Myocardial Infarction Area Research Articles

Application Potential of Probiotics in Acute Myocardial Infarction

Myocardial infarction (MI) is associated with high rates of death and disability, and is the main cause of death due to cardiovascular disease and the most frequent cause of death in the developed world. Recent studies have shown that, in addition to traditional risk factors, such as hypertension, diabetes, hyperlipidemia, obesity, smoking and the environment, the gut microbiota plays an important role in MI development and progression. The discovery of an enteric-cardioid axis provides a new route to examine the complex mechanism of MI and has become a research hotspot in recent years. Experiments have suggested that probiotics decrease ischemia/reperfusion injury and inflammation, regulate lipid metabolism and decrease the myocardial infarction area. In this review, we discuss the relationship between probiotics and MI as well as potential underlying mechanisms, to provide new ideas for the prevention and treatment of MI.

Factors Related to COVID-19 Vaccine Uptake in Black American Communities

Black/African Americans represent 13% of the population, yet account for more than 24% of COVID-19 deaths. Emerging evidence indicates that Black Americans are receiving COVID-19 vaccines at lower rates than whites. However, there is minimal information about why vaccination rates are lower. To address this gap, we examined the effects of the COVID-19 pandemic among Black Americans, with an emphasis on understanding trust and vaccine uptake. Data were collected between July and September 2020 using 8 virtual focus groups in Detroit, MI and San Francisco Bay Area, CA with 33 older Black Americans and 11 caregivers of older Black Americans with cognitive impairment. Inductive/deductive content analysis was used to identify themes. The first theme pointed to a sense of feeling abandoned by healthcare providers and the government at local and state levels, which exacerbated uncertainty and fear about the vaccine and in general. The second theme emphasized a sense of deep distrust towards healthcare providers and the government, especially during the pandemic. The third theme pointed to a reluctance in receiving the vaccine because of distrust of pharmaceutical companies and the government, as well as misinformation and the rapid speed of vaccine development. These findings suggest that underlying systemic issues need to be addressed immediately to accelerate vaccine uptake among older Black Americans. New initiatives are needed to foster trust and address abandonment by healthcare and government systems. In addition, public health campaigns with reliable information about the COVID-19 vaccine are needed.

730 Prediction of type 4a myocardial infarction with the angiography-derived haemodynamic (added) index

Abstract Aims Percutaneous coronary intervention (PCI) is frequently complicated by type 4a myocardial infarction (MI). We assessed the usefulness of the angiography-derived haemodynamic index (ADDED) index in predicting type 4a MI in patients with chronic coronary syndrome (CCS) undergoing PCI. Methods and results We enrolled 442 patients treated with single-vessel PCI. The ADDED index was calculated as the ratio of the Duke Jeopardy Score (DJS) to the minimum lumen diameter (MLD) assessed with quantitative angiography analysis (QCA). Patients in the higher ADDED tertile presented higher occurrence of type 4a MI (17.7%, P < 0.0001). At ROC curve analysis, the ADDED index could significantly discriminate between patients with and without type 4a MI (area under the curve 0.745). At multivariate analysis, an ADDED index value >5.25 was the strongest independent predictor type 4a MI. Conclusions Our results support the role of the ADDED index as a predictor of type 4a MI in patients with CCS treated with elective PCI.

Naringenin alleviates myocardial ischemia/reperfusion injury by regulating the nuclear factor-erythroid factor 2-related factor 2 (Nrf2) /System xc-/ glutathione peroxidase 4 (GPX4) axis to inhibit ferroptosis

ABSTRACT Ferroptosis is an important form of myocardial cell death in myocardial ischemia-reperfusion injury (MIRI). Naringenin (NAR), as a flavonoid, has a significant advantage in improving MIRI. But the regulatory effect and mechanism of NAR on ferroptosis in MIRI have not been reported. After the rats were given NAR and induced to form myocardial ischemia-reperfusion (MI/R) injury, Tetrazolium chloride (TTC) staining was used to detect the myocardial infarction area of rats, and Hematoxylin-eosin (H&E) staining was used to detect myocardial injury. The markers of tissue inflammation were detected by ELISA. Serum creatine kinase Serum creatin kinase (CPK), Lactate dehydrogenase (LDH), and lipid peroxide (LPO) and oxidative stress related levels were measured. In addition, iron detection kits were used to detect total iron and Fe2+ levels in cardiac tissues, and western blot was used to detect the expression of ferroptosis-related proteins and the expression of nuclear factor-erythroid factor 2-related factor 2 (Nrf2) and glutathione peroxidase 4 (GPX4). At the cellular level, H9C2 cardiomyocytes were induced by hypoxia/reoxygenation (H/R), and ferroptosis inducer Erastin was administered to detect cell viability, ferroptosis-related indicators, oxidative stress related indicators, and expressions of Nrf2 and GPX4, to explore the mechanisms involved. NAR alleviated MI/R-induced pathological damage, inflammation and lipid peroxidation in myocardial tissue of rats. NAR adjusted the NRF2 /System xc – /GPX4 axis and improved ferroptosis. At the cellular level, ferroptosis inducer Erastin reversed the protective effect of NAR on H/R-induced H9C2 cardiomyocytes. In conclusion, NAR can alleviate MIRI by regulating the Nrf2/System xc-/GPX4 axis to inhibit ferroptosis.

