Ischemia-reperfusion Injury In Patients Research Articles

Remote ischemic preconditioning for reduction of ischemia-reperfusion injury after hepatectomy: A randomized sham-controlled trial

BackgroundRemote ischemic preconditioning reduces ischemia-reperfusion injury in patients undergoing hepatectomy. Moreover, there is evidence that the protective effects of remote ischemic preconditioning may be more pronounced in pre-damaged livers. The objective of this trial was to investigate the extent to which remote ischemic preconditioning can attenuate ischemia-reperfusion injury after hepatectomy and Pringle maneuver in patients with chronic liver disease. MethodsIn this randomized, controlled, triple-blind monocenter trial, a total of 102 patients with chronic liver disease and planned hepatectomy were enrolled between December 2019 and March 2022. Eligible patients were randomized to the remote ischemic preconditioning or sham arms. Remote ischemic preconditioning was induced through 3 10-minute cycles of alternating ischemia and reperfusion of the upper extremity. The study was prospectively registered in the German Clinical Trials Registry (DRKS00018931). ResultsA total of 102 patients were included in the study and were randomized (51 per arm). The median age was 69.5 years, approximately two-thirds of the patients were male (69/102, 67.7%), and the mean body mass index was 25.6 kg/m2. Most patients were classified as American Society of Anesthesiologists II (55/102, 53.9%) or III (45/102, 44.1%). The primary endpoint, the transaminases on the first postoperative day (alanine aminotransferase /aspartate aminotransferase: remote ischemic preconditioning arm: 250 (35–1721)/320 (42–1525) U/L versus sham control arm: 283 (32–792)/356 (20–1851) U/L, P = .820/0.639), clinical outcomes as well as remote ischemic preconditioning biomarker levels were comparable between both arms. ConclusionRemote ischemic preconditioning did not achieve a significant reduction in postoperative transaminase levels, nor did it affect clinical results and biomarkers.

Cardiomyocyte-specific beta3-adrenergic receptor expression reduces infarct size inhibiting the autophagic flux in mice

Abstract Background Since the discovery of β3-adrenergic receptor (β3AR), the third class of β-adrenergic receptors, expression in in both cardiomyocytes and endothelial cells of the cardiovascular system, it has come to the focus due to it´s possible implication in cardiovascular diseases. Although it´s expression is low compared to β1 and β2 subtypes (1), its been demonstrated that β3AR agonists have a cardioprotective effect in ischemia/reperfusion (IR) injury though inhibition of mitochondrial pore opening (2). Purpose In this project we determined the cellular origin of the β3AR cardioprotection and its role on cellular autophagic machinery. Methods Mice with overexpression of the β3AR in cardiomyocytes or endothelial cells and their control littermates were subjected to left coronary artery occlusion for 45 min followed reperfusion after 24h and 7days. Left ventricular function was assessed by echocardiography at day 7. Then, heart samples were collected at baseline and 24h and 7 days after IRI. Mitochondrial number were analyzed by transmission electron microscopy. Proteins related to autophagy signaling pathways were measured by western blot and RT-qPCR. Results Cardiomyocyte-specific β3AR overexpression protects the heart upon IR injury, reduced cardiac fibrosis which improved cardiac function and maintained heart mass. Studying the effects at baseline to understand the molecular mechanisms of cardioprotection, we found that β3AR overexpression in cardiomyocytes showed a reduction in autophagy markers such as LC3B and Parkin, meaning there is an alteration in the autophagic flux. Conclusions Cardiomyocyte-specific overexpression of β3-adrenergic receptor reduces infarct size and protects the heart affecting the autophagy machinery. Our results shed light on the role of the β3AR in the mitochondrial quality control system, offering evidence of its potential use as a target to decrease IR injury in patients with acute myocardial infarction.

Protective role of remote ischemic conditioning in renal transplantation and partial nephrectomy: A systematic review and meta-analysis of randomized controlled trials.

Studies have shown that remote ischemic conditioning (RIC) can effectively attenuate ischemic-reperfusion injury in the heart and brain, but the effect on ischemic-reperfusion injury in patients with kidney transplantation or partial nephrectomy remains controversial. The main objective of this systematic review and meta-analysis was to investigate whether RIC provides renal protection after renal ischemia-reperfusion injury in patients undergoing kidney transplantation or partial nephrectomy. A computer-based search was conducted to retrieve relevant publications from the PubMed database, Embase database, Cochrane Library and Web of Science database. We then conducted a systematic review and meta-analysis of randomized controlled trials that met our study inclusion criteria. Eleven eligible studies included a total of 1,145 patients with kidney transplantation or partial nephrectomy for systematic review and meta-analysis, among whom 576 patients were randomly assigned to the RIC group and the remaining 569 to the control group. The 3-month estimated glomerular filtration rate (eGFR) was improved in the RIC group, which was statistically significant between the two groups on kidney transplantation [P < 0.001; mean difference (MD) = 2.74, confidence interval (CI): 1.41 to 4.06; I 2 = 14%], and the 1- and 2-day postoperative Scr levels in the RIC group decreased, which was statistically significant between the two groups on kidney transplantation (1-day postoperative: P < 0.001; MD = 0.10, CI: 0.05 to 0.15, I 2 = 0; 2-day postoperative: P = 0.006; MD = 0.41, CI: 0.12 to 0.70, I 2 = 0), but at other times, there was no significant difference between the two groups in Scr levels. The incidence of delayed graft function (DGF) decreased, but there was no significant difference (P = 0.60; 95% CI: 0.67 to 1.26). There was no significant difference between the two groups in terms of cross-clamp time, cold ischemia time, warm ischemic time, acute rejection (AR), graft loss or length of hospital stay. Our meta-analysis showed that the effect of remote ischemia conditioning on reducing serum creatinine (Scr) and improving estimate glomerular filtration rate (eGFR) seemed to be very weak, and we did not observe a significant protective effect of RIC on renal ischemic-reperfusion. Due to small sample sizes, more studies using stricter inclusion criteria are needed to elucidate the nephroprotective effect of RIC in renal surgery in the future.

