Reperfusion Injury In Patients Research Articles

The role of arginine vasopressin in the pathophysiology of microvascular dysfunction after ST-elevation myocardial infarction

Abstract Background Coronary microvascular dysfunction (CMD) after ST-elevation myocardial infarction (STEMI), in part due to impaired vasomotor tone, predicts heart failure and mortality at one year. Arginine vasopressin (AVP) may be implicated in CMD as it is released during MI and has known vasoconstrictor effects, but data in humans are lacking. We examined the role of copeptin, a stable plasma surrogate marker of AVP, in humans with STEMI. Methods We included three cohorts. The first cohort prospectively recruited patients presenting with STEMI eligible for primary percutaneous coronary intervention (PPCI) (n= 55). In this cohort, the index of microcirculatory resistance (IMR) and coronary flow reserve (CFR) were measured in the culprit artery at the end of the procedure. The second cohort included 45 patients from a sub-study of the CAPRI trial (Evaluating the effectiveness of intravenous Ciclosporin on reducing reperfusion injury in pAtients undergoing PRImary PCI; NCT02390674). In this cohort, patients underwent cardiac magnetic resonance (CMR) imaging at one and 12 weeks post-MI, allowing precise measurement of infarct size and microvascular obstruction (MVO), the imaging hallmark of CMD. Both cohorts had serum copeptin measured at four time points. The 3rd cohort included two patients undergoing trans-coronary alcohol ablation of septal hypertrophy (TASH). Serial copeptin measurements were performed in this cohort to assess copeptin release in an induced ischaemia setting. Results One hundred patients were included from both STEMI cohorts. Copeptin levels paralleled AVP plasma levels closely, with mean levels falling in the 24 hours after reperfusion from 92.5 pmol/L to 6.4 pmol/L, and this was mirrored in the TASH patients. Copeptin release wasinversely linked to admission diastolic blood pressure (DBP) (Spearman’s rho r= -0.431, p=0.001), but did not correlate with systolic blood pressure. Copeptin levels at 24 hours were significantly associated with high IMR (r=0.372, p=0.011) and low CFR (r=-0.467, p=0.001). Patients with IMR >40 also had significantly higher mean copeptin concentration at 24 hours than those with lower IMR (19.1 vs 7.1pmol/L, p=0.019, Figure 1). Finally, patients with MVO on early CMR showed a trend towards higher mean copeptin concentration at baseline, although this was not statistically significant. Notably, copeptin levels were not associated with infarct size on either early or late CMR. Conclusions Copeptin, and therefore AVP, is released secondary to acute myocardial ischaemia, particularly in response to reduced coronary perfusion, as evidenced by the inverse correlation with DBP, and normalises by 24 hours. However, evidence of CMD was seen in patients with persistently elevated copeptin at 24 hours, suggesting AVP may contribute to microcirculatory dysfunction. AVP receptor antagonists may represent a novel therapeutic option in patients with STEMI and evidence of microvascular dysfunction.

The role of therapeutic hypothermia in reducing of the reperfusion injury in patients with STEMI

Despite timely coronary reperfusion, about 7% of patients with acute myocardial infarction die during hospitalization and around 23% survivors develop heart failure within one year. Reperfusion injury is largely responsible for the final infarct size. Although, there is some progress in myocardial revascularization, prevention and treatment of the reperfusion injury in myocardial infarction patients is not successful enough in clinical practice. Hypothermia can reduce reperfusion injury and improve survival and reduce the number of complications in patients with myocardial infarction.

Ischemic Postconditioning Confers No Benefit to Left Ventricular Systolic Function: A Meta-Analysis of Cardiac Magnetic Resonance Imaging Results