Lingbao Huxin Pill Alleviates Apoptosis and Inflammation at Infarct Border Zone through SIRT1-Mediated FOXO1 and NF- κ B Pathways in Rat Model of Acute Myocardial Infarction

To investigate whether Lingbao Huxin Pill (LBHX) protects against acute myocardial infarction (AMI) at the infarct border zone (IBZ) of myocardial tissue by regulating apoptosis and inflammation through the sirtuin 1 (SIRT1)-mediated forkhead box protein O1 (FOXO1) and nuclear factor-κ B (NF-κ B) signaling pathways. Six-week-old Wistar rats with normal diet were randomized into the sham, the model, Betaloc (0.9 mg/kg daily), LBHX-L (0.45 mg/kg daily), LBHX-M (0.9 mg/kg daily), LBHX-H (1.8 mg/kg daily), and LBHX+EX527 (0.9 mg/kg daily) groups according to the method of random number table, 13 in each group. In this study, left anterior descending coronary artery (LADCA) ligation was performed to induce an AMI model in rats. The myocardial infarction area was examined using a 2,3,5-triphenyltetrazolium chloride solution staining assay. A TdT-mediated dUTP nick-end labeling (TUNEL) assay was conducted to assess cardiomyocyte apoptosis in the IBZ. The histopathology of myocardial tissue at the IBZ was assessed with Heidenhain, Masson and hematoxylineosin (HE) staining assays. The expression levels of tumor necrosis factor α (TNF-α), interleukin (IL)-6, IL-1 β, and intercellular adhesion molecule-1 were measured using enzyme-linked immunosorbent assays (ELISAs). The mRNA expressions of SIRT1 and FOXO1 were detected by real-time qPCR (RT-qPCR). The protein expressions of SIRT1, FOXO1, SOD2, BAX and NF- κ B p65 were detected by Western blot analysis. The ligation of the LADCA successfully induced an AMI model. The LBHX pretreatment reduced the infarct size in the AMI rats (P<0.01). The TUNEL assay revealed that LBHX inhibited cardiomyocyte apoptosis at the IBZ. Further, the histological examination showed that the LBHX pretreatment decreased the ischemic area of myocardial tissue (P<0.05), myocardial interstitial collagen deposition (P<0.05) and inflammation at the IBZ. The ELISA results indicated that LBHX decreased the serum levels of inflammatory cytokines in the AMI rats (P<0.05 or P<0.01). Furthermore, Western blot analysis revealed that the LBHX pretreatment upregulated the protein levels of SIRT1, FOXO1 and SOD2 (P<0.05) and downregulated NF- κ B p65 and BAX expressions (P<0.05). The RT-qPCR results showed that LBHX increased the SIRT1 mRNA and FOXO1 mRNA levels (P<0.05). These protective effects, including inhibiting apoptosis and alleviating inflammation in the IBZ, were partially abolished by EX527, an inhibitor of SIRT1. LBHX could protect against AMI by suppressing apoptosis and inflammation in AMI rats and the SIRT1-mediated FOXO1 and NF- κ B signaling pathways were involved in the cardioprotection effect of LBHX.

Low-dose dobutamine cardiovascular magnetic resonance segmental strain study of early phase of intramyocardial hemorrhage rats