The Neuroprotective Effects of Ginsenoside Rd Pretreatment in a Rat Model of Spinal Cord Ischemia-Reperfusion Injury.

Paraplegia may develop as a result of spinal cord ischemia-reperfusion injury in patients who underwent thoracoabdominal aortic surgery. The objective of this research is to determine the neuroprotective effects of ginsenoside Rd pretreatment in a rat model of spinal cord ischemia-reperfusion injury. Sprague-Dawley rats (n=36) were randomly assigned to three groups. The sham (n=12) and control (n=12) groups received normal saline orally. The Rd group (n=12) received ginsenoside Rd (100 mg/kg) orally 48 hours before the induction of spinal cord ischemia. Spinal cord ischemia was induced by aortic occlusion using a Fogarty balloon catheter in the Rd and control groups. A neurological assessment according to the motor deficit index and a histological evaluation of the spinal cord were performed. To evaluate the antioxidant activity of ginsenoside Rd, malondialdehyde levels and superoxide dismutase activity were determined. Further, the tissue levels of tumor necrosis factor-alpha and interleukin-1 beta were measured. The Rd group showed significantly lower motor deficit index scores than did the control group throughout the entire experimental period (P<0.001). The Rd group demonstrated significantly greater numbers of normal motor neurons than did the control group (P=0.039). The Rd group exhibited decreased malondialdehyde levels (P<0.001) and increased superoxide dismutase activity (P=0.029) compared to the control group. Tumor necrosis factor-alpha and interleukin-1 beta tissue levels were significantly decreased in the Rd group (P<0.001). Ginsenoside Rd pretreatment may be a promising treatment to prevent ischemia-reperfusion injury in patients who undergo thoracoabdominal aortic surgery.

Protective Biomolecular Mechanisms of Glutathione Sodium Salt in Ischemia-Reperfusion Injury in Patients with Acute Coronary Syndrome-ST-Elevation Myocardial Infarction

Ischemia-Reperfusion Injury (IRI) is responsible for adverse outcomes in patients with ST-Elevation Myocardial Infarction (STEMI). Oxidative stress, resulting from the production of Reactive Oxygen Species (ROS) and low availability of Glutathione (GSH), are the two main mediators of IRI. The effectiveness of exogenous antioxidant therapy in this scenario is still debated, since the encouraging results obtained in animal models have not been fully reproduced in clinical studies. In this review we focus on the role of GSH, specifically on the biomolecular mechanisms that preserve myocardial cells from damage due to reperfusion. In this regard, we provide an extensive discussion about GSH intrinsic antioxidant properties, its current applications in clinical practice, and the future perspectives.

Evaluation of myocardial viability in patients with myocardial ischemia reperfusion injury using the dual-energy CT myocardial blood pool imaging.

To evaluate myocardial viability in patients with myocardial ischemia reperfusion injury (MIRI) via dual-energy computed tomography myocardial blood pool imaging (DECT MBPI). Between September 2017 and January 2019, we prospectively recruited 59 patients with acute myocardial infarction (AMI) who developed MIRI after revascularization during invasive coronary angiography (ICA). Then, they received DECT MBPI, SPECT, and PET sequentially within 1 week after the onset of MIRI. A total of 1003 myocardial segments of 59 patients were recruited for this study. The iodine reduction areas and delayed enhancement areas were calculated by cardiac iodine map with SPECT rest myocardial perfusion imaging (MPI) + PET myocardial metabolism imaging (MMI) as reference criteria. The paired sample t-test was used to measure the difference of the myocardial iodine value. Cohen's Kappa analysis was used to test the consistency among different observers. ROC analysis was used to calculate the myocardial viability of DECT MBPI. ROC showed the AUCs of DECT MBPI iodine value to identify a normal myocardium, an ischemic myocardium, and an infarcted myocardium were 0.957, 0.900, and 0.906 (p < 0.001). The sensitivity, specificity, and accuracy of DECT MBPI in identifying an ischemic myocardium were 87.6%, 89.3%, and 97.9% (p < 0.001). The sensitivity, specificity, and accuracy of DECT MBPI in identifying an infarcted myocardium were 88.9%, 92.2%, and 98.6% (p < 0.001). The cutoff value for DECT MBPI to differentiate between an ischemic and a normal myocardium was 0.84 mg I/mL. The cutoff value for DECT MBPI to differentiate between an infarct and a normal myocardium was 2.01 mg I/mL. DECT MBPI can be used to assess myocardial viability in patients with MIRI with high sensitivity and specificity. • Dual-energy computed tomography myocardial blood pool imaging (DECT MBPI) can evaluate myocardial viability of myocardial ischemia-reperfusion injury (MIRI). • DECT MBPI is a non-invasive and timesaving method for evaluation on myocardial ischemia-reperfusion injury in patients with acute myocardial infarction after coronary intervention.

