Abstract-Oxidative stress plays a pivotal role in the pathogenesis of atherosclerosis and can be effectively influenced by radical scavenging enzyme activity and expression. The vasoprotective effects of estrogens may be related to antioxidative properties. Therefore, effects of 17␤-estradiol on production of reactive oxygen species and radical scavenging enzymes were investigated. 17␤-estradiol diminished angiotensin II-induced free radical production in vascular smooth muscle cells (DCF fluorescence laser microscopy). 17␤-estradiol time-and concentration-dependently upregulated manganese (MnSOD) and extracellular superoxide dismutase (ecSOD) expression (Northern and Western blotting) and enzyme activity (photometric assay). Nuclear run-on assays demonstrated that 17␤-estradiol increases MnSOD and ecSOD transcription rate. Half-life of MnSOD mRNA was not influenced, whereas ecSOD mRNA was stabilized by estrogen. Copper-zinc SOD, glutathione-peroxidase, and catalase were not affected by estrogen. Estrogen deficiency in ovariectomized mice induced a downregulation of ecSOD and MnSOD expression, which was associated with increased production of vascular free radicals and prevented by estrogen replacement or treatment with PEG-SOD. In humans, increased estrogen levels led to enhanced ecSOD and MnSOD expression in circulating monocytes. Estrogen acts antioxidative at least to some extent via stimulation of MnSOD and ecSOD expression and activity, which may contribute to its vasoprotective effects.

Atrial fibrosis is important for the pathogenesis of atrial fibrillation (AF) but the underlying signal transduction is incompletely understood. We therefore studied the role of microRNA-21 (miR-21) and its downstream target Sprouty 1 (Spry1) during atrial fibrillation. Left atria (LA) from patients with AF showed a 2.5-fold increased expression of miR-21 compared to matched LA of patients in sinus rhythm. Increased miR-21 expression correlated positively with atrial collagen content and was associated with a reduced protein expression of Spry1 and increased expression of connective tissue growth factor (CTGF), lysyl oxidase and Rac1-GTPase. Neonatal cardiac fibroblasts treated with angiotensin II (AngII) or CTGF showed an increased miR-21 and decreased Spry1 expression. Pretreatment with an inhibitor of Rac1 GTPase, NSC23766, reduced the AngII-induced upregulation of miR-21. A small molecule inhibitor of lysyl oxidase, BAPN, prevented the AngII as well as the CTGF-induced miR-21 expression. Transgenic mice with cardiac overexpression of Rac1, which develop spontaneous AF and atrial fibrosis with increasing age, showed upregulation of miR-21 expression associated with reduced Spry1 expression. miR-21 expression and signalling in vivo were prevented by long-term treatment of the mice with statins. Direct inhibition of miR-21 by antagomir-21 prevented fibrosis of the atrial myocardium post-myocardial infarction. Left atria of patients with atrial fibrillation are characterized by upregulation of miR-21 und reduced expression of Spry1. Activation of Rac1 by angiotensin II leads to a CTGF- and lysyl oxidase-mediated increase of miR-21 expression contributing to structural remodelling of the atrial myocardium.

Chronic cardiac overexpression of Rac1 represents a novel mouse model for AF. Rac1 GTPase contributes to the pathogenesis of AF and identifies a target for the prevention and treatment of AF.

IMPORTANCE Transferring patients with large-vessel occlusion (LVO) or intracranial hemorrhage (ICH) to hospitals not providing interventional treatment options is an unresolved medical problem. OBJECTIVE To determine how optimized prehospital management (OPM) based on use of the Los Angeles Motor Scale (LAMS) compares with management in a Mobile Stroke Unit (MSU) in accurately triaging patients to the appropriate hospital with (comprehensive stroke center [CSC]) or without (primary stroke center [PSC]) interventional treatment. DESIGN, SETTING, AND PARTICIPANTS In this randomized multicenter trial with 3-month follow-up, patients were assigned week-wise to one of the pathways between June 15, 2015, and November 15, 2017, in 2 regions of Saarland, Germany; 708 of 824 suspected stroke patients did not meet inclusion criteria, resulting in a study population of 116 adult patients. INTERVENTIONS Patients received either OPM based on a standard operating procedure that included the use of the LAMS (cut point Ն4) or management in an MSU (an ambulance with vascular imaging, point-of-care laboratory, and telecommunication capabilities). MAIN OUTCOMES AND MEASURESThe primary end point was the proportion of patients accurately triaged to either CSCs (LVO, ICH) or PSCs (others).RESULTS A predefined interim analysis was performed after 116 patients of the planned 232 patients had been enrolled. Of these, 53 were included in the OPM group (67.9% women; mean [SD] age, 74 [11] years) and 63 in the MSU group (57.1% women; mean [SD] age, 75 [11] years). The primary end point, an accurate triage decision, was reached for 37 of 53 patients (69.8%) in the OPM group and for 63 of 63 patients (100%) in the MSU group (difference, 30.2%; 95% CI, 17.8%-42.5%; P < .001). Whereas 7 of 17 OPM patients (41.2%) with LVO or ICH required secondary transfers from a PSC to a CSC, none of the 11 MSU patients (0%) required such transfers (difference, 41.2%; 95% CI, 17.8%-64.6%; P = .02). The LAMS at a cut point of 4 or higher led to an accurate diagnosis of LVO or ICH for 13 of 17 patients (76.5%; 6 triaged to a CSC) and of LVO selectively for 7 of 9 patients (77.8%; 2 triaged to a CSC). Stroke management metrics were better in the MSU group, although patient outcomes were not significantly different. CONCLUSIONS AND RELEVANCEWhereas prehospital management optimized by LAMS allows accurate triage decisions for approximately 70% of patients, MSU-based management enables accurate triage decisions for 100%. Depending on the specific health care environment considered, both approaches are potentially valuable in triaging stroke patients.

The data identify CTGF as an important mediator of atrial structural remodeling during AF. Angiotensin II activates CTGF via activation of Rac1 and nicotinamide adenine dinucleotide phosphate oxidase, leading to up-regulation of Cx43, N-cadherin, and interstitial fibrosis and therefore contributing to the signal transduction of atrial structural remodeling.