BackgroundThis study investigates the segmental myocardial strain of the early phase of intramyocardial hemorrhage (IMH) caused by reperfused myocardial infarction (MI) in rats by low-dose dobutamine (LDD) cardiovascular magnetic resonance (CMR) feature-tracking.MethodsNine sham rats and nine rats with 60-min myocardial ischemia followed by 48-h reperfusion were investigated using CMR, including T2*-mapping sequence and fast imaging with steady-state precession (FISP)–cine sequence. Another FISP–cine sequence was acquired after 2 min of dobutamine injection; the MI, IMH, and Non-MI (NMI) areas were identified. The values of peak radial strains (PRS) and peak circumferential strains (PCS) of the MI, IMH and NMI segments were acquired. The efficiency of PRS and PCS (EPRS and EPCS, respectively) were calculated on the basis of the time of every single heartbeat.ResultsThe PRS, PCS, EPRS, and EPCS of the sham group increased after LDD injection. However, the PRS, PCS, EPRS, and EPCS of the IMH segment did not increase. Moreover, the PRS and PCS of the MI and NMI segments did not increase, but the EPRS and EPCS of these segments increased. The PRS, PCS, EPRS, and EPCS of the IMH segment were lower than those of the MI and NMI segments before and after LDD injection, but without a significant difference between MI segment and NMI segment before and after LDD injection.ConclusionsLDD could help assess dysfunctions in segments with IMH, especially using the efficiency of strain. IMH was a crucial factor that decreased segmental movement and reserved function.

Monocytic and lymphocytic inflammatory reaction during myocardial infarction complicated with acute heart failure in patients with type 2 diabetes mellitus

Background. The processes of inflammation and repair in the area of myocardial infarction (MI) are carried out and regulated by various populations of immune cells, including monocytes, lymphocytes, and NK-cells. The success of myocardial recovery after infarction and the risk of developing acute heart failure (AHF) depend on their adequate interaction. The presence of type 2 diabetes mellitus (T2DM), in which chronic low-gradient inflammation occurs, can affect the monocytic and lymphocytic response in MI, which may contribute to the development of AHF.Objective. to assess the features of monocytic and lymphocytic responses in patients with MI T2DM complicated by the development of AHF.Design and methods. The study included 121 patients with MI T2DM (38 of them with AHF). The control group included 59 patients without diabetes mellitus (including 13 patients with AHF). For all patients within 1 day, on days 3, 5 and 12 of MI, the total number of monocytes and lymphocytes, the monocytes-to-lymphocytes ratio (MLR), subpopulations of monocytes and T-lymphocytes with NK cells (T&amp;NK-cells) were determined by flow cytometry.Results. In patients with T2DM, the number of monocytes of different subpopulations did not differ depending on the development of AHF. In patients without T2DM with MI, complicated by AHF, compared with patients without AHF, on day 3, the number of CD14(+)CD16(-)monocytes was higher: 1018 (824; 1144) vs 593 (557; 677) cells/μL, p &lt;0,01, and on days 3 and 5, the number of CD16(+) T&amp;NK-cells was lower: 122 (95; 275) cells/μL and 307 (220; 406) cells/μL, respectively (p = 0,03); (117 (61; 228) and 437 (408; 545) cells/μL, respectively, p &lt; 0,01. On the 12th day of MI in patients with T2DM and AHF lymphocytes and CD16(+)T&amp;NK-cells counts were lower in comparison with patients without AHF: 1856 (1245; 1975) cells/μL and 2294 (1827; 2625) cells/μL, respectively, p = 0,04; 268 (128; 315) cells/μL and 344 (226 ; 499) cells/ μL, respectively, p = 0,04.Conclusion. In patients with T2DM, the development of AHF is associated with a low number of lymphocytes in the absence of a pronounced monocytic response. In non-diabetic patients, the development of AHF is associated with an increase in CD16(-)monocytes and a lower number of CD16 (+) T&amp;NК-cells.

Injectable conductive gelatin methacrylate / oxidized dextran hydrogel encapsulating umbilical cord mesenchymal stem cells for myocardial infarction treatment

Umbilical cord mesenchymal stem cells (UCMSCs) transplantation has been proposed as a promising treatment modality for myocardial infarction (MI), but the low retention rate remains a considerable challenge. Injectable natural polymer hydrogels with conductivity ability are highly desirable as cell delivery vehicles to repair infarct myocardium and restore the cardiac function. In this work, we developed a hydrogel system based on gelatin methacrylate (GelMA) and oxidized dextran (ODEX) as cell delivery vehicles for MI. And dopamine could be used as a reductant of graphene oxide (GO) to form reductive GO (rGO). By adjusting the amount of rGO, the conductivity of hydrogels with 0.5 mg/mL rGO concentration (≈10−4 S/cm) was similar to that of natural heart tissue. In vitro cell experiments showed that the prepared hydrogels had excellent biocompatibility and cell delivery ability of UCMSCs. More importantly, GelMA-O5/rGO hydrogel could promote UCMSCs growth and proliferation, improve the myocardial differentiation ability of UCMSCs, and up-regulate the expression of cTnI and Cx43. Further in vivo experiments demonstrated that GelMA-O5/rGO/UCMSCs Hydrogel could significantly improve the ejection fraction (EF) of rats and significantly reduce myocardial infarct area compared to PBS group, promote the survival of UCMSCs, enhance the expression level of cTnI and Cx43, and decrease the expression level of caspase-3. The findings of this study suggested that the injectable conductive GelMA-O5/rGO hydrogel encapsulating UCMSCs could improve damaged myocardial tissue and reconstruct myocardial function, which will be a promising therapeutic strategy for cardiac repair.