Risk Factors of Ischemia Reperfusion Injury After PCI in Patients with Acute ST-Segment Elevation Myocardial Infarction and its Influence on Prognosis.

PurposeTo explore the risk factors of ischemia reperfusion injury (IRI) after percutaneous coronary intervention (PCI) in patients with acute ST-segment elevation myocardial infarction (STEMI) and its influence on prognosis.MethodsThe clinical data of 80 patients with STMEI undergoing PCI in our hospital from June 2020 to June 2021 were collected. According to whether IRI occurred after PCI, STMEI patients were divided into IRI group and non-IRI group. The basic information, clinical characteristics, examination parameters and other data of all patients were collected, and the prognosis of the two groups was observed. Risk factors were analyzed by fitting binary Logistic regression model. The survival prognosis was analyzed by Kaplan-Meier survival curve.ResultsLogistic regression analysis showed that type 2 diabetes mellitus (T2DM), pre-hospital delay time (PHD) and door-to-balloon expansion time (DTB) were the influencing factors of IRI in patients with STMEI (p < 0.05). MACE occurred in 11 cases (32.35%) in the IRI group and 13 cases (28.26%) in the non-IRI group. Log-rank test showed p = 0.503, indicating no statistically significant difference.ConclusionT2DM, PHD and DTB were the influencing factors of IRI in patients with STMEI, and IRI will not reduce the prognosis of patients.

The expression of oxidative stress genes related to myocardial ischemia reperfusion injury in patients with ST-elevation myocardial infarction.

We aimed to investigate the gene expression of myocardial ischemia/reperfusion injury (MIRI) in patients with acute ST-elevation myocardial infarction (STEMI) using stress and toxicity pathway gene chip technology and try to determine the underlying mechanism. The mononuclear cells were separated by ficoll centrifugation, and plasma total antioxidant capacity (T-AOC) was determined by the ferric reducing ability of plasma (FRAP) assay. The expression of toxic oxidative stress genes was determined and verified by oligo gene chip and quantitative real-time polymerase chain reaction (qRT-PCR). Additionally, gene ontology (GO) enrichment analysis was performed on DAVID website to analyze the potential mechanism further. The total numbers of white blood cells (WBC) and neutrophils (N) in the peripheral blood of STEMI patients (the AMI group) were significantly higher than those in the control group (WBC: 11.67±4.85 ×109/L vs. 6.41±0.72 ×109/L, P<0.05; N: 9.27±4.75 ×109/L vs. 3.89±0.81 ×109/L, P<0.05), and WBCs were significantly associated with creatine kinase-myocardial band (CK-MB) on the first day (Y=8.945+0.018X, P<0.05). In addition, the T-AOC was significantly lower in the AMI group comparing to the control group (12.80±1.79 U/mL vs. 20.48±2.55 U/mL, P<0.05). According to the gene analysis, eight up-regulated differentially expressed genes (DEGs) included GADD45A, PRDX2, HSPD1, DNAJB1, DNAJB2, RAD50, TNFSF6, and TRADD. Four down-regulated DEGs contained CCNG1, CAT, CYP1A1, and ATM. TNFSF6 and CYP1A1 were detected by polymerase chain reaction (PCR) to verify the expression at different time points, and the results showed that TNFSF6 was up-regulated and CYP1A1 was down-regulated as the total expression. GO and kyoto encyclopedia of genes and genomes (KEGG) enrichment analysis suggested that the oxidative stress genes mediate MIRI via various ways such as unfolded protein response (UPR) and apoptosis. WBCs, especially neutrophils, were the critical cells that mediating reperfusion injury. MIRI was regulated by various genes, including oxidative metabolic stress, heat shock, DNA damage and repair, and apoptosis-related genes. The underlying pathway may be associated with UPR and apoptosis, which may be the novel therapeutic target.

Association between CD137 and ischemia-reperfusion injury in patients with acute ST-segment elevation myocardial infarction

