P = 0.041; $p = 0.01, #p = 0.03; Fig. 1b)
Summary
Electrical conduction occurring along atria from the sinus node to the ventricles can be reflected by the PR interval in electrocardiography. Electrophysiological causes of PR interval prolongation include intra-atrial conduction defects, conduction disease in the AV node, conduction disease in the His Bundle, increased vagal tone and the presence of medicine leading to increased AV nodal conduction delay[8]. In our VLDL-injection mouse model, the atrial remodeling and AF susceptibility to sympathetic stimulation are observed with injection of MetS-VLDL, but not with injection of Normal-VLDL3. Using this model, the study was aimed to examine the hypothesis that MetS-VLDL can modulate atrial connexins expression and slow atrial conduction. Whether MetS-VLDL induces O-GlcNAcylation of Cx40 and/or Cx43 in atrial myocytes and whether O-GlcNAcylation would change the gap junction stability were assessed. The results are of general importance with respect to pathogenesis of AF in MetS
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