Ischemic postconditioning (IPoC) is a technique suggested to reduce reperfusion injury in patients suffering acute ST-elevation myocardial infarction (STEMI), although its use is highly controversial. This meta-analysis aimed to evaluate the effect of IPoC with percutaneous coronary intervention in patients with acute STEMI, as measured by follow-up left ventricular ejection fraction (LVEF) on cardiac magnetic resonance imaging. The investigators searched PubMed, Embase, and Web of Science for all randomized controlled trials published during the last 2 decades. After the removal of duplicates, 2,021 articles from online databases had been identified using relevant search criteria. The included randomized controlled trials had studied patients with acute STEMI and Thrombolysis in Myocardial Infarction flow 0 to 1 at presentation and had measured follow-up LVEF using cardiac magnetic resonance imaging. Overall, 11 studies (n=1,339 patients) qualified for inclusion. In each study, the control group did not differ significantly from the experimental group. The pooled data from included studies were analyzed using standardized mean difference between IPoC and control groups, and the 95% confidence interval for LVEF; the results were visualized using a forest plot. Bivariate regression analyses and 1-way analyses of LVEF coefficient ratios were done to isolate for various clinical and procedural parameters. An analysis of pooled data of the IPoC (n=674) and control (n=665) groups showed that IPoC did not significantly impact follow-up LVEF (using standardized mean difference 0.10, 95% confidence interval 0.00 to 0.21). Further analysis showed that IPoC did not improve follow-up LVEF when isolating for relevant clinical and procedural parameters. In conclusion, the use of IPoC as an adjunctive therapy to percutaneous coronary intervention seemingly provides no benefit to left ventricular systolic function, as quantified with cardiac magnetic resonance imaging, in patients with acute STEMI with Thrombolysis in Myocardial Infarction flow 0 to 1.

Cardioprotective Effects of Melatonin in Patients Undergoing PPCI

Background: One of the pitfalls of primary percutaneous coronary intervention (PPCI) is myocardial reperfusion injury caused by several pathophysiological mechanisms. Melatonin has been shown to be effective against this condition in various organs. Some of the biological effects of melatonin are associated with its capability to scavenge free radicals and reinforce the activity of antioxidant enzymes. Methods: The study population included 128 patients admitted with a diagnosis of acute ST-elevation myocardial infarction (STEMI) to the Emergency Department of Modarres Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran, who subsequently underwent PPCI. The patients were randomly assigned to two groups, each consisting of 64 cases, with those receiving 3 mg of melatonin in the emergency department before adding PPCI to the standard treatment (test group) and those receiving the standard therapy alone (control group). The myocardial blush grade (MBG) and thrombolysis in myocardial infarction frame count were assessed visually on the angiogram to evaluate microvascular integrity. Results: In the study as a whole and in subgroup analysis, the MBG showed a significant difference with melatonin prescription (2.8 ± 0.3 and 2.3 ± 0.7 in the test and control groups, respectively; P < 0.001). In patients with coronary risk factors, no difference was observed between the two groups. Nevertheless, melatonin significantly improved the MBG in patients without such risk factors. Melatonin had significant protective effects in both the right coronary and left anterior descending culprit arteries. Conclusions: This study demonstrated the effect of melatonin on preventing reperfusion injury in patients with STEMI undergoing PPCI.

Imatinib attenuates reperfusion injury in a rat model of acute myocardial infarction

Following an acute myocardial infarction, reperfusion of an occluded coronary artery is often accompanied by microvascular injury, leading to worse long-term prognosis. Experimental studies have revealed the potential of tyrosine-kinase inhibitor imatinib to reduce vascular leakage in various organs. Here, we examined the potential of imatinib to attenuate microvascular injury in a rat model of myocardial reperfusion injury. Isolated male Wistar rat hearts (n = 20) in a Langendorff system and male Wistar rats (n = 37) in an in vivo model were randomly assigned to imatinib or placebo and subjected to ischaemia and reperfusion. Evans-blue/Thioflavin-S/TTC staining and Cardiac Magnetic Resonance Imaging were performed to assess the extent of reperfusion injury. Subsequently, in vivo hearts were perfused ex vivo with a vascular leakage tracer and fluorescence and electron microscopy were performed. In isolated rat hearts, imatinib reduced global infarct size, improved end-diastolic pressure, and improved rate pressure product recovery compared to placebo. In vivo, imatinib reduced no-reflow and infarct size with no difference between imatinib and placebo for global cardiac function. In addition, imatinib showed lower vascular resistance, higher coronary flow, and less microvascular leakage in the affected myocardium. At the ultrastructural level, imatinib showed higher preserved microvascular integrity compared to placebo. We provide evidence that low-dose imatinib can reduce microvascular injury and accompanying myocardial infarct size in a rat model of acute myocardial infarction. These data warrant future work to examine the potential of imatinib to reduce reperfusion injury in patients with acute myocardial infarction.