Objective: To explore the relationship between the levels of serum soluble CD137 (sCD137) and membrane-bound CD137 (mCD137) and the occurrence of ischemia reperfusion injury (IRI) in patients with acute ST-segment elevation myocardial infarction (STEMI). Methods: This is a cross-sectional study. Consecutive patients with acute STEMI, who underwent emergency percutaneous coronary intervention (PCI) in the Department of Cardiology, Jiangsu University Affiliated Hospital from May 2019 to September 2020, were enrolled. According to the absence or presence of IRI, patients were divided into IRI group and non-IRI group. Clinical data of the two groups were collected and compared. sCD137 level was detected by enzyme linked immunosorbent assay. Ficoll density gradient centrifugation was used to separate peripheral blood mononuclear cells (PBMC) and RNA was extracted, mCD137 mRNA expression level was detected by PCR. Serum sCD137 levels and the mCD137 mRNA levels of PBMC before, after PCI and 24 hours after PCI were compared. The correlation between serum sCD137 level, PBMC mCD137 mRNA level and clinical indicators was observed. The univariate and multivariate logistic binary regression analyses were performed to evaluate the related risk factors of IRI. ROC curve was used to analyze the predictive value of defined parameters for IRI. Results: A total of 112 STEMI patients were enrolled. There were 42 cases (of which 33 were males (78.6%), mean age was (58.6±12.7) years) in non-IRI group and 70 cases(of which 56 were males (80.0%), mean age was (64.5±11.6) years) in IRI group. Compared with the non-IRI group, patients in the IRI group had longer hospital stays, older age, lower rates of obesity, lower systolic and diastolic blood pressure at admission, higher proportion of the the right coronary artery as culprit vessel, lower rate of the use of angiotensin-converting enzyme inhibitor/angiotensin-Ⅱ receptor blocker/angiotensin receptor neprilysin inhibitor, higher levels of urea nitrogen and creatinine, lower glomerular filtration rate, lower triglycerides, higher D-dimer and B-type natriuretic peptidemax, higher proportion of Killip grade Ⅳ and cardiovascular adverse events (all P<0.05). sCD137 levels at the preoperative, postoperative and 24 hours after surgery were significantly higher in the IRI group than in the non-IRI group, while the mRNA levels of CD137 was similar between the two groups. The level of sCD137 in patients after PCI was lower than that before operation, the level of mCD137 mRNA was higher than that before operation (P<0.05). Serum sCD137 levels were positively correlated with hospitalization days, age, B-type natriuretic peptide, creatinine, ischemic time, C Reactive protein (CRP) and CRP/albumin (P<0.05), and negatively correlated with body mass index, glomerular filtration rate and albumin (P<0.05). The mCD137 mRNA expression level of PBMC was positively correlated with hospital stay, age, B-type natriuretic peptide, ischemic time, CRP and CRP/albumin (P<0.05), and negatively correlated with body mass index, glomerular filtration rate, albumin (P<0.05). Multivariate logistic regression analysis showed that higher sCD137 (OR=1.038, 95%CI: 1.009-1.069), aspartate aminotransferase, (OR=1.029, 95%CI: 1.009-1.050) and lower albumin (OR=0.829, 95%CI: 0.703-0.829) before surgery were independent risk factors of IRI (P<0.05). Receiver operating characteristic curve showed that the area under the curve of sCD137 was 0.672 (95%CI: 0.574-0.770, P=0.002) for the prediction of IRI, the best cut-off value was 28.43×10-3 μg/L with sensitivity of 95.2% and specificity of 48.6%. Conclusion: The significantly increased level of sCD137 in acute STEMI patients is positively correlated with reperfusion injury, which is an independent risk factor of IRI and may be related to the prognosis of patients with IRI.

Role of biomarkers of myocardial injury and inflammation in predicting ischemia-reperfusion injury in patients with ST-segment elevation acute coronary syndrome undergoing endovascular revascularization

Aim. To evaluate the informative value of biomarkers (cardiac troponin l (cTnl), high-sensitivity C-reactive protein (hsCRP), N-terminal pro-brain natriuretic peptide (NTproBNP), stimulating growth factor (ST2)) as laboratory markers of myocardial ischemia-reperfusion injury in patients with ST-segment elevation acute coronary syndrome (STEACS) undergoing endovascular revascularization.Material and methods. The study included 115 patients with STEACS who underwent endovascular myocardial revascularization. To identify the informative value of biomarkers, the levels of cTnl, NTproBNP, hsCRP, sST2 were analyzed at baseline, as well as after reperfusion therapy on the 2nd (cTnl) and 5th (sST2, hsCRP, NTproBNP) days. Contrast-enhanced cardiac magnetic resonance imaging was performed 5 days after endovascular intervention.Results. Microvascular obstruction was detected in 54 patients (47%), of which 24 (44%) patients had a combination of microvascular obstruction and myocardial hemorrhage. ln 61 cases (53%), no microvascular damage was registered. lt was found that with an increase in the threshold initial NTproBNP levels &gt;590 pg/ml, the odds ratio (OR) of myocardial reperfusion injury was 12,2 (95% confidence interval (CI), 4,81-30,92, p&lt;0,001). In addition, we analyzed biomarker levels in the early period after myocardial infarction, at which threshold values of reperfusion injury parameters were established as follows: for cTnI &gt;8,1 ng/ml, OR=7,17 (95% CI, 3,11-16,53, p=0,001); for hsCRP &gt;14 mg/L, OR=12,71 (95% CI, 5,03-32,08, p=0,001); for NTproBNP &gt;334 pg/ml, OR=11,8 (95% CI, 4,88-28,59, p=0,001); for sST2 &gt;41 ng/ml, OR=7,17 (95% CI, 3,11-16,53, p=0,001). According to multivariate analysis, predictors of microvascular injury were the initial NTproBNP values, as well as the cTnI, hsCRP, and sST2 values in the early postinfarction period (sensitivity — 89,5%, specificity — 83,3%).Conclusion. Thus, the initial NTproBNP, as well as cTnI, hsCRP, sST2 values after percutaneous coronary intervention are more informative for assessing the risk of microvascular damage.

