Increased Infarct Size Research Articles

TREK-1 protects the heart against ischemia-reperfusion-induced injury and from adverse remodeling after myocardial infarction.

The TWIK-related K+ channel (TREK-1) is a two-pore-domain potassium channel that produces background leaky potassium currents. TREK-1 has a protective role against ischemia-induced neuronal damage. TREK-1 is also expressed in the heart, but its role in myocardial ischemia-reperfusion (IR)-induced injury has not been examined. In the current study, we used a TREK-1 knockout (KO) mouse model to show that TREK-1 has a critical role in the cardiac I/R-induced injury and during remodeling after myocardial infarction (MI). At baseline, TREK-1 KO mice had similar blood pressure and heart rate as the wild-type (WT) mice. However, the lack of TREK-1 was associated with increased susceptibility to ischemic injury and compromised functional recovery following ex vivo I/R-induced injury. TREK-1 deficiency increased infarct size following permanent coronary artery ligation, resulting in greater systolic dysfunction than the WT counterpart. Electrocardiographic (ECG) analysis revealed QT interval prolongation in TREK-1 KO mice, but normal heart rate (HR). Acutely isolated TREK-1 KO cardiomyocytes exhibited prolonged Ca2+ transient duration associated with action potential duration (APD) prolongation. Our data suggest that TREK-1 has a protective effect against I/R-induced injury and influences the post-MI remodeling processes by regulating membrane potential and maintaining intracellular Ca2+ homeostasis. These data suggest that TREK-1 activation could be an effective strategy to provide cardioprotection against ischemia-induced damage.

Selective intracoronary hypothermia in patients with ST-elevation myocardial infarction. Rationale and design of the EURO-ICE trial.

In ST-elevation myocardial infarction (STEMI), early restoration of blood flow, preferably by primary percutaneous coronary intervention (PPCI), is paramount to limit infarct size (IS) and improve long-term outcomes 1. However, reperfusion by itself may also cause damage to the myocardium and increase IS. This has been termed myocardial reperfusion injury 2. In animal models of acute myocardial infarction, it has been demonstrated that hypothermia decreases IS 3. In contrast, human studies applying systemic cooling methods have not yet been able to confirm this protective effect. Recently, we developed a new method to provide selective intracoronary hypothermia during PPCI 4. The EUROpean Intracoronary Cooling Evaluation in patients with ST-elevation myocardial infarction (EURO-ICE) trial will assess the efficacy of this method. Methods STUDY OBJECTIVES The primary objective of the EURO-ICE trial is to evaluate the effect of selective intracoronary hypothermia (SIH) on IS.

Extent to Which Network Hubs Are Affected by Ischemic Stroke Predicts Cognitive Recovery.

Background and Purpose- It is uncertain what determines the potential for cognitive recovery after ischemic stroke. The extent to which strategic areas of the brain network, so-called hubs, are affected by the infarct could be a key factor. We developed a lesion impact score, which estimates the damage to network hubs by integrating information on infarct size with healthy brain network topology. We verified whether the lesion impact score indeed reflects global network disturbances in patients and assessed if it could predict cognitive recovery. Methods- Seventy-five ischemic stroke patients without signs of a prestroke cognitive disorder were included, all with evidence of a cognitive disorder during hospitalization. A brain magnetic resonance imaging and neuropsychological assessment were performed 5 weeks (±1 week) after stroke. Neuropsychological testing was repeated after 1 year to assess cognitive recovery. Brain networks were reconstructed from diffusion-weighted data and consisted of 90 gray matter regions (ie, network nodes). A standard brain network map, indicating the hub-score of each node, was obtained from network data of 44 cognitively healthy adults. For each patient, we calculated the lesion impact score by multiplying the percentage of node volume affected by the infarct with the node's corresponding hub-score. The patients' maximum lesion impact score was used as outcome predictor. Results- A higher lesion impact score in patients, indicating an increasing infarct size in nodes with a higher hub-score, was related to lower global brain network efficiency (β=-0.528 [-0.776 to -0.277]; P<0.001), independent of age, brain volume, infarct volume, and white matter hyperintensity severity. A lower lesion impact score, however, was an independent predictor of cognitive recovery 1 year after stroke (odds ratio=0.434 [0.193-0.978]; P=0.044). Conclusions- We introduced a lesion impact score that combines information on infarct size and network topology to predict long-term recovery after stroke. This score can potentially be used in a clinical setting, also without availability of high-resolution diffusion-weighted magnetic resonance imaging.