Abstract 10576: Long-Acting Fc-elabela Improves Heart Functional Performance and Markedly Reduces the Infarction Area in a Non-Human Primate Model of Myocardial Infarction

Introduction: Agonists for the apelin receptor APJ have exhibited cardioprotective and anti-heart failure effects in numerous basic and clinical studies. Besides apelin, elabela is a new endogenous peptide ligand for APJ. In a previous study, we have shown that Fc-Elabela (Fc-ELA) has an in vivo half-life of 44 hours in mice and mitigates heart dysfunctions in the rat model of myocardial infarction. Hypothesis: We hypothesized that we could reproduce Fc-ELA’s cardioprotective effects in non-human primates. Methods: Sixteen 3-6 kg male cynomolgus monkeys were divided into 2 groups of vehicle (Veh, n=9) and Fc-ELA (n=7), each with a mean LVEF of 73%. The animals were subjected to ligation of the LAD for 60 min of ischemia and reperfusion to induce myocardial infarction (MI) and heart failure, and received administration of Fc-ELA at 1 mg/kg, s.c., daily for 4 weeks or vehicle, starting at reperfusion. Ultrasound was performed before operation, after reperfusion, and 1, 2, 3 and 4 weeks after operation. Hemodynamics were measured before and 4 weeks after the procedure. At the end of the experiment, TTC staining for the infarction area and CD31staing for microvessels were performed. Results: LVEF decreased from baseline 73% to 64% after MI, gradually decreasing to 50% by the end of week 4 in the Veh group, whereas LVEF remained between 63% and 66% in the entire 4 weeks of Fc-ELA treatment (p &lt;0.001 vs. Veh at Week 2, 3 and 4). dP/dt increased from 2,235 to 3,975 mmHg/s with Veh, but from 2,249 to 5,893 mmHg/s with Fc-ELA (p &lt; 0.05 between groups). LVEDP decreased by 63% with Fc-ELA, but did not change with Veh (p &lt; 0.05 between groups). Systolic BP increased with Fc-ELA as compared to Veh . Fc-ELA reduced the infarct area by 48.2% (MI area ratio: Veh vs. Fc-ELA; 5.0% vs 2.6%, p &lt; 0.01. In addition, the Fc-ELA treatment increased the expression of CD31, a vascular endothelial marker, by 26.3% (p &lt; 0.01), compared to the Veh group. Conclusions: In non-human primates, Fc-ELA showed significant cardioprotective effects. Fc-ELA markedly reduced MI infarction area and significantly increased the microvessel density in the model, supporting Fc-ELA as a potential therapeutic for heart failure and MI.

Inhibition of miR-218-5p reduces myocardial ischemia–reperfusion injury in a Sprague-Dawley rat model by reducing oxidative stress and inflammation through MEF2C/NF-κB pathway

Following myocardial ischemia, myocardial reperfusion injury causes oxidative stress (OS) and inflammation, leading to myocardial cell apoptosis and necrosis. Recently, emerging studies have shown that microRNAs (miRNAs) contribute to the pathophysiology associated with myocardial ischemia–reperfusion (I/R). In this study, we conducted both in-vitro and in-vivo experiments to explore the role of miR-218-5p in ischemia–reperfusion (I/R)- or oxygen and glucose deprivation/reperfusion (OGD/R)-mediated cardiomyocyte injury. A total 44 Sprague-Dawley (SD) rats were used, and randomly divided into four groups, control group (n = 11), miR-218-5p-in group (n = 11), I/R group (n = 11), I/R + miR-218-5p-in group (n = 11). Our data showed that miR-218-5p was overexpressed in H9C2 cardiomyocytes under OGD/R treatment. miR-218-5p inhibition reduced the lactate dehydrogenase (LDH) activity and the levels of reactive oxygen species (ROS), malondialdehyde (MDA) and superoxide dismutase (SOD), as well as the expression of tumor necrosis factor alpha (TNF-α), interleukin (IL-1β), and IL-6. Oppositely, miR-218-5p overexpression aggravated OGD/R-mediated damage on H9C2 cells, whereas nuclear factor kappa B (NF-κB) pathway inhibition or myocyte enhancer factor 2C (MEF2C) upregulation reversed miR-218-5p mimics-mediated effects. Bioinformatics analysis predicted that miR-218-5p targeted and dampened its expression, which was testified by the dual-luciferase reporter assay and RNA pull-down assay. In vivo, inhibiting miR-218-5p declined LDH activities and ROS, MDA and SOD levels in rat myocardial tissues under I/R injury, alleviated myocardial fibrosis and inflammatory reactions, and reduced myocardial infarction area. Overall, inhibition of miR-218-5p choked oxidative stress and inflammation in myocardial I/R injury via targeting MEF2C/NF-κB axis, thus relieving the disease progression.