Abstract P1047: Imatinib Attenuates Reperfusion Injury In A Rat Model Of Acute Myocardial Infarction

Background: Reperfusion of an occluded coronary artery is often accompanied by injury of the microvasculature (MVI), which portends a worse long term prognosis after an acute myocardial infarction (AMI). In previous experimental studies, the tyrosine-kinase inhibitor imatinib has shown to reduce vascular leakage and therefore could have a potential role to prevent MVI. This study aims to provide a potential therapeutic approach using imatinib to attenuate reperfusion injury. Methods: First, 16 isolated male Wistar rat hearts were randomly assigned to 10 μM imatinib or placebo and subjected to 40 min of global ischemia followed by 120 min of reperfusion ex vivo in a Langendorff setup. Global infarct size and mechanical function were assessed. Second, 25 male Wistar rats were randomly assigned to 30 mg/kg imatinib or placebo intravenously and subjected to 45 min of left anterior descending coronary artery ligation followed by 180 min of reperfusion in vivo. Cardiovascular magnetic resonance imaging was performed to assess infarct size and cardiac function. Subsequently, hearts were perfused ex vivo with a fluorescent vascular leakage tracer and used for fluorescence- and electron microscopy. Results: In isolated hearts, imatinib reduced global infarct size (imatinib 36.2±7.9 vs placebo 50.0±8.0% infarcted area/total area, p<0.01), improved end diastolic pressure (imatinib 44.2±8.0 vs placebo 59.5±13.5 mmHg, p<0.05) and rate pressure product recovery (imatinib 39.0±6.8 vs placebo 26.2±7.6% of baseline, p<0.05). In vivo, imatinib reduced infarct size (imatinib 12.6±8.8 vs placebo 25.6±9.3% infarcted area/left ventricle, p<0.01), but did not improve global cardiac function. At the end of reperfusion, imatinib showed lower vascular resistance, higher coronary flow and less microvascular leakage (all p<0.05). At the ultrastructural level, imatinib showed better preserved microvascular integrity compared to placebo. Conclusion: This study provides evidence that imatinib attenuates reperfusion injury in an ex vivo and in vivo AMI rat model, mainly by protection of the coronary microcirculation. These data warrant future work to examine the potential of imatinib to reduce reperfusion injury in patients with AMI.

Changes of creatine phosphokinase MB levels in the context of myocardial reperfusion injury

In patients with initially elevated levels of creatine phosphokinase MB (CPK-MB), its increase after percutaneous coronary intervention (PCI) may be due not only to additional injury, but also to natural release during myocardial infarction. Therefore, CPK-MB should be evaluated relative to the initial values.Aim. To compare the CPK-MB dynamics after myocardial reperfusion relative to baseline values and the upper limit of normal (ULN) for the optimal approach to determining myocardial reperfusion injury in patients with acute coronary syndrome.Material and methods. A single center observational study was conducted with the participation of 90 patients hospitalized with a diagnosis of acute coronary syndrome. Patients underwent a biochemical blood test for CPK-MB twice and its dynamics was determined relative to the initial value and ULN.Results. Between the ischemia time and CPK-MB dynamics relative to the initial values, there is a moderate negative correlation. At the same time, the ratio of CPKMB after surgery to ULN is not associated with ischemia time. Analysis of covariance showed that the CPK-MB dynamics, determined relative to the initial values, is 20% dependent on the ischemia time. Individual features of coronary system anatomy, localization of the infarct-associated artery and the subsequent reperfusion procedure together explain the CPK-MB dynamics after surgery by 27%. When the ratio of CPK-MB to ULN is included in the analysis of covariance, all the above factors lose statistical significance.Conclusion. Thus, for a more accurate assessment of myocardial reperfusion injury after PCI, not the upper limit of normal should be analyzed, but the initial values of CPK-MB. In patients with the left heart dominant, as well as in the infarction localization in the system of right or left anterior descending artery, there is a slight change in the marker. On the contrary, more pronounced dynamics is observed in patients with tortuous coronary arteries and with implantation of 2 or more stents. At the same time, the assessment of CPK-MB in relation to ULN is not associated with the ischemia time and does not depend on the clinical and angiographic characteristics and tactics of the operation.

