What is the clinical evidence from this study?

Study design: Other. Population: Metabolic Syndrome (n=63). Intervention: MetS-VLDL (Very-low-density lipoprotein from metabolic syndrome individuals) vs. Saline (Control) and Normal-VLDL. Primary outcome: PR interval duration (msec) (p=0.014).

September 15, 2017Open Access

Very-Low-Density Lipoprotein of Metabolic Syndrome Modulates Gap Junctions and Slows Cardiac Conduction

Q: What does this research mean for the field?

Very-low-density lipoproteins from individuals with metabolic syndrome delay cardiac conduction and prolong PR intervals by downregulating and enhancing O-GlcNAcylation of gap junction proteins Cx40 and Cx43. Novelty: ClaimNovelty.NOVEL_FINDING. Consensus alignment: ConsensusAlignment.NEUTRAL.

Key Result

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.

Structured PICO

Does VLDL from individuals with metabolic syndrome slow cardiac conduction and modulate gap junctions in a mouse model?

Population

C57BL/6 mice

Intervention

Injection of VLDL separated from individuals with Metabolic Syndrome (MetS-VLDL) at 15 µg/g for 6 weeks

Comparator

Injection of VLDL from normal individuals (Normal-VLDL) at 15 µg/g or equivalent volumes of saline (CTL) for 6 weeks

Outcome

Electrocardiographic parameters (P wave, PR interval, QRS duration, QTc interval) and cardiac conduction via optical mappingsurrogate

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.

Main Result

Absolute Event Rate: 71.4% vs 47.4%

p-value: p=0.014

Limitations

Potential immune response in mice against the injected foreign (human) VLDL cannot be excluded.
Unavailability of data regarding VLDL particle size, VLDL levels after injection, and lipidomics of the VLDL samples used.

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.

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