Abstract 312: SGLT1 is Essential for Cardioprotection During Ischemia-Reperfusion Injury via Enhanced Glucose Utilization in Diet-induced Obese Mice

Recent large clinical trials have shown that sodium-glucose cotransporter 2 (SGLT2) inhibitors reduced cardiovascular events in diabetic patients. However, the regulation and functional role of cardiac SGLTs (SGLT1 is the dominant isoform) compared with those of other glucose transporters (insulin-dependent GLUT4 is the major isoform) remain incompletely understood. Given that glucose is a preferential substrate for myocardial metabolism during ischemia-reperfusion injury (IRI), we hypothesized that SGLT1 contributes to cardioprotection during IRI via enhanced glucose transport, particularly in insulin-resistant phenotypes. The hearts from mice fed a high-fat diet (HFD) for 12 weeks or a normal-fat diet (NFD) were perfused with either non-selective SGLT-inhibitor phlorizin (to inhibit SGLT1) or selective SGLT2-inhibitors (tofogliflozin, ipragliflozin, canagliflozin) during IRI using Langendorff model. After ischemia-reperfusion, HFD impaired left ventricular developed pressure (LVDP) recovery compared with NFD. Although phlorizin-perfusion impaired LVDP recovery in NFD, a further impaired LVDP recovery and dramatically increased infarct size (indicated by CPK release into perfusate and TTC staining) were observed in HFD with phlorizin-perfusion. Meanwhile, none of the SGLT2-inhibitors significantly affected cardiac function or myocardial injury after ischemia-reperfusion under either diet condition. The plasma membrane expression of GLUT4 was significantly increased after IRI in NFD but was substantially attenuated in HFD, the latter of which was associated with a significant reduction in both myocardial glucose uptake and cardiac tissue ATP content. In contrast, regardless of the diet condition, SGLT1 expression remained constant during IRI, whereas SGLT2 was not detected. Of note, phlorizin considerably reduced myocardial glucose uptake and decreased cardiac tissue ATP content after IRI, particularly in HFD. In conclusion, cardiac SGLT1 but not SGLT2 plays a compensatory protective role and contributes to cardiac energy metabolism during acute phase of IRI via enhanced glucose utilization, particularly under insulin-resistant conditions, in which IRI-induced GLUT4 upregulation is compromised.

Myocardial injury and mortality in patients with excessive oxygen administration before cardiac arrest.

Hyperoxia after cardiac arrest may be associated with higher mortality, and trials have found that excess oxygen administration in patients with myocardial infarction is associated with increased infarct size. The effect of hyperoxia before cardiac arrest is sparsely investigated. Our aim was to assess the association between excessive oxygen administration before cardiac arrest and the extent of subsequent myocardial injury. We performed a retrospective study including patients who had in-hospital cardiac arrest during 2014 in the Capital Region of Denmark. We excluded patients without peripheral oxygen saturation measurements within 48hours before cardiac arrest. Patients were divided in three groups of pre-arrest oxygen exposure, based on average peripheral oxygen saturation and supplemental oxygen. Primary outcome was peak troponin concentration within 30days. Secondary outcomes included 30-day mortality. Data were analyzed using multiple logistic regression and Wilcoxon rank sum test. Of 163 patients with cardiac arrest, 28 had excessive oxygen administration (17%), 105 had normal oxygen administration (64%) and 30 had insufficient oxygen administration (18%) before cardiac arrest. Peak troponin was median 224ng/L in the excessive oxygen administration group vs 365ng/L in the normal oxygen administration group (P=.54); 20 of 28 (71%) in the excessive oxygen administration group died within 30days compared to 54 of 105 (51%) in the normal oxygen administration group. (OR 1.87, 95% CI 0.56-6.19) CONCLUSIONS: Excessive oxygen administration within 48hours before in-hospital cardiac arrest was not statistically associated with significantly higher peak troponin or mortality.