Preventative effects of dapagliflozin on early ventricular dysfunction and remodeling in patients with acute anterior STEMI - The PREDOMINACE trial

BackgroundSodium glucose cotransporter 2 inhibitors (SGLT-2i) are oral hypoglycemic drugs that can reduce the risk of deteriorating heart failure (HF) or cardiovascular death in patients with HF. Although some animal models have shown that SGLT-2i can effectively inhibit reperfusion injury after acute myocardial infarction (AMI), there is no clinical evidence to prove that SGLT-2i can also play a significant role in improving reperfusion injury in patients with AMI. Therefore, PREDOMINACE study enrolled patients with acute anterior large ST-segment elevation myocardial infarction, who are at high risk of developing HF in the future. The aim of this trial is to study the prevention effects of dapagliflozin on early ventricular dysfunction and remodeling in patients with acute anterior ST-segment elevation myocardial infarction (STEMI), and to explore the efficacy and safety of dapagliflozin in the treatment of patients with diabetes and without diabetes after acute anterior STEMI. MethodsWithin a multi-center, randomized, single-blind, controlled trial we will recruit patients with acute anterior STEMI from the Second Hospital of Tianjin Medical University and Tianjin Chest Hospital, who are randomly divided into intervention group or control group in a 1:1 ratio. The intervention group was given dapagliflozin (10 mg once daily) before primary percutaneous coronary intervention (PPCI) and 30 days after PPCI, while the control group is not given SGLT-2i. The primary endpoint is the impact of dapagliflozin on changes of NT-proBNP levels in 30 days of acute anterior STEMI. Secondary endpoints include changes in echocardiographic left ventricular remodeling parameters (LVESV, LVEDV, EF), and the changes of ECG (Q wave leads 30 days after PPCI/ST-segment elevation leads at baseline,ST-segment decline degree 24 h and 7 days after PPCI). Hospitalization rate due to HF or other causes, incidence of malignant arrhythmias, and all-cause mortality will be assessed as exploratory secondary endpoints. DiscussionThe PREDOMINACE trial will test dapagliflozin in patients with acute anterior STEMI, regardless of the presence or absence of diabetes. Therefore, the PREDOMINACE trial may support that the effects of SGLT-2i on improving cardiac remodeling, reducing cardiac pre and after load and improving cardiac metabolism are independent of its antidiabetic effects. Results will provide the clinical rationale for SGLT-2i to improve prognosis in patients with AMI.Trial registration: Chinese Clinical Trial Registry. Identifier: ChiCTR2100048157. Registered 23 September 2021.

Hypothermia for Cardioprotection in Patients with St-Elevation Myocardial Infarction: Do Not Give It the Cold Shoulder Yet!

The timely revascularization of an occluded coronary artery is the cornerstone of treatment in patients with ST-elevation myocardial infarction (STEMI). As essential as this treatment is, it can also cause additional damage to cardiomyocytes that were still viable before reperfusion, increasing infarct size. This has been termed “myocardial reperfusion injury”. To date, there is still no effective treatment for myocardial reperfusion injury in patients with STEMI. While numerous attempts have been made to overcome this hurdle with various experimental therapies, the common denominator of these therapies is that, although they often work in the preclinical setting, they fail to demonstrate the same results in human trials. Hypothermia is an example of such a therapy. Although promising results were derived from experimental studies, multiple randomized controlled trials failed to do the same. This review includes a discussion of hypothermia as a potential treatment for myocardial reperfusion injury, including lessons learned from previous (negative) trials, advanced techniques and materials in current hypothermic treatment, and the possible future of hypothermia for cardioprotection in patients with STEMI.

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.

Effect of Shenfu Injection on Reperfusion Injury in Patients Undergoing Primary Percutaneous Coronary Intervention for ST Segment Elevation Myocardial Infarction: A Pilot Randomized Clinical Trial.

