Background and purpose: Spain has been one of the countries heavily stricken by COVID-19. But this epidemic has not affected all regions equally. We analyzed the impact of the COVID-19 pandemic on hospital stroke admissions and in-hospital mortality in tertiary referral hospitals from North-West Spain. Methods: Spanish multicenter retrospective observational study based on data from tertiary hospitals of the NORDICTUS network. We recorded the number of patients admitted for ischemic stroke between 30 December 2019 and 3 May 2020, the number of IVT and EVT procedures, and in-hospital mortality. Results: In the study period, 2737 patients were admitted with ischemic stroke. There was a decrease in the weekly mean admitted patients during the pandemic (124 vs. 173, p<0.001). In-hospital mortality of stroke patients increased significantly (9.9% vs. 6.5%, p = 0.003), but there were no differences in the proportion of IVT (17.3% vs. 16.1%, p = 0.405) or EVT (22% vs. 23%, p = 0.504). Conclusion: We found a decrease in the number of ischemic stroke admissions and an increase in in-hospital mortality during the COVID-19 epidemic in this large study from North-West Spain. There were regional changes within the network, not fully explained by the severity of the pandemic in different regions.

Despite recent advances in treatment options, stroke remains a highly prevalent and devastating condition with significant socioeconomic impact. Recanalization therapies, including intravenous thrombolysis and endovascular treatments, have revolutionized stroke management and prognosis, providing a promising framework for exploring new therapeutic strategies. Endothelial dysfunction plays a critical role in the pathophysiology, progression, and prognosis of stroke. This review aims to synthesize the current evidence regarding the involvement of the nitric oxide (NO)/endothelium pathway in ischemic stroke, with a particular focus on aging, response to recanalization therapies, and therapeutic approaches. While significant progress has been made in recent years in understanding the relationship between endothelial dysfunction and stroke, many uncertainties persist, and although treatments targeting this pathway are promising, they have yet to demonstrate clear clinical benefits.

Background: Inflammatory response plays an important role in many processes related to acute ischemic stroke (AIS). Calprotectin (S100A8/S100A9), released by monocytes and neutrophils, is a key protein in the regulation of inflammation and thrombosis. The purpose of this study is to evaluate the association of circulating calprotectin with other inflammatory biomarkers and AIS prognosis, as well as the calprotectin content in stroke thrombi. Methods: Among the 748 patients treated at a comprehensive stroke center between 2015 and 2017, 413 patients with confirmed acute ischemic injury were prospectively evaluated. Patients with systemic inflammation or infection at onset were excluded. Plasma calprotectin was measured by ELISA in blood samples of AIS patients within the first 24 h. Univariate and multivariate logistic regression models were performed to evaluate its association with mortality and functional independence (FI) at 3 months (defined as modified Rankin Scale < 3) and hemorrhagic transformation (HT) after ischemic stroke. Further, S100A9 was localized by immunostaining in stroke thrombi (n = 44). Results: Higher calprotectin levels were associated with 3-month mortality, HT, and lower 3-month FI. After adjusting for potential confounders, plasma calprotectin remained associated with 3-month mortality [OR (95% CI) 2.31 (1.13–4.73)]. Patients with calprotectin ≥ 2.26 μg/mL were 4 times more likely to die [OR 4.34 (1.95–9.67)]. Addition of calprotectin to clinical variables led to significant improvement in the discrimination capacity of the model [0.91 (0.87–0.95) vs 0.89 (0.85–0.93); p < 0.05]. A multimarker approach demonstrated that patients with increased calprotectin, CRP, and NLR had the poorest outcome with a mortality rate of 42.3% during follow-up. S100A9 protein, as part of the heterodimer calprotectin, was present in all thrombi retrieved from AIS patients. Mean S100A9 content was 3.5% and tended to be higher in patients who died (p = 0.09). Moreover, it positively correlated with platelets (Pearson r 0.46, p < 0.002), leukocytes (0.45, p < 0.01), and neutrophil elastase (0.70, p < 0.001) thrombus content. Conclusions: Plasma calprotectin is an independent predictor of 3-month mortality and provides complementary prognostic information to identify patients with poor outcome after AIS. The presence of S100A9 in stroke thrombi suggests a possible inflammatory mechanism in clot formation, and further studies are needed to determine its influence in resistance to reperfusion.

Matrix metalloproteinases (MMPs) are proteolytic zinc-endopeptidases regulated by tissue Inhibitors of matrix metalloproteinases (TIMPs). We evaluated the potential of MMPs and TIMPs as clinical tools for Intracranial Haemorrhage (ICH). Spontaneous non‐traumatic ICH patients were recruited from two hospitals: Complejo Hospitalario de Navarra (CHN = 29) and Vall d´Hebron (VdH = 76). Plasmatic levels of MMP-1, −2, −7, −9, −10 and TIMP-1 and their relationship with clinical, radiological and functional variables were evaluated. We further studied the effect of TIMP-1 (0.05–0.2 mg/Kg) in an experimental tail-bleeding model. In CHN, TIMP-1 was associated with admission-hematoma volume and MMP-7 was elevated in patients with deep when compared to lobar hematoma. In VdH, admission-hematoma volume was associated with TIMP-1 and MMP-7. When data from both hospitals were combined, we observed that an increase in 1 ng/ml in TIMP-1 was associated with an increase of 0.14 ml in haemorrhage (combined β = 0.14, 95% CI = 0.08–0.21). Likewise, mice receiving TIMP-1 (0.2 mg/Kg) showed a shorter bleeding time (p < 0.01). Therefore, the association of TIMP-1 with hematoma volume in two independent ICH cohorts suggests its potential as ICH biomarker. Moreover, increased TIMP-1 might not be sufficient to counterbalance MMPs upregulation indicating that TIMP-1 administration might be a beneficial strategy for ICH.