Basic/Translational Science -> Whole Animal Electrophysiology and Pharmacology (includes Neurohumoral Modulation) D-AB20 - New Mechanistic Insights on Arrhythmia Initiation and Perpetuation (ID 40) Abstract

D-AB20-05 - The Vascular Endothelial Barrier: A Novel Therapeutic Target For Preventing Atrial Fibrillation (ID 1446)


Background: Atrial fibrillation (AF) is associated with inflammation and vascular dysfunction. AF patients have elevated levels of vascular endothelial growth factor (VEGF; 90-580 pg/ml), which promotes vascular leak and edema. We have previously identified edema-induced disruption of sodium channel (NaV1.5) -rich intercalated disk (ID) nanodomains as a novel arrhythmia mechanism.
Objective: (i) Elevated VEGF levels promote AF by disrupting ID nanodomains, and slowing atrial conduction. (ii) Protection of the vascular barrier can prevent these arrhythmias.
Methods: Combined with results.
Results: Clinically-relevant VEGF levels (500 pg/ml, 60 minutes) increased FITC-dextran extravasation (99.3% vs. 24.3% in vehicle controls) in WT mouse hearts, consistent with increased vascular leak. Electron microscopy revealed ID nanodomain swelling, near both gap junctions (perinexi; 64±9nm vs 17±1nm) and mechanical junctions (63±4nm vs 27±2nm) in VEGF-treated hearts relative to controls. Super-resolution STORM microscopy revealed NaV1.5 enrichment at perinexi (9±2 fold) and N-cadherin-rich sites (7±1 fold) relative to non-junctional ID sites in control hearts. VEGF reduced NaV1.5 enrichment at both sites (6±1 and 4±1 fold, respectively), consistent with NaV1.5 translocation from ID nanodomains. Atrial conduction, assessed by optical mapping, was slowed by VEGF (10±0.4 cm/s vs 21.3±1.3 cm/s at baseline). VEGF increased atrial arrhythmia burden both ex vivo (80% vs 0% in vehicle controls) and in vivo (70% vs 20% in vehicle controls). Vascular-specific heterozygous deletion of VEGF-receptor-2 shortened VEGF-induced atrial arrhythmias (4.3±0.9s vs. 10.2±6.6s in WT). Next, we tested two strategies shown to prevent vascular barrier breakdown. Blocking connexin43 hemichannels (αCT11 peptide) decreased both incidence (40%) and duration (1.45±3.42s) of VEGF-induced arrhythmias. Likewise, blocking pannexin1 channels (Panx1-IL2 peptide) dose-dependently shortened VEGF-induced arrhythmias (3.02±3.78s with 0.16µM Panx1 and 2.48±0.83s with 0.8µM Panx1).
Conclusion: These results highlight VEGF-induced vascular leak as a novel mechanism for AF, and suggest vascular barrier protection as an anti-arrhythmic strategy.