Background: Shenfu injection is a traditional Chinese medicine formulation that alleviates ischemia-reperfusion injury through multiple pharmacologic effects. However, no data are available regarding its efficacy in patients with myocardial infarction. We aimed to examine the effects of Shenfu injection on infarct size in patients with ST segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI).Methods: From April 2016 to February 2018, 40 patients with first-time anterior STEMI undergoing primary PCI within 6 h of symptom onset were randomized 1:1 to intravenous Shenfu injection (80 ml Shenfu injection + 70 ml 5% glucose injection) or placebo (150 ml 5% glucose injection) before reperfusion. Treatment started before PCI and maintained for 5 days after PCI. The primary end point was infarct size assessed by CK-MB area under the curve (AUC) over 72 h and cardiac magnetic resonance (CMR) imaging 4 ± 1 days after PCI.Results: Infarct size by area under the curve for CK-MB over 72 h did not differ between the Shenfu injection and placebo groups (5602.5 [3539.4–7526.4] vs. 6403.2 [2234.4–8340.6] ng·h/ml, P = 0.82). Among 32 patients who underwent CMR Imaging, a nominal reduction in infarct size was observed in the Shenfu injection group compared with the placebo group (23.9 [15.2–28.5] % vs. 27 [21.9–31.9] %, P = 0.42). After excluding patients with no or minimal infarct, there was a trend toward reduction in infarct size in the Shenfu injection group (24.1 [20.3–29.3] % vs. 29.1 [24.5–32] %, P = 0.18). Incidence of adverse events was similar between the groups.Conclusions: This pilot study showed that the use of Shenfu injection was safe but did not reduce infarct size by CMR Imaging and CK-MB release kinetics in reperfused patients with STEMI. Larger studies (confining to patients with extensive infarct size) to evaluate the efficacy of Shenfu injection on reperfusion injury are warranted.Clinical Trail Registration: clinicaltrials.gov, identifier: NCT02709798.

Glycaemic status and reperfusion injury in patients with ST-segment elevation myocardial infarction

Abstract Background Failed myocardial tissue reperfusion due to microvascular injury despite successful culprit lesion percutaneous coronary intervention (PCI) is associated with poor clinical outcome in patients with ST-elevation myocardial infarction (STEMI). A possible influence of dysglycaemia on myocardial reperfusion injury is unclear. Objectives To investigate the association between glycaemic status and microvascular injury determined by magnetic resonance imaging in STEMI patients. Methods This prospective observational cohort study included 260 consecutive STEMI patients undergoing primary PCI between 2016 and 2019. Peripheral venous blood samples for glucose and HbA1c measurements were drawn on admission. Primary microvascular injury endpoint was defined as presence of intramyocardial haemorrhage (IMH) assessed by cardiac magnetic resonance T2* mapping at 4 (interquartile range [IQR]:2–5) days after PCI. Results HbA1c (odds ratio [OR]: 1.73 [95% CI: 1.24–2.40]; p=0.001), pre-diagnosis of diabetes (OR: 2.63 [95% CI: 1.18–5.90]; p=0.02) and glucose concentration (OR: 1.01 [95% CI: 1.00–1.01]; p=0.01) significantly predicted IMH, which was present in 90 (35%) patients. Of these three parameters, only HbA1c remained significantly associated with IMH (OR: 2.12 [95% CI: 1.12–3.99]; p=0.02) after adjusting for total ischemic time, culprit lesion location, pre- and post-interventional TIMI flow and peak biomarker concentrations (troponin, N-terminal pro-B-type natriuretic peptide and C-reactive protein). The rate of IMH was 24% in patients with HbA1c &amp;lt;5.7%, 43% in patients with HbA1c ≥5.7 to 6.4% and 59% in patients with HbA1c ≥6.5% (p&amp;lt;0.001). Conclusions In STEMI patients undergoing primary PCI, admission HbA1c was independently associated with reperfusion injury as determined by IMH. These findings suggest that IMH could represent the underlying pathophysiological link between dysglycaemia and adverse outcomes following STEMI. Funding Acknowledgement Type of funding sources: Public grant(s) – EU funding. Main funding source(s): FWF - Austrian Science Fund; ÖKG - Austrian Society of Cardiology Figure 1. This figure illustrates the relation between HbA1c and IMH by two patient examples successfully treated with PCI (intervention with stent implantation schematically shown on the very left side). The first patient (upper line), representing the patient group with HbA1c &amp;lt;5.7% (associated IMH risk 24%), showed an anterior wall STEMI without IMH (T2* mapping on the very right, corresponding schematic picture of the infarct area without IMH next on the left). The second patient (lower line), representing the patients with HbA1c ≥5.7% (associated IMH risk 47%), showed an anterior wall STEMI with large IMH (arrows point to the hypo-intense core on the T2* mapping image and to the corresponding dark-red area in the schematic illustration). The zoomed view of one microvessel indicates the complex pathophysiology of IMH (including endothelial destruction, embolisation of thrombotic material and inflammation). (Created with BioRender)

Joint Cardioprotective Effect of Vitamin C and Other Antioxidants against Reperfusion Injury in Patients with Acute Myocardial Infarction Undergoing Percutaneous Coronary Intervention.

