Graft-derived extracellular vesicles transported across subcapsular sinus macrophages elicit B cell alloimmunity after transplantation.

Despite the role of donor-specific antibodies (DSAs) in recognizing major histocompatibility complex (MHC) antigens and mediating transplant rejection, how and where recipient B cells in lymphoid tissues encounter donor MHC antigens remains unclear. Contrary to the dogma, we demonstrated here that migration of donor leukocytes out of skin or heart allografts is not necessary for B or T cell allosensitization in mice. We found that mouse skin and cardiac allografts and human skin grafts release cell-free donor MHC antigens via extracellular vesicles (EVs) that are captured by subcapsular sinus (SCS) macrophages in lymph nodes or analog macrophages in the spleen. Donor EVs were transported across the SCS macrophages, and donor MHC molecules on the EVs were recognized by alloreactive B cells. This triggered B cell activation and DSA production, which were both prevented by SCS macrophage depletion. These results reveal an unexpected role for graft-derived EVs and open venues to interfere with EV biogenesis, trafficking, or function to restrain priming or reactivation of alloreactive B cells.

Safety and Efficacy of Prasugrel and Ticagrelor in Acute Coronary Syndrome. Results of a "Real World" Multicenter Registry.

INTRODUCTION AND OBJECTIVES: The incorporation of the new antiplatelet agents (NAA) prasugrel and ticagrelor into routine clinical practice is irregular and data from the "real world" remain scarce. We aimed to assess the time trend of NAA use and the clinical safety and efficacy of these drugs compared with those of clopidogrel in a contemporary cohort of patients with acute coronary syndromes (ACS). METHODS: A multicenter retrospective observational study was conducted in patients with ACS admitted to coronary care units and prospectively included in the ARIAM-Andalusia registry between 2013 and 2015. In-hospital rates of major cardiovascular events and bleeding with NAA vs clopidogrel were analyzed using propensity score matching and multivariate regression models. RESULTS: The study included 2906 patients: 55% received clopidogrel and 45% NAA. A total of 60% had ST-segment elevation ACS. Use of NAA significantly increased throughout the study. Patients receiving clopidogrel were older and were more likely to have comorbidities. Total mortality, ischemic stroke, and stent thrombosis were lower with NAA (2% vs 9%, P < .0001; 0.1% vs 0.5%, P = .025; 0.07% vs 0.5%, P = .025, respectively). There were no differences in the rate of total bleeding (3% vs 4%; P = NS). After propensity score matching, the mortality reduction with NAA persisted (OR, 0.37; 95%CI, 0.13 to 0.60; P < .0001) with no increase in total bleeding (OR, 1.07; 95%CI, 0.18 to 2.37; P = .094). CONCLUSIONS: In a "real world" setting, NAA are selectively used in younger patients with less comorbidity and are associated with a reduction in major cardiac events, including mortality, without increasing bleeding compared with clopidogrel.

Prognostic implication of early ventricular fibrillation among patients with ST elevation myocardial infarction.

OBJECTIVE: The aim of this study was to analyze the prognosis of patients presenting early ventricular fibrillation (VF) in the setting of ST elevation myocardial infarction (STEMI). PATIENTS AND METHODS: Among patients included in the ARIAM (Análisis del Retraso en el Infarto Agudo de Miocardio) registry with the diagnosis of STEMI, those who received primary revascularization and were admitted in the first 12 h were analyzed retrospectively. RESULTS: From January 2007 to January 2012, 8340 patients were included in the STEMI cohort and 680 (8.2%) of them presented with VF before admission to the ICU (VF). This group comprised younger patients with fewer comorbidities. They received more often primary angioplasty (33.7 vs. 24.9%; P<0.001), had more prevalence of Killip class greater than or equal to 2 at admission (37.5 vs. 17.8%; P<0.001), and suffered more often cardiogenic shock (18.5 vs. 5.9%, P<0.001). By logistic regression analysis, VF was associated with a greater in-hospital mortality [odds rate (OR): 2.08, 95% confidence interval (CI): 1.57-2.81, P<0.001]. After a propensity score matching process, VF was associated with in-hospital mortality (OR: 1.53, 95% CI: 1.05-2.25, P=0.028). However, when analyzing patients treated by primary angioplasty, the mortality was not significantly related to VF (OR: 0.86, 95% CI: 0.45-1.61, P=0.628). CONCLUSION: Our results show that VF before ICU admission was an independent predictor of in-hospital outcome in a cohort of patients in whom fibrinolysis was the most used revascularization therapy. However, this prognostic value was not found in patients treated with primary angioplasty.