Cardioprotective Effect of Pretreatment with A Single High-Dose Atorvastatin via Regulating Myocardial Uncoupling Protein 3 in a Rat Ischemia/Reperfusion Model

Objective: Since ischemia/reperfusion (I/R) can cause malignant arrhythmia, we explored the cardioprotective effect of pretreatment with a single and large dose of atorvastatin in the SD rat model. Methods: Rats were distributed into atorvastatin (Ator), I/R model and sham groups (n = 8/group) by random number table method. In Ator group, atorvastatin was gavaged with a single dose (80 mg/kg) 12 h before I/R. The heart was treated with ischemia for 30 min and then reperfusion for 2 h. Results: Myocardial infarct area was induced by I/R when compared with Sham group. Compared with I/R group, the pretreatment of atorvastatin significantly reduced area at risk/left ventricle (40.78 ± 1.39% vs. 46.76 ± 1.42%, p &lt; 0.01), infarct area/area at risk (21.47 ± 1.65% vs. 29.16 ± 1.21%, p &lt; 0.01), and lactate dehydrogenase activity (3056.17 ± 136.22 RFU vs. 3864.15 ± 162.92 RFU, p &lt; 0.05). I/R induced uncoupling protein 3 (UCP3) in transcriptional and translational levels, but atorvastatin significantly increased the UCP3 expression when compared with I/R group, 1.91 ± 0.42 vs. 1.42 ± 0.21 fold (p &lt; 0.05) in mRNA levels measured by RT-PCR and 2.07 ± 0.18 versus 1.45 ± 0.23 fold in protein levels by Western blots. Conclusion: A single high-dose atorvastatin pretreatment 12 h before I/R reduces the infarct area in I/R model in rats. The cardioprotection may be via regulating myocardial UCP3.

Preparation of Puerarin Nanocrystals and Their Application on Rats with Myocardial Ischemic Injury Combined with Electroacupuncture-PC6 (Neiguan)

The effect of electroacupuncture PC6 (Neiguan) combined with puerarin nanocrystal preparation (PUE-NP) on myocardial injury and autophagy in a rat model with myocardial ischemia was explored in this study. PUE-NPs were first prepared, and there was an analysis on the fourier transform infrared spectroscopy (FTIR), particle size distribution of nanocrystalline preparation, Zeta potential, and X-ray diffractometry (XRD) characterization, so as to analyze the difference in the in vitro cumulative release rate of PUE and PUE-NPs. Secondly, Sprague-Dawley (SD) rats were taken as the subjects investigated. Besides, they were divided randomly into a sham surgery group (Sham), a myocardial ischemia model group (Model), an electroacupuncture Neiguan acupoint pretreatment model group (EA+M), an electroacupuncture Neiguan acupoint pretreatment combined with PUE treatment model group (EA+PUE+M), and an acupuncture Neiguan point pretreatment combined with PUENPs treatment model group (EA+PUE-NPs+M). Then, the rats were treated with abdominal anesthesia, and their serums were extracted to detect the differences in serum creatine kinase MB isoenzyme (CK-MB) and lactate dehydrogenase (LDH) concentrations. After the rats were sacrificed, myocardial tissues were taken out, and the Western blot, hematoxylin-eosin (HE) staining, and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) staining were employed to detect apoptosis index, pathological changes of myocardial tissue morphology, and expression differences of autophagy-related protein, such as Beclin-1, LC3, and mammalian target of rapamycin (mTOR). It was found that the average particle size of PUE-NPs was 155.9±17.3 nm, and the average Zeta potential was −15.3±2.1 mV. FTIR and XRD maps displayed that PUE-NPs nanoparticles were successfully prepared, and had a longer lasting in vitro release rate compared with PUE bulk drugs. The results of animal experiments indicated that the myocardial infarction area, serum LDH and CK-MB concentration, and myocardial cell apoptosis index, LC3II/I ratio, mTOR phosphorylation level, and Beclin-1 protein expression level of rats from the EA+M group, EA+PUE+M group, and EA+PUENPs+ M group reduced sharply compared with the model group (P &lt; 0.05). Compared with the EA+M group, the above indicators of rats from the EA+PUE+M group and EA+PUE-NPs +M group dropped steeply (P &lt; 0.05). Besides, the above indicators of rats from the EA +PUE-NPs+M group were lower obviously than those indicators of the EA+PUE+M group (P &lt; 0.05). In conclusion, the above results revealed that the combination of electroacupuncture PC6 (Neiguan) and PUE preparation could improve myocardial cell apoptosis and autophagy levels in rats with myocardial ischemia, while the improvement effect of combining PUE-NPs was more marked.