Role of glucagon-like peptide-1 agonist in patients undergoing percutaneous coronary intervention or coronary artery bypass grafting: A meta-analysis

ImportanceGlucagon-like peptide-1 (GLP-1) protects against ischemia-reperfusion injury in patients with acute myocardial infarction (AMI). Controversy exists on the effects of GLP-1 on AMI patients undergoing percutaneous coronary intervention (PCI) and coronary artery bypass graft (CABG) surgery. Study objectiveWe aimed to investigate the cardioprotective effects of GLP-1 in AMI patients after PCI and CABG. DesignWe searched PubMed, Web of Science, EBSCO, Scopus, and the Cochrane Library for relevant randomized controlled trials (RCTs) up to June 2021, with no restriction on publication date. The following search terms are used: “percutaneous coronary intervention” or “coronary artery bypass grafting” or “myocardial infarction” and “glucagon-like peptide 1” or “exenatide” or “liraglutide”. Study selectionArticles were independently assessed by 2 reviewers. We included RCTs only that compared GLP-1 with control in AMI patients. Data extraction and synthesisContinuous data were pooled as mean differences (MDs), while dichotomous variables were pooled as odds ratios (ORs), with 95% confidence interval (CI), using R software (meta package) for windows. Subgroup analysis according to the intervention type and GLP-agents were conducted. We assessed the heterogeneity among RCTs using the Q statistic and I2 statistic. We also tested publication bias by funnel plot–based methods. The quality of each study was assessed with the Cochrane risk of bias tool. Main outcomes and measuresPrimary outcomes were changes of left ventricular ejection fraction (LVEF), myocardial infarct characteristics, salvage index. Secondary outcomes included major adverse cardiac events (MACE), gastrointestinal events, and hypoglycemia. ResultsNine RCTs (14 reports) including 1216 patients were included in this meta-analysis. At 3 months follow up, GLP-1 was associated with improved LVEF (MD = 2.81, 95% CI [0.69, 4.94]), infarct size in grams (MD = −5.71, 95% CI [−10.24, −1.18]), and salvage index (MD = 0.09, 95% CI [0.05, 0.14]). While, GLP-1 had less MACE rate than control (RR = 0.64, 95% CI [0.41, 0.99]), and higher gastrointestinal side effects (RR = 4.21, 95% CI [2.39, 7.41]). Conclusions and relevanceThis meta-analysis illustrated that GLP-1 was associated with better LVEF and reduced infarct size in patients with AMI undergoing PCI and CABG surgery, although the mechanism on how this agent provide this benefit is not clear. Key pointsQuestion: What is the effectiveness of Glucagon-like peptide-1 (GLP-1) agonist in patients with acute myocardial infarction (AMI) undergoing percutaneous coronary intervention (PCI) and coronary artery bypass graft (CABG) surgery.Findings: This systematic review and meta-analysis illustrated that GLP-1 was associated with better left ventricular ejection fraction and reduced infarct size in patients with AMI undergoing PCI and CABG surgery, probably by reducing reperfusion injury.Meaning: GLP-1 could improve systolic and diastolic function, lowering the cardiovascular risk of morbidity and mortality in AMI patients.

Remote ischemic conditioning fails to protect against ischemia-reperfusion injury in patients with untreated familial hypercholesterolemia

Abstract Background/Introduction Remote ischemic conditioning (RIC) is the action of brief periods of ischemia to a remote tissue and has been suggested to protect against myocardial ischemia-reperfusion (IR) injury. The outcomes of clinical trials in terms of clinical endpoints and infarct size reduction have been variable, which may be related to influence of comorbidities on the effect of RIC. Animal studies suggest that hypercholesterolemia attenuates the cardioprotective effect of RIC, but no data from study on patients are available. Hence, our aim was to investigate the response of RIC on IR-induced endothelial dysfunction in patients with familial hypercholesterolemia (FH). Purpose To investigate if RIC protects against endothelial dysfunction induced by IR in patients with FH with high (≥5.5 mmol/L) and low (≤2.5 mmol/L) LDL-cholesterol levels. Methods All subjects with FH (n=12) with LDL ≥5.5 mmol/L, FH with LDL &amp;lt;2.5 mmol/L (n=12), and age-matched healthy control subjects (n=12) participated in two protocols separated by at least one week. In both protocols, endothelium-dependent vasodilatation was assessed by determination of flow-mediated vasodilatation (FMD) of the brachial artery at baseline and again after 20 minutes of forearm ischemia and 20 minutes of reperfusion. Forearm ischemia was induced by inflating a blood pressure cuff on the upper arm to 200 mmHg. An additional inflatable cuff was placed around the left thigh. In one protocol (IR+sham), this cuff was left uninflated. In the second protocol (IR+RIC), it was inflated to 200 mmHg in four cycles of 5 minutes inflation and 5 min deflation with the first cycle starting at the onset of forearm ischemia. Results Plasma mean LDL-cholesterol was significantly higher in the FH group with high LDL (6.6±1.4 mmol/L) compared to the control group (2.4±0.7 mmol/L; p&amp;lt;0.01) and the low LDL FH group (2.0±0.6 mmol/L; p&amp;lt;0.001). FMD was markedly reduced (p&amp;lt;0.05) in all subjects following IR+sham, indicating IR-induced endothelial dysfunction in all three groups. As expected, RIC prevented the reduction in FMD after IR in the control group (Fig 1). By contrast, in the FH group with high LDL, RIC failed to protect from IR-induced endothelial dysfunction. Thus, in this group the decrease in FMD was similar after IR+RIC and IR+ sham (Fig 1). In the FH group with LDL &amp;lt;2.5 mmol/L, the decrease in FMD induced by IR was attenuated by RIC (p=0.05). Conclusion These observations suggest that RIC, which protects from IR-induced endothelial dysfunction in healthy controls, fails to protect from IR-induced endothelial dysfunction in patients with FH and LDL-cholesterol &amp;gt;5.5 mmol/L. The protective effect of RIC is restored after treatment of hypercholesterolemia. This finding may have bearings on the clinical efficacy of RIC in patients with ST-elevation myocardial infarction. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): Heart-lung foundation

