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On-pump cardiac surgery provokes a predictable perioperative myocardial ischaemia–reperfusion injury which is associated with poor clinical outcomes. We determined the occurrence of time-of-the-day variation in perioperative myocardial injury in patients undergoing aortic valve replacement and its molecular mechanisms. We studied the incidence of major adverse cardiac events in a prospective observational single-centre cohort study of patients with severe aortic stenosis and preserved left ventricular ejection fraction (>50%) who were referred to our cardiovascular surgery department at Lille University Hospital (Lille, France) for aortic valve replacement and underwent surgery in the morning or afternoon. Patients were matched into pairs by propensity score. We also did a randomised study, in which we evaluated perioperative myocardial injury and myocardial samples of patients randomly assigned (1:1) via permuted block randomisation (block size of eight) to undergo isolated aortic valve replacement surgery either in the morning or afternoon. We also evaluated human and rodent myocardium in ex-vivo hypoxia–reoxygenation models and did a transcriptomic analysis in myocardial samples from the randomised patients to identify the signalling pathway(s) involved. The primary objective of the study was to assess whether myocardial tolerance of ischaemia–reperfusion differed depending on the timing of aortic valve replacement surgery (morning vs afternoon), as measured by the occurrence of major adverse cardiovascular events (cardiovascular death, myocardial infarction, and admission to hospital for acute heart failure). The randomised study is registered with ClinicalTrials.gov, number NCT02812901. In the cohort study (n=596 patients in matched pairs who underwent either morning surgery [n=298] or afternoon surgery [n=298]), during the 500 days following aortic valve replacement, the incidence of major adverse cardiac events was lower in the afternoon surgery group than in the morning group: hazard ratio 0·50 (95% CI 0·32–0·77; p=0·0021). In the randomised study, 88 patients were randomly assigned to undergo surgery in the morning (n=44) or afternoon (n=44); perioperative myocardial injury assessed with the geometric mean of perioperative cardiac troponin T release was significantly lower in the afternoon group than in the morning group (estimated ratio of geometric means for afternoon to morning of 0·79 [95% CI 0·68–0·93; p=0·0045]). Ex-vivo analysis of human myocardium revealed an intrinsic morning–afternoon variation in hypoxia–reoxygenation tolerance, concomitant with transcriptional alterations in circadian gene expression with the nuclear receptor Rev-Erbα being highest in the morning. In a mouse Langendorff model of hypoxia–reoxygenation myocardial injury, Rev-Erbα gene deletion or antagonist treatment reduced injury at the time of sleep-to-wake transition, through an increase in the expression of the ischaemia–reperfusion injury modulator CDKN1a/p21. Perioperative myocardial injury is transcriptionally orchestrated by the circadian clock in patients undergoing aortic valve replacement, and Rev-Erbα antagonism seems to be a pharmacological strategy for cardioprotection. Afternoon surgery might provide perioperative myocardial protection and lead to improved patient outcomes compared with morning surgery. Fondation de France, Fédération Française de Cardiologie, EU-FP7-Eurhythdia, Agence Nationale pour la Recherche ANR-10-LABX-46, and CPER-Centre Transdisciplinaire de Recherche sur la Longévité.

ObjectiveTo evaluate the efficacy of electro-acupuncture (EA) or transcutaneous electrical acupoint stimulation (TEAS) on perioperative cerebral blood flow (CBF) and neurological function in ischemic stroke (IS) patients undergoing carotid artery stenting (CAS).MethodsIn total, 124 consecutive IS patients were randomly allocated to the EA, TEAS, and sham groups (groups A, T, and S; 41, 42, and 41 cases, respectively) by software-derived random-number sequence. Groups A and T received EA and TEAS, respectively, at the Shuigou (GV 26) and Baihui (GV 20), Hegu (LI4) and Waiguan (TE 5) acupoints. Group S received sham EA. The stimulation was started from 30 min before surgery until the end of the operation. The primary outcome was the CBF at 30 min after surgery, which was measured by transcranial Doppler sonography. The secondary outcomes included hyperperfusion incidence and neurological function. National Institutes of Health Stroke Scale (NIHSS) and General Evaluation Scale (GES) scores were recorded at 1 week, 1 month, and 3 months postoperatively.ResultsMean CBF velocity at 30 min after surgery in groups A and T was much lower than that in Group S (P < 0.05); the incidence of hyperperfusion in Groups A and T was also lower than that in group S (P <0.05). Acupuncture was an independent factor associated with reduced incidence of hyperperfusion (OR=0.042; 95% CI: 0.002–0.785; =0.034). NIHSS and GES scores improved significantly at 1 week postoperatively in Groups A and T than in Group S (P < 0.05). Relative to Group S, groups A and T exhibited significantly lower incidences of moderate pain, as well as higher incidences of satisfaction with anesthesia, at 1 day postoperatively (P < 0.05).ConclusionsEA or TEAS administered in combination with local anesthesia during CAS can inhibit transient increases in CBF, reduce the incidence of postoperative hyperperfusion, and improve neurological function. (Registration No. ChiCTR-IOR-15007447)