Hyperleptinemia results in systemic inflammation and the exacerbation of ischemia-reperfusion myocardial injury

AimHyperleptinemia potentiates the effects of many atherogenic factors, such as inflammation, platelet aggregation, migration, hypertrophy, proliferation of vascular smooth muscle cells, and endothelial cell dysfunction. The present study analysed the effects of long-term hyperleptinemia in an in vivo myocardial ischemia-reperfusion model to demonstrate whether the in vivo deleterious effect also affects cardiac structure and function. Main methodsRats were subcutaneously administered leptin for 8 days to estimate the involvement of the JAK/STAT pathway. Data from 58 male Wistar rats were included in the final analysis. Myocardial infarction (MI) was modelled by the 30-minute ligation of the main left coronary artery followed by 120-minute reperfusion. Hemodynamic measurements, electrocardiography monitoring, echocardiography, myocardial infarct size and area at risk, blood biochemical parameters, leptin, IL-6, TNF-alpha, FGF-21, and cardiomyocyte morphology were measured. The expression of JAK2, p-JAK2, STAT3, p-STAT3 was assessed by Western Blot analysis. Statistical analyses were performed using IBM SPSS Statistics v.26. Key findingsEight-day hyperleptinemia in rats leads to an increase in blood pressure and heart rate, myocardial hypertrophy, impaired LV function, the frequency of ischemic arrhythmias, dyslipidemia, systemic inflammation, and the size of induced myocardial infarction. Significance: The blockade of the JAK/STAT signalling pathway effectively reverses the negative effects of leptin, including increased blood pressure and total cholesterol.

Iguratimod Alleviates Myocardial Ischemia/Reperfusion Injury Through Inhibiting Inflammatory Response Induced by Cardiac Fibroblast Pyroptosis via COX2/NLRP3 Signaling Pathway.

Background: NLRP3 inflammasome contributes a lot to sterile inflammatory response and pyroptosis in ischemia/reperfusion (I/R) injury. Cardiac fibroblasts (CFs) are regarded as semi-professional inflammatory cells and they exert an immunomodulatory role in heart. Iguratimod provides a protective role in several human diseases through exerting a powerful anti-inflammatory effect. However, it is still unclear whether iguratimod could alleviate myocardial I/R injury and whether inflammation triggered by NLRP3-related pyroptosis of CFs is involved in this process.Methods: Transcriptomics analysis for GSE160516 dataset was conducted to explore the biological function of differentially expressed genes during myocardial I/R. In vivo, mice underwent ligation of left anterior descending coronary artery for 30 min followed by 24 h reperfusion. In vitro, primary CFs were subjected to hypoxia for 1 h followed by reoxygenation for 3 h (H/R). Iguratimod was used prior to I/R or H/R. Myocardial infarct area, serum level of cardiac troponin I (cTnI), pathology of myocardial tissue, cell viability, lactate dehydrogenase (LDH) release, and the expression levels of mRNA and protein for pyroptosis-related molecules were measured. Immunofluorescence was applied to determine the cellular localization of NLRP3 protein in cardiac tissue.Results: During myocardial I/R, inflammatory response was found to be the most significantly enriched biological process, and nucleotide-binding oligomerization domain (NOD)-like receptor signaling was a crucial pathway in mediating cardiac inflammation. In our experiments, pretreatment with iguratimod significantly ameliorated I/R-induced myocardial injury and H/R-induced pyroptosis of CFs, as evidenced by reduced myocardial infarct area, serum cTnI level, and LDH release in supernatants, as well as improved pathology of cardiac tissue and cell viability. Immunofluorescence analysis showed that NLRP3 was mainly localized in CFs. Moreover, iguratimod inhibited the expression of pro-inflammatory cytokines and pyroptosis-related molecules, including NLRP3, cleaved caspase-1, and GSDMD-N.Conclusion: Our results suggested that inflammatory response mediated by NOD-like receptor signaling is of vital importance in myocardial I/R injury. Iguratimod protected cardiomyocytes through reducing the cascade of inflammation in heart by inhibiting cardiac fibroblast pyroptosis via the COX2/NLRP3 signaling pathway.

Microcirculation of intramyocardial hemorrhage caused by reperfused myocardial infarctions with ultrasmall superparamagnetic iron oxide cardiac magnetic resonance imaging.