Percutaneous coronary intervention (PCI) has long remained the gold standard therapy to restore coronary blood flow after acute myocardial infarction (AMI). However, this procedure leads to the development of increased production of reactive oxygen species (ROS) that can exacerbate the damage caused by AMI, particularly during the reperfusion phase. Numerous attempts based on antioxidant treatments, aimed to reduce the oxidative injury of cardiac tissue, have failed in achieving an effective therapy for these patients. Among these studies, results derived from the use of vitamin C (Vit C) have been inconclusive so far, likely due to suboptimal study designs, misinterpretations, and the erroneous conclusions of clinical trials. Nevertheless, recent clinical trials have shown that the intravenous infusion of Vit C prior to PCI-reduced cardiac injury biomarkers, as well as inflammatory biomarkers and ROS production. In addition, improvements of functional parameters, such as left ventricular ejection fraction (LVEF) and telediastolic left ventricular volume, showed a trend but had an inconclusive association with Vit C. Therefore, it seems reasonable that these beneficial effects could be further enhanced by the association with other antioxidant agents. Indeed, the complexity and the multifactorial nature of the mechanism of injury occurring in AMI demands multitarget agents to reach an enhancement of the expected cardioprotection, a paradigm needing to be demonstrated. The present review provides data supporting the view that an intravenous infusion containing combined safe antioxidants could be a suitable strategy to reduce cardiac injury, thus improving the clinical outcome, life quality, and life expectancy of patients subjected to PCI following AMI.

Association of ApoA1 to ApoB ratio and other serum ratios with ischemia and reperfusion injury in patients with acute myocardial infarction

Association of ApoA1 to ApoB ratio and other serum ratios with ischemia and reperfusion injury in patients with acute myocardial infarction

Pharmacologic Prevention of Myocardial Ischemia-Reperfusion Injury in Patients With Acute Coronary Syndrome Undergoing Percutaneous Coronary Intervention.

Establishing efficient perfusion into the myocardium is the main purpose in patients with acute coronary syndrome, but the process of reperfusion is not without risk and can damage the myocardium paradoxically. Unfortunately, there is no effective treatment for reperfusion injury, and efforts to find an efficient preventive approach are still ongoing. In the past 3 decades, there have been many successful animal studies on how to prevent reperfusion injury; nonetheless, translation to the clinical setting has almost always proven disappointing. In this article, we review clinical studies on the prevention of reperfusion injury in patients with acute coronary syndrome undergoing primary percutaneous coronary intervention in a pharmacologic-based approach. We categorize all the agents that are evaluated for the prevention of myocardial reperfusion injury based on their mechanisms of action into 5 groups: drugs that can reduce oxidative stress, drugs that can affect cellular metabolism, rheological agents that target microvascular obstruction, anti-inflammatory agents, and agents with mixed mechanisms of action. Then, review all the clinical studies of these agents in the setting of primary percutaneous coronary intervention. Finally, we will discuss the possible reasons for the failure in translation of studies into practice and propose potential solutions to overcome this problem.

Interferon-gamma inducible protein IP-10 and left ventricular remodelling post-acute myocardial infarction: a longitudinal cardiovascular magnetic resonance imaging substudy of CAPRI clinical trial

