MetS-VLDL significantly prolonged PR intervals and delayed cardiac conduction in mice by downregulating and enhancing O-GlcNAcylation of gap junction proteins Cx40 and Cx43.
Does VLDL from individuals with metabolic syndrome slow cardiac conduction and modulate gap junctions in a mouse model?
VLDL from patients with metabolic syndrome delays cardiac conduction and downregulates gap junction proteins in mice, providing a potential mechanism for increased arrhythmia risk in metabolic syndrome.
Absolute Event Rate: 71.4% vs 47.4%
p-value: p=0.014
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.
Lee et al. (2017) studied Metabolic Syndrome (n=63). MetS-VLDL (Very-low-density lipoprotein from metabolic syndrome individuals) vs. Saline (Control) and Normal-VLDL was evaluated on PR interval duration (msec) (p=0.014). MetS-VLDL significantly prolonged PR intervals and delayed cardiac conduction in mice by downregulating and enhancing O-GlcNAcylation of gap junction proteins Cx40 and Cx43.