Cardiac ischemia\u2013reperfusion injury under insulin-resistant conditions: SGLT1 but not SGLT2 plays a compensatory protective role in diet-induced obesity

BackgroundRecent large-scale clinical trials have shown that SGLT2-inhibitors reduce cardiovascular events in diabetic patients. However, the regulation and functional role of cardiac sodium–glucose cotransporter (SGLT1 is the dominant isoform) compared with those of other glucose transporters (insulin-dependent GLUT4 is the major isoform) remain incompletely understood. Given that glucose is an important preferential substrate for myocardial energy metabolism under conditions of ischemia–reperfusion injury (IRI), we hypothesized that SGLT1 contributes to cardioprotection during the acute phase of IRI via enhanced glucose transport, particularly in insulin-resistant phenotypes.Methods and resultsThe hearts from mice fed a high-fat diet (HFD) for 12 weeks or a normal-fat diet (NFD) were perfused with either the non-selective SGLT-inhibitor phlorizin or selective SGLT2-inhibitors (tofogliflozin, ipragliflozin, canagliflozin) during IRI using Langendorff model. After ischemia–reperfusion, HFD impaired left ventricular developed pressure (LVDP) recovery compared with the findings in NFD. Although phlorizin-perfusion impaired LVDP recovery in NFD, a further impaired LVDP recovery and a dramatically increased infarct size were observed in HFD with phlorizin-perfusion. Meanwhile, none of the SGLT2-inhibitors significantly affected cardiac function or myocardial injury after ischemia–reperfusion under either diet condition. The plasma membrane expression of GLUT4 was significantly increased after IRI in NFD but was substantially attenuated in HFD, the latter of which was associated with a significant reduction in myocardial glucose uptake. In contrast, SGLT1 expression at the plasma membrane remained constant during IRI, regardless of the diet condition, whereas SGLT2 was not detected in the hearts of any mice. Of note, phlorizin considerably reduced myocardial glucose uptake after IRI, particularly in HFD.ConclusionsCardiac SGLT1 but not SGLT2 plays a compensatory protective role during the acute phase of IRI via enhanced glucose uptake, particularly under insulin-resistant conditions, in which IRI-induced GLUT4 upregulation is compromised.

Physiological and pharmacological effects of melatonin on remote ischemic perconditioning after myocardial ischemia-reperfusion injury in rats: Role of Cybb, Fas, NfκB, Irisin signaling pathway.

It has been found that remote organ/limb temporary ischemia, known as remote ischemic conditioning, can provide protection against the formation of lethal ischemic outcome. Current evidence suggests that aging and age-releated comorbidities impair the cardioprotective effects of conditionings. In conjuction with aging, decrease in melatonin synthesis from pineal gland can have role in the pathogenesis of aging and age-related cardiovascular diseases. In this study, we investigated the effects of remote ischemic perconditioning (RIPerC) and physiological and pharmacological concentrations of melatonin on the infarct size, Fas gene, cytochrome b-245 beta chain (Cybb) gene, nuclear factor-kappa B (NfκB), and irisin using an in vivo model of myocardial ischemia/reperfusion (I/R) injury. Sprague-Dawley rats that were divided into two groups first as non-pinealectomized (Non-Px) and pinealectomized (Px), and then (a) Control; (b) I/R (30-minute ischemia, 120-minute reperfusion caused by left coronary artery ligation); (c) I/R+RIPerC (when myocardial ischemia initiated, three cycles of 5-minute occlusion followed by 5-minute reperfusion); (d) I/R+Mel; (e) Px; (f) Px+I/R; (g) Px+I/R+RIPerC; (h) Px+I/R+RIPerC+Mel groups. The infarct size was determined by TTC staining and analyzed by the ImageJ program. Molecular parameters were evaluated by qRT-PCR and Western blot. Results showed that increased infarct size in Non-Px groups decreased with RIPerC and melatonin. However, increased infarct size in Px groups was decreased minimally with RIPerC and significantly decreased with RIPerC+Melatonin. Fold change in Fas gene was associated with the infarct size. RIPerC and melatonin reduced expressions of Cybb, NfκB, and irisin genes. The physiological release and pharmacological concentration of melatonin may improve protective effect of RIPerC against I/R-induced infarct size by modulating Cybb, Fas, NfκB, Irisin signaling pathways.

Time-Dependent Myocardial Necrosis in Patients With ST-Segment-Elevation Myocardial Infarction Without Angiographic Collateral Flow Visualized by Cardiac Magnetic Resonance Imaging: Results From the Multicenter STEMI-SCAR Project.