Abstract Background Adverse left ventricular (LV) remodelling is associated with development of heart failure and poor outcomes in patients with acute myocardial infarction (AMI). Understanding the immunomodulatory mechanisms of LV remodelling is an essential step for the development of novel therapies. Interferon-γ-inducible protein-10 (IP-10)/CXCL10 is a chemokine involved in the recruitment of activated T cells into sites of tissue inflammation. Although IP-10 was reported to reduce adverse LV remodeling in a preclinical myocardial infarction model, its role in LV remodeling in humans with AMI remains unknown. Purpose To determine the clinical predictive value of serum IP-10 in LV remodeling in patients with ST-segment elevation myocardial infarction (STEMI). Methods This is a substudy of the double-blind, randomised controlled trial “Evaluating the effectiveness of intravenous ciclosporin on reducing reperfusion injury in patients undergoing primary percutaneous coronary intervention” (CAPRI; ClinicalTrials.gov registry number NCT02390674), which enrolled 52 acute STEMI patients. LV remodeling was assessed by cardiovascular magnetic resonance (CMR) imaging and was defined as the 12-week vs. the 3-day post-myocardial infarction change of the left ventricular ejection fraction (ΔLVEF), LV end-diastolic volume (ΔEDV) or LV end-systolic volume (ΔESV). Serum IP-10 was measured before and 5min, 15min, 30min, 90min and 24h after reperfusion by ELISA. Linear regression analysis was used to determine the independent association of IP-10 with the endpoints of the study. Results Serum IP-10 concentration peaked at 30min after reperfusion followed by a 2-fold decrease at the 24h post reperfusion compared to pre-reperfusion levels (P&amp;lt;0.001 for all). Comparison of the 12-week CMR to the baseline CMR imaging revealed that baseline pre-reperfusion as well as 5min, 15min, 30min and 90min, but not 24h, post-reperfusion IP-10 serum levels associated with increased LVEF and decreased ESV at 12-weeks (range correlation coefficient r=[0.35–0.41], P&amp;lt;0.05 with ΔLVEF and r=[−0.33 to −0.44], P&amp;lt;0.05 with ΔESV) indicating that the increase of IP-10 at the acute phase of myocardial infarction confers a cardioprotective role. Multivariable linear regression analysis for ΔLVEF showed that in a model including baseline pre-reperfusion or 5min or 15min or 30min or 90min post-reperfusion IP-10 and age, gender, traditional risk factors (arterial hypertension, body-mass index, hyperlipoproteinemia, diabetes mellitus, smoking, family history of CAD), infarct location, admission high-sensitivity troponin T, door-to-balloon time and ciclosporin treatment, only IP-10 was the independent determinant of ΔLVEF. Conclusions Increased serum IP-10 levels early after reperfusion are associated with reverse LV remodeling in patients with STEMI undergoing primary PCI. The clinical application of IP-10 as a novel biomarker of LV remodeling post-AMI should be further explored and validated. Funding Acknowledgement Type of funding source: None

Remifentanil preconditioning protects against hypoxia-induced senescence and necroptosis in human cardiac myocytes in vitro.

Remifentanil and other opioids are suggested to be protective against ischemia-reperfusion injury in animal models and coronary artery bypass surgery patients, however the molecular basis of such protection is far from being understood. In the present study, we have used a model of human cardiomyocytes treated with the hypoxia-mimetic agent cobalt chloride to investigate remifentanil preconditioning-based adaptive responses and underlying mechanisms. Hypoxic conditions promoted oxidative and nitrosative stress, p21-mediated cellular senescence and the activation of necroptotic pathway that was accompanied by a 2.2-, 9.6- and 8.2-fold increase in phosphorylation status of mixed lineage kinase domain-like pseudokinase (MLKL) and release of pro-inflammatory cytokine IL-8 and cardiac troponin I, a marker of myocardial damage, respectively. Remifentanil preconditioning was able to lower hypoxia-mediated protein carbonylation and limit MLKL-based signaling and pro-inflammatory response to almost normoxic control levels, and decrease hypoxia-induced pro-senescent activity of about 21% compared to control hypoxic conditions. In summary, we have shown for the first time that remifentanil can protect human cardiomyocytes against hypoxia-induced cellular senescence and necroptosis that may have importance with respect to the use of remifentanil to diminish myocardial ischemia and reperfusion injury in patients undergoing cardiac surgery.

Effect of ciclosporin on safety, lymphocyte kinetics and left ventricular remodelling in acute myocardial infarction.