Despite the enormous progress in the understanding of the course of the ischemic stroke over the last few decades, a therapy that effectively protects neurovascular units (NVUs) and significantly improves neurological functions in stroke patients has still not been achieved. The reasons for this state are unclear, but it is obvious that the cerebral ischemia and reperfusion cascade is a highly complex phenomenon, which includes the intense neuroinflammatory processes, and comorbid stroke risk factors strongly worsen stroke outcomes and likely make a substantial contribution to the pathophysiology of the ischemia/reperfusion, enhancing difficulties in searching of successful treatment. Common concomitant stroke risk factors (arterial hypertension, diabetes mellitus and hyperlipidemia) strongly drive inflammatory processes during cerebral ischemia/reperfusion; because these factors are often present for a long time before a stroke, causing low-grade background inflammation in the brain, and already initially disrupting the proper functions of NVUs. Broad consideration of this situation in basic research may prove to be crucial for the success of future clinical trials of neuroprotection, vasculoprotection and immunomodulation in stroke. This review focuses on the mechanism by which coexisting common risk factors for stroke intertwine in cerebral ischemic/reperfusion cascade and the dysfunction and disintegration of NVUs through inflammatory processes, principally activation of pattern recognition receptors, alterations in the expression of adhesion molecules and the subsequent pathophysiological consequences.

Background Macrophages in atherosclerotic plaques secrete YKL-40, a new biomarker of acute and chronic inflammation in patients with stable CAD. We hypothesized that YKL-40 may be a specific marker reflecting the burden of localized inflammation in myocardium and a predictor in patients with STEMI. In this study, we investigated the relationship of YKL-40 to in-hospital major adverse cardiac events (MACE), reperfusion parameters and its predictors in patients with STEMI. Methods In total, 80 patients with STEMI and no history of prior coronary artery disease (CAD), who underwent primary percutaneous coronary intervention (p-PCI), were enrolled consecutively. In addition, 30 patients with normal coronary arteries (NCA) were enrolled as a control group. Cardiac biomarker levels including creatinine kinase-MB fraction (CK-MB), troponin-I, admission glucose and inflammatory markers including leukocytes and YKL-40 levels were measured as admission values. Results In our study, YKL-40 levels correlated to high-sensitivity CRP levels ( r  = 0.333, p  = 0.003), TIMI risk score ( r  = 0.445, p  < 0.001), age ( r  = 0.477, p  < 0.001), pain to balloon time ( r  = 0.432, p  < 0.001), leukocyte and neutrophil count ( r  = 0.386, p  < 0.001 and r  = 0.430, p  < 0.001, respectively), hemoglobin ( r  = − 0.345, p  = 0.002), admission and fasting blood glucose ( r  = 0.388, p  < 0.001 and r  = 0.427, p  < 0.001), creatinine levels ( r  = 0.395, p  < 0.001) and myocardial blush grade ( r  = − 0.334, p  = 0.004). When the patients were divided into two groups determined by presence or absence of MACE, the patients with MACE had significantly higher levels of YKL-40 in comparison to the patients without MACE and the control group (194 ± 104, 114 ± 61 and 110 ± 53 μg/L, p  < 0.001, respectively). In multivariate logistic regression analysis in STEMI patients, only YKL-40 level (OR: 1.011, 95%CI: 1.002–1.019, p  = 0.011) and leukocyte count (OR: 1.264, 95%CI: 1.037–1.540, p  = 0.020) were the independent predictors for MACE. Sensitivity and specificity of YKL-40 to predict MACE, when 125 μg/l was accepted as a cut-off value, were 84% and 70%, respectively. Conclusion We found that serum YKL-40 is related to older age, increased admission glucose levels, leukocyte counts and decreased hemoglobin levels; YKL-40 level and leukocyte count independently predicted MACE.