BackgroundAcute complete occlusion of a coronary artery results in progressive ischemia, moving from the endocardium to the epicardium (ie, wavefront). Dependent on time to reperfusion and collateral flow, myocardial infarction (MI) will manifest, with transmural MI portending poor prognosis. Late gadolinium enhancement cardiac magnetic resonance imaging can detect MI with high diagnostic accuracy. Primary percutaneous coronary intervention is the preferred reperfusion strategy in patients with ST‐segment–elevation MI with <12 hours of symptom onset. We sought to visualize time‐dependent necrosis in a population with ST‐segment–elevation MI by using late gadolinium enhancement cardiac magnetic resonance imaging (STEMI‐SCAR project).Methods and Results ST‐segment–elevation MI patients with single‐vessel disease, complete occlusion with TIMI (Thrombolysis in Myocardial Infarction) score 0, absence of collateral flow (Rentrop score 0), and symptom onset <12 hours were consecutively enrolled. Using late gadolinium enhancement cardiac magnetic resonance imaging, the area at risk and infarct size, myocardial salvage index, transmurality index, and transmurality grade (0–50%, 51–75%, 76–100%) were determined. In total, 164 patients (aged 54±11 years, 80% male) were included. A receiver operating characteristic curve (area under the curve: 0.81) indicating transmural necrosis revealed the best diagnostic cutoff for a symptom‐to‐balloon time of 121 minutes: patients with >121 minutes demonstrated increased infarct size, transmurality index, and transmurality grade (all P<0.01) and decreased myocardial salvage index (P<0.001) versus patients with symptom‐to‐balloon times ≤121 minutes.ConclusionsIn MI with no residual antegrade and no collateral flow, immediate reperfusion is vital. A symptom‐to‐balloon time of >121 minutes causes a high grade of transmural necrosis. In this pure ST‐segment–elevation MI population, time to reperfusion to salvage myocardium was less than suggested by current guidelines.

L-α-Lysophosphatidylinositol (LPI) aggravates myocardial ischemia/reperfusion injury via a GPR55/ROCK-dependent pathway.

The phospholipid l‐α‐lysophosphatidylinositol (LPI), an endogenous ligand for GPR55, is elevated in patients with acute coronary syndrome, and a GPR55 antagonist cannabidiol (CBD) reduces experimental ischemia/reperfusion (I/R) injury. While LPI activates multiple signaling pathways, little is known about which ones are important in cardiomyocytes. In this study we explored whether activation of the Rho kinase/ROCK/p38 MAPK pathway is responsible for LPI‐induced extension of I/R injury. Using a high‐throughput screening method (dynamic mass redistribution; DMR), mouse‐ and human‐induced pluripotent stem cell (iPSC) cardiomyocytes exposed to LPI were shown to exhibit a rapid, sustained, and concentration‐dependent (1 nmol L−1‐30 μmol L−1) cellular response. Y‐27632 (ROCK inhibitor; 10 & 50 μmol L−1) and CBD (1 μmol L−1) both abolished the DMR response to LPI (10 μmol L−1). In murine iPSC cardiomyocytes, LPI‐induced ROCK and p38 MAPK phosphorylation, both of which were prevented by Y‐27632 and CBD, but did not induce JNK activation or cleavage of caspase‐3. In hearts isolated from wild type (WT) mice subjected to 30 minutes global I/R, LPI (10 μmol L−1) administered via the coronary circulation increased infarct size when applied prior to ischemia onset, but not when given at the time of reperfusion. The exacerbation of tissue injury by LPI was not seen in hearts from GPR55−/− mice or in the presence of Y‐27632, confirming that injury is mediated via the GPR55/ROCK/p38 MAPK pathway. These findings suggest that raised levels of LPI in the vicinity of a developing infarct may worsen the outcome of AMI.

Excessive Neutrophil Extracellular Trap Formation Aggravates Acute Myocardial Infarction Injury in Apolipoprotein E Deficiency Mice via the ROS-Dependent Pathway

Genetically human apolipoprotein E (APOE) ε32 is associated with a decreased risk of ischemic heart disease. ApoE deficiency in mice impairs infarct healing after myocardial infarction (MI). After the ischemic injury, a large number of neutrophils are firstly recruited into the infarct zone and then degrade dead material and promote reparative phase transformation. The role of ApoE in inflammation response in the early stage of MI remains largely unclear. In this study, we investigated the effect of ApoE deficiency on neutrophils' function and myocardial injury after myocardial infarction. By left coronary artery ligation in ApoE −/− and wild-type (WT) mice, we observed increased infarct size and neutrophil infiltration in ApoE −/− mice. Within the infarct zone, more neutrophil extracellular traps (NETs) were observed in ApoE −/− mice, while increased ex vivo NET formation was detected in ApoE −/− mouse-derived neutrophils through the NADPH oxidase-ROS-dependent pathway. Suppressing overproduced NETs reduced myocardial injury in ApoE −/− mice after ligation. In general, our findings reveal a critical role of apolipoprotein E in regulating Ly6G+ neutrophil activation and NET formation, resulting in limiting myocardial injury after myocardial infarction. In such a process, apolipoprotein E regulates NET formation via the ROS-MAPK-MSK1 pathway.

