Platelet CFTR inhibition enhances arterial thrombosis via increasing intracellular Cl- concentration and activation of SGK1 signaling pathway.

Platelet hyperactivity is essential for thrombus formation in coronary artery diseases (CAD). Dysfunction of the cystic fibrosis transmembrane conductance regulator (CFTR) in patients with cystic fibrosis elevates intracellular Cl- levels ([Cl-]i) and enhanced platelet hyperactivity. In this study, we explored whether alteration of [Cl-]i has a pathological role in regulating platelet hyperactivity and arterial thrombosis formation. CFTR expression was significantly decreased, while [Cl-]i was increased in platelets from CAD patients. In a FeCl3-induced mouse mesenteric arteriole thrombosis model, platelet-specific Cftr-knockout and/or pre-administration of ion channel inhibitor CFTRinh-172 increased platelet [Cl-]i, which accelerated thrombus formation, enhanced platelet aggregation and ATP release, and increased P2Y12 and PAR4 expression in platelets. Conversely, Cftr-overexpressing platelets resulted in subnormal [Cl-]i, thereby decreasing thrombosis formation. Our results showed that clamping [Cl-]i at high levels or Cftr deficiency-induced [Cl-]i increasement dramatically augmented phosphorylation (Ser422) of serum and glucocorticoid-regulated kinase (SGK1), subsequently upregulated P2Y12 and PAR4 expression via NF-κB signaling. Constitutively active mutant S422D SGK1 markedly increased P2Y12 and PAR4 expression. The specific SGK1 inhibitor GSK-650394 decreased platelet aggregation in wildtype and platelet-specific Cftr knockout mice, and platelet SGK1 phosphorylation was observed in line with increased [Cl-]i and decreased CFTR expression in CAD patients. Co-transfection of S422D SGK1 and adenovirus-induced CFTR overexpression in MEG-01 cells restored platelet activation signaling cascade. Our results suggest that [Cl-]i is a novel positive regulator of platelet activation and arterial thrombus formation via the activation of a [Cl-]i-sensitive SGK1 signaling pathway. Therefore, [Cl-]i in platelets is a novel potential biomarker for platelet hyperactivity, and CFTR may be a potential therapeutic target for platelet activation in CAD.

Successful treatment of complex coronary chronic total occlusions improves midterm outcomes.

BACKGROUND: Data regarding outcomes of percutaneous coronary intervention (PCI) in patients with chronic total occlusion (CTO) is still limited. Our aim was to evaluate clinical outcomes in patients after successful CTO PCI when compared to patients with failed PCI. METHODS: The cohort study enrolled 145 eligible patients with attempted PCI of CTO. Detailed baseline clinical and procedural data, and in-hospital complications were analyzed. The primary end point was occurrence of major adverse cardiac events (MACE). RESULTS: Median follow-up was 11.49±2.01 months. Successful revascularization was associated with a significantly lower 1-year MACE compared to failed revascularization [hazard ratio (HR): 0.026; 95% confidence interval (CI): 0.004-0.176; P=0.0002]. A J-CTO score of ≥3 was associated with a significantly higher 1-year MACE compared with a J-CTO score of <3 in patients undergoing PCI (HR: 4.819; 95% CI: 1.463-15.870; P=0.0097). Moreover, in patients with a J-CTO score ≥3, success of CTO PCI was associated with significantly lower risk of 1-year MACE than failure of CTO revascularization (HR: 0.114; 95% CI: 0.023-0.569; P=0.0081). Multivariate analysis identified the J-CTO score (HR: 2.10; 95% CI: 1.09-4.04; P=0.026) as a positive predictor, and the success of CTO PCI (HR: 0.17; 95% CI: 0.05-0.59; P=0.005) as a negative significant independent predictor of MACEs. CONCLUSIONS: Among patients with CTOs, high J-CTO score was independently associated with worse clinical outcomes. Furthermore, successful PCI was associated with a lower risk of midterm MACE compared with failed revascularization of CTOs.