Complement activation is associated with neutrophil extracellular traps and all-cause mortality in ST-elevation myocardial infarction

Abstract Background The complement system and neutrophil extracellular traps (NETs) are both parts of the innate immune system, and have been implicated in the ischemia-reperfusion injury in patients with ST-elevation myocardial infarction (STEMI). There is experimental evidence of reciprocal activation between the complement system and NETs. Any such link in patients with STEMI has not been investigated. Purpose To investigate a potential association between complement activation and clinical outcomes after STEMI, and assess any interplay between complement activation and NETs in this situation. Methods Patients with ST-elevation myocardial infarction were included at a median of 18 hours after percutaneous coronary intervention (n=864). The terminal complement complex (TCC) was measured by ELISA as a marker of complement activation. As markers of NETs were myeloperoxidase-deoxynucleic acid (MPO-DNA) and citrullinated histone 3 (CitH3) measured by ELISAs, while double stranded DNA (dsDNA) was measured by a nucleic acid stain. Patients were followed for a median of 4.6 years. The primary endpoint was a composite of new myocardial infarction, unscheduled revascularization, stroke, hospitalization for heart failure and death, whichever occurred first. All-cause mortality was also recorded. Results The composite endpoint occurred in 184 (21.3%) patients, while 70 (8.1%) died during follow-up. When dichotomizing at median TCC, the group with above-median TCC levels did not have an increased risk of reaching the composite endpoint (hazard ratio (HR): 1.069, 95% CI: [0.801, 1.428], p=0.651). However, this group exhibited an increased risk of all-cause mortality (HR: 1.650, 95% CI: [1.020, 2.671], p=0.041). This risk persisted when adjusting for age, sex, hypertension and LDL-cholesterol (HR: 1.673, 95% CI: [1.014, 2.761], p=0.044), but the significance was lost when adjusting for NT-proBNP (HR: 1.492, 95% CI: [0.885, 2.515], p=0.133). TCC was correlated to dsDNA (r=0.127, p&amp;lt;0.001) and CitH3 (r=0.102, p=0.003), but not MPO-DNA. The group with both TCC and dsDNA in the highest quartile exhibited a significantly higher incidence of all-cause mortality than the remaining population (17.6% vs, 7.2%, p=0.002). When examining the predictive value of TCC and dsDNA on all-cause mortality in ROC curve analysis, the area under the curve (AUC) for TCC was 0.549 (95% CI: [0.472, 0.625]), while the AUC for dsDNA was 0.653 (95% CI: [0.584, 0.722]). When combining TCC and dsDNA the predictive value was marginally higher than for TCC alone (AUC: 0.649, 95% CI: [0.579, 0.720]) Conclusion In this STEMI population, complement activation measured by TCC was not associated with the primary composite endpoint, but was associated with increased risk of death. TCC was weakly correlated with markers of NETs. Despite a high mortality rate in patients with high levels of TCC and dsDNA, combining these variables did not increase the prognostic value compared to TCC alone. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): Stein Erik Hagen's Foundation for Clinical Heart Research Survival according to cox regression

The psychocognitive, biochemical, and electrophysiological effects of cerebral ischemia-reperfusion injury in patients undergoing carotid endarterectomy accompanied by cervical block

The psychocognitive, biochemical, and electrophysiological effects of cerebral ischemia-reperfusion injury in patients undergoing carotid endarterectomy accompanied by cervical block

Association between indocyanine green clearance test and ischemic type biliary lesions within one year after orthotopic liver transplantation

BackgroundIschemic type biliary lesions (ITBLs), a particular subset of non-anastomotic biliary strictures (NAS), are characterized by intra and extrahepatic strictures that occur in the absence of either hepatic artery thrombosis or stenosis. When they occur within the first year after liver transplantation their development is mostly related to ischemia–reperfusion injury (IRI). The indocyanine green plasma disappearance rate (ICG-PDR) might be able to predict the probability of IRI-induced graft damage after liver transplantation. ObjectiveOur aim was to evaluate the association between ICG-PDR and the occurrence of ITBLs. Secondly, we searched for evidence of IRI in patients presenting ITBLs. MethodsThis retrospective single-center observational study assessed a cohort of 60 liver transplant patients. Each patient underwent ICG-PDR on the 1st postoperative day. ITBLs were identified by means of either cholangiography or magnetic resonance imaging evidence of a deformity and narrowing of the biliary tree in the absence of hepatic artery thrombosis/stenosis. ResultsITBLs were discovered in 10 patients out of 60 liver recipients (16.67%) within one year after transplantation. A low ICG-PDR value was found to be a significant predictive factor for ITBL development, with an OR of 0.87 and a 95% CI of 0.77–0.97. Liver biopsies were performed in 56 patients presenting unexplained abnormal liver function test results. A statistically significant association was found between the development of ITBLs and anatomopathological evidence of IRI. LimitationsRetrospective, single-center study. ConclusionsThe findings from this study show a relationship between low ICG-PDR values on first post-operative-day and the occurrence of ITBLs within 1 year after transplantation.