Downregulation of microRNA-155 stimulates sevoflurane-mediated cardioprotection against myocardial ischemia/reperfusion injury by binding to SIRT1 in mice.

The inhaled sevoflurane has been demonstrated to protect against myocardial ischemia/reperfusion (I/R) injury. However, the relative mechanisms of sevoflurane-mediated cardioprotection remain largely unknown. This study intends to explore the effect of miR-155 on the sevoflurane-mediated cardioprotection by regulating Sirtuin 1 (SIRT1) in mouse models of myocardial I/R. Left anterior descending coronary artery ligation was used to induce models of myocardial I/R in mice. The I/R mice were treated with sevoflurane, sevoflurane + mimics negative control (NC) or sevoflurane + miR-155 mimics. The expression of microRNA-155 (miR-155) and SIRT1 was examined by quantitative real-time polymerase chain reaction and Western blot assay. Then cardiac functions and hemodynamic alterations were evaluated. Evans blue-2,3,5-triphenyltetrazolium chloride and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling assay staining methods were adopted to evaluate infarct size and cardiomyocyte apoptosis, respectively. In the I/R mice, miR-155 was expressed at a high level and SIRT1 at a low level. SIRT1 was confirmed to be a target gene of miR-155. The treatment of sevoflurane could reduce miR-155 expression and increased SIRT1 expression in the myocardial tissues, under which conditions, cardiac functions were promoted, accompanied by reduced infarct size and inhibited cardiomyocyte apoptosis. In response to miR-155 upregulation, the sevoflurane-treated I/R mice showed reduced cardiac functions, and increased infarct size and cardiomyocyte apoptosis. The findings obtained in this study provide evidence suggesting that miR-155 targets and negatively regulates SIRT1 expression, a mechanism by which the protection of sevoflurane is inhibited against myocardial I/R in mice.

The critical role of the zinc transporter Zip2 (SLC39A2) in ischemia/reperfusion injury in mouse hearts

Although zinc homeostasis has been demonstrated to play a role in myocardial ischemia/reperfusion (I/R) injury, the roles of zinc transporters that are critical for zinc homeostasis in I/R injury are poorly understood. The purpose of this study was to test if Zip2, an important zinc importer, plays a role in I/R injury in mouse hearts and explore the mechanism by which Zip2 expression is regulated. Zip2 expression was increased at reperfusion in in vivo mouse hearts, an effect that was abolished by ZnCl2, indicating Zip2's attempt to compensate for zinc loss at reperfusion. Further studies showed that upregulation of Zip2 expression was reversed by either pharmacological or genetic inhibition of signal transducers and activators of transcription 3 (STAT3), whereas STAT3 overexpression increased Zip2 expression, indicating that STAT3 accounts for Zip2 upregulation. In support, reperfusion enhanced STAT3 phosphorylation (Tyr705), which was blocked by ZnCl2, implying that STAT3 is activated in response to zinc loss. To determine the role of Zip2 in I/R injury, we assessed I/R injury by genetically disrupting Zip2 expression. Knockout of Zip2 genes (Zip2+/− and Zip2−/−) exacerbated I/R injury by increasing infarct size as well as the serum LDH, troponin I (cTnI), and CK-MB activities. In contrast, delivery of Zip2 genes reduced I/R injury. Delivery of STAT3 genes increased STAT3 phosphorylation and reduced I/R injury. However, delivery of the dominant negative STAT3 mutant did not reduce I/R injury. Moreover, delivery of STAT3 genes failed to reduce I/R injury in Zip2−/− mice. Zip2 upregulated upon reperfusion via STAT3 is cardioprotective and this upregulation may serve as an important intrinsic protective mechanism by which the heart is resistant to I/R injury. The factors involved in the zinc homeostasis (zinc and Zip2) are responsible STAT3 activation and its subsequent cardioprotective action.

Functional suppression of Epiregulin impairs angiogenesis and aggravates left ventricular remodeling by disrupting the extracellular-signal-regulated kinase1/2 signaling pathway in rats after acute myocardial infarction.