The actual role of the coronary microcirculation, which is massively injured by myocardial infarction (MI), in intramyocardial hemorrhage (IMH) pathophysiology is still not fully understood. To determine the change and distribution of microcirculation of myocardial edema (ME), IMH, MI, and the remote area of early reperfusion using 7.0-T cardiovascular magnetic resonance (CMR) in a rat model of acute MI. Eight rats with 60-min myocardial ischemia followed by reperfusion were investigated. On days 2 and 7, after the acquisition of T2*-mapping and T2-mapping images, late gadolinium enhancement imaging was performed to evaluate the extent of myocardial ischemia after an injection of Gd-DTPA. On days 3 and 8, after the injection of ultrasmall superparamagnetic iron oxide (USPIO), T2*- and T2-mapping images were acquired. The R2 values of ME, IMH, MI, and remote areas were measured. From days 2 to 3, R2 values increased in the IMH, MI, ME, and remote area (all P < 0.05) following administration of USPIO, while the delta R2 value of IMH and MI was larger than remote area (P < 0.05). From day 7 to day 8, there was no significant difference in the IMH, MI, ME, and remote area (all P > 0.05). Microvascular injury of IMH and MI is the most severe among all the studied myocardial injuries in the early reperfusion of MI, while microvascular density decreased during follow-up.

The impact of age on the diagnosis of type 1 myocardial infarction using high-sensitivity cardiac troponin

Abstract Background Cardiac troponin concentrations are influenced by age and comorbidities with values above the 99th centile diagnostic threshold more common in older patients without myocardial infarction. Despite this, rule-in thresholds for myocardial infarction are applied universally regardless of age or comorbidities. Purpose We sought to evaluate how age and cardiovascular comorbidities influence the diagnostic performance of high-sensitivity cardiac troponin I for myocardial infarction. Methods In a secondary analysis of a multi-centre randomised controlled trial, we identified 45,991 consecutive patients with suspected acute coronary syndrome without ST-segment elevation myocardial infarction. The diagnostic performance of high-sensitivity cardiac troponin I measured at presentation for type 1 myocardial infarction was evaluated for the sex-specific 99th centile and thresholds three and five times this value in patients stratified by age (under 50 years, between 50 and 75 years, and over 75 years). The effect of comorbidities on diagnostic accuracy was evaluated using regression modelling. Results Of the 45,991 patients, 8,187 (18%) had myocardial injury of which 7,677 (94%) had a presentation troponin above the sex-specific 99th centile. Mean age of those with myocardial injury was 74 years (range 18–108). The positive predictive value (PPV) of the 99th centile was 54.6% (95% confidence interval [CI] 50.6–58.8%), 58.8% (56.9–60.6%) and 36.6% (35.1–38.2%) in patients under 50 years, between 50 and 75 years, and over 75 years, respectively. Rule-in thresholds three and five-times the 99th centile gave a higher PPV in all age groups with a PPV of 45.5% (43.1–47.8%) and 50.4% (47.6–53.2%), respectively in those aged over 75 years (Table 1). Regardless of threshold, specificity and PPV was lowest in patients over 75 years and decreased with advancing age (Figure 1). Across all age groups, the presence of heart failure resulted in the greatest decrease in PPV (36.9% [34.6–39.2%] versus 50.6% [49.3–51.8%]). Adjusting for cardiovascular comorbidities resulted in modest change in the discrimination of cardiac troponin for myocardial infarction (area under curve 0.89 vs 0.90) and did not prevent a decline in diagnostic accuracy in older patients. Conclusion The specificity and PPV of high-sensitivity cardiac troponin I for myocardial infarction decreases with advancing age. Cardiovascular comorbidities impact the PPV of troponin, but do not explain the decline in diagnostic accuracy with age. Clinicians should be aware of these important differences in performance by age of the diagnostic and rule-in thresholds for myocardial infarction when interpreting troponin results in older patients. Funding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): University of Edinburgh Figure 1

Development of injectable graphene oxide/laponite/gelatin hydrogel containing Wharton's jelly mesenchymal stem cells for treatment of oxidative stress-damaged cardiomyocytes

