Erythropoietin alleviates post-ischemic injury of rat hearts by attenuating nitrosative stress

Aims: Nitrosative stress caused by ischemia contributes to poor functional recovery in hearts. A previous study showed that recombinant human erythropoietin (EPO) activates the Janus-tyrosine kinase 2/extracellular signal-regulated kinase (Jak2/ERK) pathway to protect myocardium against ischemia/reperfusion (IR) injury. However, it is not clear how pro-survival signals triggered by EPO affect the nitric oxide (NO) system in post-ischemic myocardial tissue. Main methods: Isolated rat hearts were subjected to IR injury and changes in protein expression in the myocardium were evaluated by immunostaining. Key findings: Compared with untreated hearts, EPO-treated IR hearts showed significant improvements in contractility and reduced myocardial injury and infarction; this was associated with attenuated caspase-3 activation. Excess formation of NO metabolites and nitrotyrosine, which cause nitrosative stress, was markedly suppressed by EPO. The mechanism underlying EPO-mediated alleviation of nitrosative stress was related to an increase in arginase II expression and to the suppression of heat shock protein 90 (HSP90)-dependent upregulation of endothelial and inducible NO synthase (NOS). Myocardial EPO content was restored after EPO treatment, which in turn recruited signal transducer and activator of transcription (STAT) 3 protein and induced ERK signaling downstream of Jak2, which increased arginase II levels and suppressed HSP90 expression, respectively. Inhibition of STAT3 and ERK specifically reversed the effects of EPO on arginase II and HSP90 expression. Significance: These results indicate that EPO triggers the Jak2-STAT3/ERK pathway to restore the balance between arginase and NOS and, thus, reduces nitrosative stress. This may form the basis of myocardial protection following IR. (C) 2012 Elsevier Inc. All rights reserved

Delirium, Subsyndromal Delirium, and Cognitive Changes in Individuals Undergoing Elective Coronary Artery Bypass Graft Surgery

Background: The course of incident delirium and subsyndromal delirium (SSD) after cardiac surgery is not well studied. ;Objective: The aim of this study was to evaluate the course of incident delirium and SSD, their risk factors, and impact on patients' cognitive function after elective coronary artery bypass graft (CABG) surgery. ;Methods: Consecutive patients scheduled for an isolated CABG at a tertiary medical center in Taiwan were enrolled if they had no preoperative delirium symptoms. Delirium was assessed daily for 1 week after surgery using the Confusion Assessment Method. Subsyndromal delirium was defined as presenting with any core symptom below the diagnostic threshold for delirium. Cognitive function was assessed by the Mini-mental State Examination. ;Results: Of 38 participants, 7 had incident (first-time) delirium (18.4% incidence) and 13 had incident SSD (34.2% incidence). Whereas SSD usually lasted 1 day, delirium changed gradually to SSD to recovery and its symptomatology lasted longer. We identified 6 delirium risk factors: older age, more comorbidities, cardiac pulmonary bypass, blood transfusion, larger transfusion volume, and longer duration of intraoperative blood pressure less than 60 mm Hg. The frequencies of these risk factors for SSD were often intermediate between those of risk factors in groups with and without delirium. By hospital discharge, participants with delirium had the longest hospital stays and lowest cognitive scores, those with SSD had intermediate stays and scores, and those without delirium had the lowest stays and scores. ;Conclusion: Delirium and SSD after CABG are common. Greater number and severity of risk factors for delirium may predict increasingly poor outcomes, with the dose-response relationship between risk factors and outcomes for SSD intermediate between that for no symptoms and full delirium. Intervention trials are indicated, particularly for patients with a greater number and severity of predisposing and precipitating risk factors