Acute myocardial infarction (AMI), a severe consequence of coronary atherosclerotic heart disease, is often associated with high mortality and morbidity. Emerging evidence have shown that the inhibition of the extracellular-signal-regulated kinase (ERK) signaling pathway appears to protect against AMI. Epiregulin (EREG) is an autocrine growth factor that is believed to activate the MEK/ERK signaling pathway. Therefore, the aim of the present study was to determine the expression patterns of EREG in AMI and to further study its effects on AMI induced experimentally in rats focusing on angiogenesis and left ventricular remodeling. Microarray-based gene expression profiling of AMI was used to identify differentially expressed genes. To understand the biological significance of EREG and whether it is involved in AMI disease through the ERK1/2 signaling pathway, rats after AMI were treated with small interfering RNA (siRNA) against EREG, an ERK1/2 pathway inhibitor, PD98059, or both of them. The microarray data sets GSE66360 and GSE46395 showed that EREG was robustly induced in AMI. Both siRNA-mediated depletion of EREG and PD98059 treatment were shown to significantly increase infarct size and left ventricular cardiomyocyte loss and enhance left ventricular remodeling. In addition, we also found that the ERK1/2 signaling pathway was inhibited following siRNA-mediated EREG inhibition and PD98059 could enhance the effects of EREG inhibition on AMI. In conclusion, these findings highlight that the silencing of EREG inhibits angiogenesis and promotes left ventricular remodeling by disrupting the ERK1/2 signaling pathway, providing a novel therapeutic target for limiting AMI.

The cardiovascular effects of Aspalathus linearis supplementation in male Wistar rats receiving fixed-dose combination first-line antiretroviral therapy.

HIV-infected populations receiving antiretroviral therapy (ART) have an increased risk of cardiovascular disease. The beneficial cardiovascular effects of rooibos are well described; however, it is unknown whether rooibos ameliorates harmful ART-induced cardiovascular side effects. We investigated the cardiometabolic effects of rooibos co-treatment in rats receiving ART (efavirenz, emtricitabine, tenofovir) for nine weeks. Rooibos treatment reduced total cholesterol levels; however, triglyceride, phospholipid and thiobarbituric acidreactive substance levels were unaffected by ART, rooibos or combination treatment. In isolated hearts exposed to ischaemia-reperfusion injury, ART resulted in increased infarct sizes compared to controls, which was not observed when co-treated with rooibos. Vascular studies showed reduced aortic relaxation with ART, and improved relaxation when co-treated with rooibos. In conclusion, we show that rooibos treatment reduced total cholesterol levels in control rats, and that rooibos co-treatment ameliorated the harmful ART-induced cardiovascular effects. These findings are novel and warrant further studies into underlying mechanisms and clinical relevance.

MP52: Prehospital opioid administration to acute myocardial infarction patients: a systematic review

Introduction: Opioids are routinely administered for analgesia to prehospital patients experiencing chest discomfort from acute myocardial infarction (AMI). We conducted a systematic review to determine if opioid administration impacts patient outcomes. Methods: We conducted a systematic search using MeSH terms and keywords in Medline, Embase, Cochrane Database of Systematic Reviews, Cochrane Central and Clinicaltrials.gov for relevant randomized controlled trials and observational studies comparing opioid administration in AMI patients from 1990 to 2017. The outcomes of interest were: all-cause short-term mortality (≤30 days), major adverse cardiac events (MACE), platelet activity and aggregation, immediate adverse events, infarct size, and analgesia. Included studies were hand searched for additional citations. Risk of Bias assessments were performed and GRADE methodology was employed to assess quality and overall confidence in the effect estimate. Results: Our search yielded 3001 citations of which 19 studies were reviewed as full texts and a total of 9 studies were included in the analysis. The studies predominantly reported on morphine as the opioid. Five studies reported on mortality (≤30 days), seven on MACE, four on platelet activity and aggregation, two on immediate adverse events, two on infarct size and none on analgesic effect. We found low quality evidence suggesting no benefit or harm in terms of mortality or MACE. However, low quality evidence indicates that opioids increase infarct size. Low-quality evidence also shows reduced serum P2Y12 (eg: clopidogrel and ticagrelor) active metabolite levels and increased platelet reactivity in the first several hours post administration following an increase in vomiting. Conclusion: We find low and very low quality evidence that the administration of opioids in STEMI may be adversely related to vomiting and some surrogate outcomes including increased infarct size, reduced serum P2Y12 levels, and increased platelet activity. We found no clear benefit or harm on patient-oriented clinical outcomes including mortality.