Metabolic syndrome, diabetes, and ischemic heart disease are among the leading causes of death and disability in Western countries. Diabetic cardiomyopathy is responsible for the most severe signs and symptoms. An important strategy for reducing the incidence of cardiovascular disease is regular exercise. Remote ischemic conditioning has some similarity with exercise and can be induced by short periods of ischemia and reperfusion of a limb, and it can be performed in people who cannot exercise. There is abundant evidence that exercise is beneficial in diabetes and ischemic heart disease, but there is a need to elucidate the specific cardiovascular effects of emerging and unconventional forms of exercise in people with diabetes. In addition, remote ischemic conditioning may be considered among the options to induce beneficial effects in these patients. The characteristics and interactions of diabetes and ischemic heart disease, and the known effects of exercise and remote ischemic conditioning in the presence of metabolic syndrome and diabetes, are analyzed in this brief review.

The purpose of this study was to investigate whether baseline neutrophil to lymphocyte ratio (NLR) was an independent predictor for early symptomatic intracranial hemorrhage (sICH), poor functional outcome and mortality at 3 months after reperfusion therapy in acute ischemic stroke (AIS) patients. Using PubMed and EMBASE, we searched for literature published before January 19th, 2019. Two reviewers independently confirmed each study’s eligibility, assessed risk of bias, and extracted data. One reviewer combined studies using random effects meta-analysis. 9 studies with 3651 patients were pooled in the meta-analysis. Overall, baseline NLR levels were greater in patients with poor outcome. The standardized mean difference (SMD) in the NLR levels between patients with poor functional outcome (mRS > 2) and good functional outcome (mRS ≤ 2) was 0.54 units (95% credible interval [CI] [0.38, 0.70]). Heterogeneity test showed that there were significant differences between individual studies (p = 0.02; I 2  = 72.8%). The NLR levels were associated with sICH in four included studies (n = 2003, SMD = 0.78, 95% [CI] [0.18, 1.38], I 2  = 73.9%). Higher NLR levels were positively correlated with 3-month mortality (n = 1389, ES = 1.71, 95% CI [1.01,2.42], p < 0.01, I 2  = 0%) when data were used as categorical variables. Our meta-analysis suggests that increased NLR levels are positively associated with greater risk of sICH, 3-month poor functional outcome and 3-month mortality in AIS patients undergoing reperfusion treatments. Although there are some deficits in this study, it may be feasible to predict the prognosis of reperfusion therapy in AIS patients with NLR levels.

Background Sex and hormones influence immune responses to ischemia reperfusion (IR) and could, therefore, cause sex-related differences in lung transplantation (LTx) outcomes. We compared men’s and women’s clinical and molecular responses to post-LTx IR. Methods In 203 LTx patients, we used the 2016 International Society for Heart and Lung Transplantation guidelines to score primary graft dysfunction (PGD). In a subgroup of 40 patients with blood samples collected before LTx (T0) and 6, 24, 48 (T48), and 72 h (T72) after lung reperfusion, molecular response to IR was examined through serial analysis of circulating cytokine expression. Results After adjustment, women had less grade 3 PGD than men at T48, but not at T72. PGD grade decreased from T0 to T72 more often in women than men. The evolution of PGD (the difference in mean PGD between T72 and T0) was greater in men. However, the evolution of IL-2, IL-7, IL-17a, and basic fibroblast growth factor levels was more often sustained throughout the 72 h in women. In the full cohort, we noted no sex differences in secondary clinical outcomes, but women had significantly lower peak lactate levels than men across the 72 h. Conclusions Men and women differ in the evolution of PGD and cytokine secretion after LTx: Women have a more sustained proinflammatory response than men despite a greater reduction in PGD over time. This interaction between cytokine and PGD responses warrants investigation. Additionally, there may be important sex-related differences that could be used to tailor treatment during or after transplantation.