Ticagrelor Does Not Protect Against Endothelial Ischemia-Reperfusion Injury in Patients With Coronary Artery Disease.

Ticagrelor is a recommended P2Y12 receptor inhibitor after acute coronary syndrome (ACS). Its superiority has been suggested to rely on pleiotropic effects beyond platelet inhibition. Experimental studies indicate that ticagrelor may protect from ischemia-reperfusion injury but no data are available from such studies on patients. This study aimed to determine if chronic ticagrelor treatment protects against endothelial ischemia-reperfusion injury in patients with a previous ACS. Patients with a previous ACS were studied with flow mediated dilatation of the left brachial artery to determine the degree of endothelial ischemia-reperfusion injury before and after discontinuation of ticagrelor treatment, which had been continuous since 1 year. Each patient underwent 3 identical examinations. The first examination (Visit A) was at the end of ticagrelor treatment and the following 2 (Visit B and C) were after cessation of this treatment with an interval of 2 to 4 weeks. Ischemia and reperfusion induced significant impairment of endothelial function at all 3 occasions (absolute decline in flow mediated dilatation 3.0% ± 0.7 at Visit A (P < 0.001), 1.9% ± 0.9 at Visit B (P < 0.05) and 1.9% ± 0.4 at Visit C (P < 0.0001)). However, there was no difference in the degree of endothelial ischemia-reperfusion injury or baseline endothelial function between the visits. Chronic ticagrelor treatment in patients 1 year after an ACS does not protect against endothelial ischaemia-reperfusion injury. Nor is it associated with better basal endothelial function compared to after discontinuation of treatment.

MicroRNA Expression Profile Changes after Cardiopulmonary Bypass and Ischemia/Reperfusion-Injury in a Porcine Model of Cardioplegic Arrest.

Identification of microRNAs (miRNA) associated with cardiopulmonary bypass, cardiac arrest and subsequent myocardial ischemia/reperfusion may unravel novel therapeutic targets and biomarkers. The primary aim of the present study was to investigate the effects of cardiopulmonary bypass and temperature of cardioplegic arrest on myocardial miRNA profile in pigs’ left ventricular tissue. We employed next-generation sequencing to analyse miRNA profiles in the following groups: (1) hearts were arrested with antegrade warm St Thomas Hospital No. 2 (STH2) cardioplegia (n = 5; STH2-warm, 37 °C) and (2) cold STH2 (n = 6; STH2-cold, 4 °C) cardioplegia. Sixty min of ischemia was followed by 60 min of on-pump reperfusion with an additional 90 min of off-pump reperfusion. In addition, two groups without cardiac arrest (off-pump and on-pump group; n = 3, respectively) served as additional controls. STH2-warm and STH2-cold cardioplegia revealed no hemodynamic differences. In contrast, coronary venous creatine kinase-myocardial band (CK-MB) levels were significantly lower in pigs receiving STH2-warm cardioplegia (p < 0.05). Principal component analysis revealed that cardiopulmonary bypass and cardioplegic arrest markedly affected miRNAs in left ventricular tissue. Accordingly, ssc-miR-122, ssc-miR-10a-5p, ssc-miR-193a-3p, ssc-miR-499-3p, ssc-miR-374a-5p, ssc-miR-345-5p, ssc-miR-142-3p, ssc-miR-424-5p, ssc-miR-545-3p, ssc-miR-30b-5p, ssc-miR-145-5p, ssc-miR-374b-5p and ssc-miR-139-3p were differently regulated by cardiopulmonary bypass (false discovery rate (FDR) < 0.05 versus off-pump group). However, only ssc-miR-451 was differently expressed between STH2-warm and STH2-cold (FDR < 0.05). These data demonstrate for the first time that cardiopulmonary bypass and temperature of cardioplegic solution affected the expression of miRNAs in left ventricular tissue. In conclusion, specific miRNAs are potential therapeutic targets for limiting ischemia-reperfusion injury in patients undergoing cardiac surgery.

P357 Remote ischemic post-conditioning may prevent cardiac remodeling within two years of STEMI by cardioprotective microRNA upregulation