Targeting the HIV-infected brain to improve ischemic stroke outcome

HIV-associated cerebrovascular events remain highly prevalent even in the current era of antiretroviral therapy (ART). We hypothesize that low-level HIV replication and associated inflammation endure despite antiretroviral treatment and affect ischemic stroke severity and outcomes. Using the EcoHIV infection model and the middle cerebral artery occlusion as the ischemic stroke model in mice, we present in vivo analysis of the relationship between HIV and stroke outcome. EcoHIV infection increases infarct size and negatively impacts tissue and functional recovery. Ischemic stroke also results in an increase in EcoHIV presence in the affected regions, suggesting post-stroke reactivation that magnifies pro-inflammatory status. Importantly, ART with a high CNS penetration effectiveness (CPE) is more beneficial than low CPE treatment in limiting tissue injury and accelerating post-stroke recovery. These results provide potential insight for treatment of HIV-infected patients that are at risk of developing cerebrovascular disease, such as ischemic stroke.

Gallic acid protects particulate matter (PM10) triggers cardiac oxidative stress and inflammation causing heart adverse events in rats.

Previous studies have shown that exposure to particulate matter (PM) increased variety of health problems, particularly cardiovascular diseases leading to premature mortality. The cardiac effects of particulate matter containing PM10 include increased infarct size, decreased heart function, and increased arrhythmias in experimental ischemia-reperfusion models in rats. The aim of this study was to evaluate the effects of particles with an aerodynamic diameter smaller than 10 μm (PM10) on isolated-rat heart and also to determine the efficacy of gallic acid (GA) as a preventive agent in oxidative damage. The healthy rats were divided into 8 equal groups which served as, control, GA, PM10 (0.5, 2.5, and 5 mg/kg), and PM10+GA groups. PM10 administered into the lungs via the trachea in two stages with 48-h interval. After all experiments, the electrocardiogram was recorded. Then, the hemodynamic parameters and ventricular arrhythmias in rat isolated-hearts were assessed using Langendorff apparatus and according to the Lambeth conventions. In addition, the inflammation and oxidative stress factors in cardiac tissues were evaluated in all groups. The obtained results showed that the exposure to PM caused to decrease in cardiac hemodynamic and electrocardiogram parameters. Also, in PM10 rat groups, the IL-6, TNF-α, and oxidative stress parameters were increased. Gallic acid preserved the value of cardiac parameters and inflammation in rat hearts. In summary, we added a novel therapeutic effect of gallic acid for cardiac dysfunction induced by particulate matter. These findings could be related to antioxidant and antiinflammation properties and the obtained results suggest that natural antioxidant like gallic acid could be a therapeutic agent in prevention and management of health issues in the polluted areas of the world.

Clinical and procedural predictors of suboptimal myocardial reperfusion in primary percutaneous coronary intervention

BackgroundSuboptimal myocardial perfusion in primary PCI is associated with increased infarct size, left ventricular (LV) dysfunction and higher mortality rates as compared as those with optimal myocardial perfusion. We identified clinical and procedural predictors of suboptimal myocardial reperfusion as judged by myocardial plush grade (MBG) in primary PCI. Methods and Results100 patients with acute STEMI who underwent primary PCI were prospectively subjected to clinical, ECG, laboratory and angiographic evaluation. Patients were classified into: Optimal myocardial reperfusion group: (n=73) who had final MBG=3. Suboptimal myocardial reperfusion group: (n=27) who had persistent final MBG ≤ 2. Suboptimal myocardial reperfusion group had statistically significant little history of angina prior to MI 5 (18.5%) vs 44 (60.3%), little current aspirin intake 6(22%) vs 38 (52% ), increased blood sugar on admission (240 ± 101 mg/dl vs 171 ± 72 mg/dl), increased total leucocytic count on admission (12.1 ± 3.6 vs 10.2 ± 3.3) 103/mm3, longer reperfusion time (6.1 ± 2.8 vs 4.3 ± 2.1 h ), higher thrombus burden 12 (44.4 % ) vs 13 (17.8 %), higher predilatation pressure (16 ± 2.3 vs 14 ± 1.8 ATM), repeated balloon inflation during predilatation 24 (92.3 % ) vs 46 (69.7%) as compared optimal myocardial reperfusion group, (P < 0.05 for all). ConclusionLonger reperfusion time, repeated balloon inflations, high predilatation pressure> 15 ATM , high thrombus burden, neither history of angina nor aspirin intake prior to AMI, high total leucocytic count > 10103/mm3 and high blood glucose level > 160mg/dl were predictors for persistent suboptimal myocardial reperfusion in primary PCI.