Chronic thromboembolic pulmonary hypertension (CTEPH) can be treated with pulmonary thromboendarterectomy (PTE) which may lead to reperfusion lung injury (RPLI) and postoperative pneumonia. We aimed to describe the incidence, diagnostic characteristics, and clinical outcomes of post-PTE pneumonia compared to RPLI. A retrospective study involving CTEPH subjects who underwent PTE at a large referral center was conducted. Data included demographics, hemodynamics, microbiologic diagnostics, and clinical outcomes. Post-PTE pneumonia was diagnosed based on documentation, signs/symptoms, or microbiologic sampling within seven days of surgery. Among 75 PTE subjects, 21 (28%) had RPLI, and 18 (24%) had post-PTE pneumonia. Of those with RPLI, 48% had pneumonia, suggesting overlap. Eight of 75 (11%) subjects underwent bronchoscopic sampling, and five (63%) samples yielded positive results indicative of infection. Subjects with post-PTE pneumonia and RPLI had longer hospital and ICU lengths of stay and mechanical ventilation duration than either group alone. Post-PTE pneumonia is prevalent and overlaps with RPLI in CTEPH subjects. The study highlights the importance of systematic evaluation and early detection of pneumonia in subjects with RPLI post-PTE. Timely diagnosis and management of pneumonia may improve outcomes. Further research is needed to understand risk factors and develop preventive strategies for post-PTE pneumonia.

Background Advancements in graft selection, surgical and anesthetic techniques have improved the outcomes of pediatric liver transplantation over the last few decades. In this study, we evaluate preoperative factors, the incidence of post-reperfusion syndrome, rejection, and survival among 523 pediatric patients who received whole vs. partial liver transplantation. Methods In a six-year retrospective observational study on 523 pediatric liver transplantation recipients (age < 18 years old) in Abu-Ali Sina Organ Transplantation Hospital, we collected recipients’ demographic data, warm and cold ischemic time, post reperfusion syndrome, and postoperative outcomes, including mechanical ventilation time, ICU length of stay, acute renal failure, acute cellular rejection, re-transplantation, and patients’ survival. We compared these preoperative, operative, and postoperative outcomes among whole and partial graft recipients using SPSS software for Windows. Results 259 cases received partial and 264 cases received whole organ transplantation. We compared the donor factors, preoperative, intraoperative recipient factors, and postoperative outcomes between the two groups. The donors’ age and percentage of macrovesicular steatotic changes of the partial donor graft were significantly higher than the whole donor graft, respectively (33.5 vs. 6, p  < 0.001) (31% vs. 17%, p  < 0.001). The recipients of partial graft had younger age (3.5 (1.5-8) vs. 9 (5–14) years, P  < 0.001) than recipients of whole organ graft. Although partial organ recipients had shorter cold ischemic time (25 (15–30) vs. 480 (390–570) minutes, P  < 0.001), they significantly developed post-reperfusion syndrome more than whole organ recipients (14% vs. 7.5%, P  = 0.01). The outcome of partial organ recipients also seemed to be poorer compared with whole organ recipients; they had longer ICU stays (18 (11–29) vs. 14 (9–20) days, P  = 0.004) and lower survival (61.4% vs. 81.8%, P  < 0.001). Conclusion Although partial organ transplantation provides more chances for pediatric liver transplant candidates to survive, we observed that physicians have faced many challenges, and children had more complications and lower survival after partial organ transplantation.

Hepatic steatosis is one of the most common hepatic disorders in developed countries. The epidemic of obesity in developed countries has increased with its attendant complications, including metabolic syndrome and non-alcoholic fatty liver disease. Steatotic livers are particularly vulnerable to ischemia/reperfusion injury, resulting in an increased risk of postoperative morbidity and mortality after liver surgery, including liver transplantation. There is growing understanding of the molecular and cellular mechanisms and therapeutic approaches for treating ischemia/reperfusion injury in patients with steatotic livers. This review discusses the mechanisms underlying the susceptibility of steatotic livers to ischemia/reperfusion injuries, such as mitochondrial dysfunction and signal transduction alterations, and summarizes the clinical impact of steatotic livers in the setting of hepatic resection and liver transplantation. This review also describes potential therapeutic approaches, such as ischemic and pharmacological preconditioning, to prevent ischemia/reperfusion injury in patients with steatotic livers. Other approaches, including machine perfusion, are also under clinical investigation; however, many pharmacological approaches developed through basic research are not yet suitable for clinical application.