Abstract Background Remote ischemic post-conditioning attenuates ischemia-reperfusion injury in patients with STEMI. However, its biochemical mechanisms, including micro-RNA expression, and effects on cardiac remodeling have not been defined. Methods We examined 80 patients with STEMI and 20 healthy controls. All patients had been evaluated by cardiac echocardiography. The conditioning protocol utilised a single ischemic stimulus by brachial cuff inflation of both arms at 200mmHg for 5 minutes, while 20 patients underwent a sham conditioning procedure by way of cuff inflation omission after its placement. Blood samples were taken before and after the conditioning protocol; thus, the expression of microRNA-144,-150,-499 (cardioprotective action), -21, and -208 (remodeling stimuli) was quantified at baseline and after the ischemic conditioning procedure, by polymerase chain reaction. Additionally, cardiac remodeling was evaluated by repeat echocardiography after a 2-year follow-up period, in 40 patients. Results Our conditioning protocol resulted in a statistically significant increase in miR-144,-150, -499, -21, and -208 expression (55.9 vs 7.4/U6sn, p &amp;lt; 0.001; 3.4 vs 1.8/U6sn, p &amp;lt; 0.05, p = 0.01; 3.5 vs 1.6/U6sn, p &amp;lt; 0.001; 2.1 vs 1.2/U6sn; 2.4 vs 1.9/U6sn) compared to baseline; none of the aforementioned measurements was affected by the sham procedure. Furthermore, both left-ventricular end-diastolic (LVEDV) and end-systolic volume (LVESV) were decreased after the 2-year follow-up period (from 99.3 ± 6.7 to 85.9 ± 5.7, p= 0.004, and from 55.3± 6.1 to 48.6± 5.2, p= 0.04, respectively). In addition, the increase in mir-144 and mir-499 was significantly correlated with a decrease in LVESV (r=-0.355, p &amp;lt; 0.05; r=-0.368, p &amp;lt; 0.05, respectively), while the increase in mir-499 was also significantly correlated with a decrease in LVEDV (r=-0.374, p &amp;lt; 0.05) at follow-up. Conclusion Remote ischemic conditioning may prevent adverse myocardial remodelling within 2 years of the index ischemic event, likely by up-regulation of cardio-protective microRNAs expression.

Effect of the Aortic Root Infusion of Sufentanil on Ischemia-Reperfusion Injury in Patients Undergoing Coronary Artery Bypass Grafting: A Randomized Clinical Trial

Background: Ischemic postconditioning is a novel strategy for attaining cardioprotection. Remarkable evidence from various in vitro and in vivo animal and human studies have shown significant opioid-induced cardioprotection against myocardial ischemia/reperfusion (I/R) injury. The purpose of this study was to assess the cardioprotective effect of sufentanil against I/R injury after on-pump coronary artery bypass grafting (CABG). Methods: Between June 2016 and July 2017, 80 consecutive patients with triple-vessel disease undergoing on-pump CABG were enrolled in this prospective randomized study. The patients assigned to the sufentanil group received a single dose of sufentanil (0.2 μg/kg diluted with 50 cc of saline) 5 minutes before the removal of the aorta cross-clamp, with the sufentanil injected via a cardioplegia needle into the aortic root. In the control group, the same volume of normal saline was injected as a placebo. Cardiac enzymes, the inotrope score, and the outcome data were compared between the 2 groups. Results: The mean age of the patients was 60.48±7.50 years (range=41-69 y), and men comprised 65.0% of the study population. The levels of CK-MB and cardiac troponin I were significantly lower in the sufentanil group (P<0.001). The amount of inotrope use (P<0.001), the incidence of atrial fibrillation (P=0.014), electrical shock (P=0.007), and the mechanical ventilation time (P<0.001) decreased in the sufentanil group compared with the control group. However, the use of intra-aortic balloon pumps (P=0.247) and the ICU length of stay (P=0.867) were not significantly different between the 2 groups. Conclusion: The injection of a single dose of sufentanil into the aortic root prior to aorta cross-clamp removal diminished cardiac injury during on-pump CABG in our patients.

Effect of remote ischemic preconditioning on hepatic ischemia-reperfusion injury in patients undergoing liver resection: a randomized controlled trial.

Studies in animal models have shown that remote ischemic preconditioning (RIPC) could protect the liver from hepatic ischemia-reperfusion injury (HIRI). The aim of this study was to examine whether RIPC could reduce HIRI in patients undergoing liver resection. A total of 120 patients were randomly assigned to three groups: a control group receiving no conditioning, an ischemic preconditioning (IPC) group, and an RIPC group. In the IPC group, the hepatoduodenal ligament was blocked for 10 min followed by 10 min of reperfusion prior to hepatic resection. Patients in the RIPC group received three cycles of 5-min ischemia followed by 5-min reperfusion to the right arm. Alanine transaminase (ALT), aspartate transaminase (AST), and tumor necrosis factor-like weak inducer of apoptosis (TWEAK) were examined before and after surgery. A total of 105 patients completed the trial: 39 in the control group, 32 in the IPC group, and 34 in the RIPC group. In comparison to the control, serum ALT and AST levels significantly decreased in the IPC (ALT: 507.0±401.3 vs. 1040.7±649.5 IU/L, P<0.001; AST: 495.8±369.4 vs. 935.9±640.7 IU/L, P=0.001) and RIPC (ALT: 680.8±291.5 vs. 1040.7±649.5 IU/L, P=0.002; AST: 661.7±290.6 vs. 935.9±640.7 IU/L, P=0.014) groups on the first postoperative day. In comparison to the control, TWEAK significantly decreased in the IPC group (IPC 57.99±17.8 vs. control 76.13±12.4 ng/L, P=0.025) after surgery. TWEAK did not differ between the RIPC and IPC groups (RIPC 64.84±14.2 vs. IPC 57.99±17.8 ng/L, P=0.385). RIPC could reduce hepatic ischemia-reperfusion injury after liver resection.