TRAF2 protects against cerebral ischemia-induced brain injury by suppressing necroptosis

Necroptosis contributes to ischemia-induced brain injury. Tumor necrosis factor (TNF) receptor associated factor 2 (TRAF2) has been reported to suppress necroptotic cell death under several pathological conditions. In this study, we investigated the role of TRAF2 in experimental stroke using a mouse middle cerebral artery occlusion (MCAO) model and in vitro cellular models. TRAF2 expression in the ischemic brain was assessed with western blot and real-time RT-PCR. Gene knockdown of TRAF2 by lentivirus was utilized to investigate the role of TRAF2 in stroke outcomes. The expression of TRAF2 was significantly induced in the ischemic brain at 24 h after reperfusion, and neurons and microglia were two of the cellular sources of TRAF2 induction. Striatal knockdown of TRAF2 increased infarction size, cell death, microglial activation and the expression of pro-inflammatory markers at 24 h after reperfusion. TRAF2 expression and necroptosis were induced in mouse primary microglia treated with conditioned medium collected from neurons subject to oxygen and glucose deprivation (OGD) and in TNFα-treated mouse hippocampal neuronal HT-22 cells in the presence of the pan-caspase inhibitor Z-VAD. In addition, TRAF2 knockdown exacerbated microglial cell death and neuronal cell death under these conditions. Moreover, pre-treatment with a specific necroptosis inhibitor necrostatin-1 (nec-1) suppressed the cell death exacerbated by TRAF2 knockdown in the brain following MCAO, indicating that TRAF2 impacted ischemic brain damage through necroptosis mechanism. Taken together, our results demonstrate that TRAF2 is a novel regulator of cerebral ischemic injury.

Inflammatory biomarkers kinetic in STEMI patients and their relationship with infarct size and LVEF

Myocardial infarction (MI) is followed by an intense inflammatory response which is necessary for the healing of the infarcted area, but which can also have deleterious effect by increasing infarct size (IS). A good knowledge of this inflammatory response is necessary to develop new treatments targeting this phase. Our study aims at describing the temporal kinetic of inflammatory biomarkers in ST-elevation MI (STEMI) patients and to evaluate their correlation with IS and left ventricular ejection fraction (LVEF). We included 100 patients of our HIBISCUS cohort (STEMI patients cohort) with blood samples collected at admission (H0), then 4 (H4), 24 (H24), 48 hours (H48) and 1 month (M1) after reperfusion. C-reactive protein (CRP), interleukin(IL)-1β, IL-1α, IL-6, IL-8, IL-10, tumor necrosis factor (TNFα), Growth Differentiation Factor 15 (GDF15) and interleukin 1 receptor-like 1 (ST2) were assessed in the serum by ELISA. All patients underwent a cardiac magnetic resonance imaging (CMR) at 1 month. Patient were aged of 57 ± 10 years. Contrary to other biomarkers, IL-1β, IL-1α and TNFα were weakly detectable in the serum. CRP reached a peak at H48 with a median of 11.7 mg/L interquartile range (IQR) [2.3–29.1]. IL-6 peaked at H24 with 4.8 pg/mL IQR [1.9–14.3], IL-8 at H24 with 2.6 pg/mL IQR [1.3–4.7], IL-10 at H0 with 5.7 pg/mL IQR [2.9–11.3], GDF15 at H0 with 203.7 pg/mL IQR [106.0–301.6] and ST2 at H24 with 25.6 pg/mL IQR [16.8–37.7]. Only CRP, IL-6, IL-10 and ST2 were significantly corelated with IS (respectively r = 0.51, P < 0.0001; r = 0.57, p < 0.0001; r = 0.53, P < 0.0001; r = 0.35, P = 0.0004) and inversed correlated with LVEF (respectively r = −0.38, P = 0.0002; r = −0.50, P < 0.0001; r = −0.41, P < 0.0001; r = −0.23, P = 0.02) assessed by CMR. During STEMI, we observed a specific kinetic for each biomarker with variable peak time. CRP, IL-6, IL-10 and ST2 were significantly correlated with IS and inversely correlated with LVEF.