AimsFollowing a favourable pilot trial using a single bolus of ciclosporin, it has been unclear why 2 large studies (CYCLE and CIRCUS) failed to prevent reperfusion injury and reduce infarct size in STEMI (ST elevation myocardial infarction). The purpose of this study was to assess the effect of ciclosporin on myocardial injury, left ventricular remodelling and lymphocyte kinetics in patients with acute STEMI undergoing primary percutaneous coronary intervention.MethodsIn this double‐blind, single centre trial, we randomly assigned 52 acute STEMI patients with an onset of pain of <6 hours and blocked culprit artery to a single bolus of ciclosporin (n = 26) or placebo (n = 26, control group) prior to reperfusion by stent percutaneous coronary intervention. The primary endpoint was infarct size at 12 weeks.ResultsMean infarct size at 12 weeks was identical in both groups (9.1% [standard deviation= 7.0] vs 9.1% [standard deviation = 7.0], P = .99; 95% confidence interval for difference: −4.0 to 4.1). CD3 T‐lymphocytes dropped to similar levels at 90 minutes (867 vs 852 cells/μL, control vs ciclosporin) and increased to 1454 vs 1650 cells/μL at 24 hours.ConclusionIn our pilot trial, a single ciclosporin bolus did not affect infarct size or left ventricular remodelling, matching the results from CYCLE and CIRCUS. Our study suggests that ciclosporin does either not reach ischaemic cardiomyocytes, or requires earlier application during first medical contact. Finally, 1 bolus of ciclosporin is not sufficient to inhibit CD4 T‐lymphocyte proliferation during remodelling. We therefore believe that further studies are warranted.(Evaluating the effectiveness of intravenous Ciclosporin on reducing reperfusion injury in pAtients undergoing PRImary percutaneous coronary intervention [CAPRI]; NCT02390674)

Nafamostat mesylate attenuates the pathophysiologic sequelae of neurovascular ischemia.

Nafamostat mesylate, an apparent soi-disant panacea of sorts, is widely used to anticoagulate patients undergoing hemodialysis or cardiopulmonary bypass, mitigate the inflammatory response in patients diagnosed with acute pancreatitis, and reverse the coagulopathy of patients experiencing the commonly preterminal disseminated intravascular coagulation in the Far East. The serine protease inhibitor nafamostat mesylate exhibits significant neuroprotective effects in the setting of neurovascular ischemia. Nafamostat mesylate generates neuroprotective effects by attenuating the enzymatic activity of serine proteases, neuroinflammatory signaling cascades, and the endoplasmic reticulum stress responses, downregulating excitotoxic transient receptor membrane channel subfamily 7 cationic currents, modulating the activity of intracellular signal transduction pathways, and supporting neuronal survival (brain-derived neurotrophic factor/TrkB/ERK1/2/CREB, nuclear factor kappa B. The effects collectively reduce neuronal necrosis and apoptosis and prevent ischemia mediated disruption of blood-brain barrier microarchitecture. Investigational clinical applications of these compounds may mitigate ischemic reperfusion injury in patients undergoing cardiac, hepatic, renal, or intestinal transplant, preventing allograft rejection, and treating solid organ malignancies. Neuroprotective effects mediated by nafamostat mesylate support the wise conduct of randomized prospective controlled trials in Western countries to evaluate the clinical utility of this compound.

Investigation of the underlying hub genes and mechanisms of reperfusion injury in patients undergoing coronary artery bypass graft surgery by integrated bioinformatic analyses.

Although coronary artery bypass graft (CABG) surgery is the main method to revascularize the occluded coronary vessels in coronary artery diseases, the full benefits of the operation are mitigated by ischemia-reperfusion (IR) injury. Although many studies have been devoted to reducing IR injury in animal models, the translation of this research into the clinical field has been disappointing. Our study aimed to explore the underlying hub genes and mechanisms of IR injury. A weighted gene co-expression network analysis (WGCNA) was executed based on the expression profiles in patients undergoing CABG surgery (GSE29396). Functional annotation and protein-protein interaction (PPI) network construction were executed within the modules of interest. Potential hub genes were predicted, combining both intramodular connectivity (IC) and degrees. Meanwhile, potential transcription factors (TFs) and microRNAs (miRNAs) were predicted by corresponding bioinformatics tools. A total of 336 differentially expressed genes (DEGs) were identified. DEGs were mainly enriched in neutrophil activity and immune response. Within the modules of interest, 5 upregulated hub genes (IL-6, CXCL8, IL-1β, MYC, PTGS-2) and 6 downregulated hub genes (C3, TIMP1, VSIG4, SERPING1, CD163, and HP) were predicted. Predicted miRNAs (hsa-miR-333-5p, hsa-miR-26b-5p, hsa-miR-124-3p, hsa-miR-16-5p, hsa-miR-98-5p, hsa-miR-17-5p, hsa-miR-93-5p) and TF (STAT1) might have regulated gene expression in the most positively related module, while hsa-miR-333-5p and HSF-1 were predicted to regulate the genes within the most negatively related module. Our study illustrates an overview of gene expression changes in human atrial samples from patients undergoing CABG surgery and might help translate future research into clinical work.