Primary catheter ablation is an increasingly used therapeutic strategy for the management of atrial fibrillation. In this consensus statement, the National Heart Foundation of Australia presents general recommendations to health care providers to assist them in the care of these patients.

BACKGROUND: Despite antiplatelet therapy, some patients remain at high ischemic risk because of drug nonresponsiveness or high residual platelet reactivity. We aimed to target an orphan platelet GPCR (G protein–coupled receptor) from the OR (olfactory receptor) family as a novel antithrombotic strategy. METHODS: Using an engineered reporter cell line expressing human OR2L13 , an orphan GPCR implicated in limiting platelet reactivity, we conducted a high-throughput screen of 8000 nonodorant bioactive compounds with counterscreen validation. Subsequent studies assessed platelet function in healthy subjects and patients with coronary artery and peripheral artery disease. Phospho-proteomics revealed key signaling pathways, whereas ex vivo and in vivo studies evaluated the impact of a lead compound on platelet signaling, biomechanics, and thrombosis in both arterial and venous vasculature. RESULTS: We identified 6 OR2L13 (olfactory receptor family 2 subfamily L member 13)-specific agonists that suppressed platelet aggregation and α-granule exocytosis through multiple receptors, suggesting a shared downstream mediator. The lead agonist (CCF0054500) phosphorylated platelet HSP27 (heat shock protein 27), disrupting the actin cytoskeleton and reducing clot retraction (clot area, 70.6 versus 5.2; P <0.0001), an effect reversed by HSP27 inhibition. In a murine arterial injury model, CCF0054500 decreased platelet accumulation by 88.9% ( P <0.0003) without affecting fibrin generation or hemostasis. In a myocardial infarction model with high residual platelet reactivity, CCF0054500 lowered platelet reactivity ( P <0.0001) and improved left ventricular function ( P =0.007). CONCLUSIONS: We describe and characterize the first nonolfactory probe for the purpose of inhibiting platelet activation and thrombosis through downstream HSP27 in a comprehensive investigation using a first-of-its-kind platelet inhibitor targeting an orphan platelet GPCR.

Background: Intervention for patients with symptomatic varicose veins is largely driven by a combination of symptoms, the magnitude of venous reflux, clinical severity scoring algorithms, and unresponsiveness to conservative medical therapy. Our goal was to evaluate biological features of superficial veins from patients with symptomatic varicose veins, comparing these to healthy veins for biological insight into the progression of superficial vein disease. Methods: RNA was extracted from incompetent great saphenous veins at the time of phlebectomy and compared with residual healthy superficial veins from patients following coronary artery bypass graft surgery. The venous wall transcriptome was interrogated by NanoString. PANTHER and Gene Ontology identified biological pathways of interest. Based on these data, plasma biomarkers from patients with varicose veins or matched controls were evaluated. Results: Multiple genes were upregulated and downregulated for pathways involving angiogenesis, collagen biosynthesis, and inflammation. COL1A1 was upregulated in varicose veins by fourfold, and interleukin-6 ( IL-6 ) was downregulated by 21-fold. The blood IL-6 concentration was higher in the validation cohort of patients with varicose veins compared with relatively healthy patients (4.8 vs 1.3 pg/mL, p = 0.0085). Blood collagen 1A1 (COL1A1) was lower in patients with varicose veins compared with healthy patients (66,355 vs 82,661 pg/mL, p = 0.0497). A positive association was observed between circulating COL1A1 concentration and the Venous Clinical Severity Score, suggesting its potential utility as a prognostic biomarker for pathological great saphenous vein remodeling in patients with varicose veins. Conclusions: This hypothesis-generating study revealed that blood COL1A1 and IL-6 concentrations may be blood biomarkers used as additional objective data that may indicate adverse vein remodeling in patients with varicose veins.