In the initial stage of myocardial infarction (MI), cardiomyocyte necrosis activates aninflammatory response and increases the reactive oxygen species (ROS) content. Graphene oxide (GO) possesses potential antioxidant properties and can provide the adequate mechanical support for cell growth. The clinical studies showed that direct injection of Wharton's jelly mesenchymal stem cells (WJ-MSCs) into infarcted areas of myocardium can reduce apoptosis and fibrosis. Gelatin is a natural polymer and can promote cell attachment. Nanoclay laponite with shear-thinning properties can be injected and gelled in-situ without chemical triggers. In the study, injectable GO/laponite/gelatin (GO-LG) hydrogel was developed and characterized. The results of cell viability showed that the optimal concentration of GO flasks (200 to 300 nm) to treat cells was 100 μg/ml. Addition of nanosized GO to the laponite/gelatin (LG) hydrogel could increase the mechanical strength and have both hemocompatibility and cytocompatibility. The release of GO from LG hydrogel could inhibit the H2O2-induced oxidative stress. The GO-LG hydrogel containing WJ-MSCs could decrease inflammation and apoptosis level and increase the cell viability of cardiomyocytes under oxidative stress. We believe that utilizing this newly developed GO-LG hydrogel containing WJ-MSCs may have potential applications in the future for treatment of MI.

Downregulation of p300/CBP-associated factor inhibits cardiomyocyte apoptosis via suppression of NF-κB pathway in ischaemia/reperfusion injury rats.

Cardiomyocyte apoptosis is the main reason of cardiac injury after myocardial ischaemia‐reperfusion (I/R) injury (MIRI), but the role of p300/CBP‐associated factor (PCAF) on myocardial apoptosis in MIRI is unknown. The aim of this study was to investigate the main mechanism of PCAF modulating cardiomyocyte apoptosis in MIRI. The MIRI model was constructed by ligation of the rat left anterior descending coronary vessel for 30 min and reperfusion for 24 h in vivo. H9c2 cells were harvested after induced by hypoxia for 6 h and then reoxygenation for 24 h (H/R) in vitro. The RNA interference PCAF expression adenovirus was transfected into rat myocardium and H9c2 cells. The area of myocardial infarction, cardiac function, myocardial injury marker levels, apoptosis, inflammation and oxidative stress were detected respectively. Both I/R and H/R remarkably upregulated the expression of PCAF, and downregulation of PCAF significantly attenuated myocardial apoptosis, inflammation and oxidative stress caused by I/R and H/R. In addition, downregulation of PCAF inhibited the activation of NF‐κB signalling pathway in cardiomyocytes undergoing H/R. Pretreatment of lipopolysaccharide, a NF‐κB pathway activator, could blunt these protective effects of PCAF downregulation on myocardial apoptosis in MIRI. These results highlight that downregulation of PCAF could reduce cardiomyocyte apoptosis by inhibiting the NF‐κB pathway, thereby providing protection for MIRI. Therefore, PCAF might be a promising target for protecting against cardiac dysfunction induced by MIRI.

Interleukin-7 aggravates myocardial ischaemia/reperfusion injury by regulating macrophage infiltration and polarization.

Interleukin (IL)‐7 is known to enhance the macrophages cytotoxic activity and that macrophages play a pivotal role in the development and progression of myocardial ischaemia/reperfusion (I/R) injury. However, the effects of IL‐7 on macrophages infiltration and polarization in myocardial I/R injury are currently unclear. This study aimed to evaluate the effects of the IL‐7 expression on myocardial I/R injury and their relationship with macrophages. The data showed that IL‐7 expression in mouse heart tissue increases following I/R injury and that IL‐7 knockout or anti‐IL‐7 antibody treatment significantly improve I/R injury, including reduction in myocardial infarction area, a serum troponin T level decreases and an improvement in cardiac function. On the other hand, recombinant IL‐7 (rIL‐7) supplementation induces opposite effects and the anti‐IL‐7 antibody significantly reduces the cardiomyocyte apoptosis and macrophage infiltration. rIL‐7 cannot directly cause apoptosis, but it can induce cardiomyocyte apoptosis through macrophages, in addition to increase the macrophages migration in vitro. Anti‐IL‐7 antibody affects the cytokine production in T helper (Th) 1 and Th2 cells and also promotes the macrophages differentiation to M2 macrophages. However, anti‐IL‐7 antibody does not reduce the M1 macrophage number, and it only increases the ratio of M2/M1 macrophages in mice heart tissues after I/R injury. Taking together, these data reveal that IL‐7 plays an intensifying role in myocardial I/R injury by promoting cardiomyocyte apoptosis through the regulation of macrophage infiltration and polarization.

MiR-24 Alleviates MI/RI by Blocking the S100A8/TLR4/MyD88/NF-kB Pathway.

Although inflammation plays an important role in myocardial ischemia/reperfusion injury (MI/RI), an anti-inflammatory treatment with a single target has little clinical efficacy because of the multifactorial disorders involved in MI/RI. MicroRNAs (miR-24) can achieve multitarget regulation in several diseases, suggesting that this factor may have ideal effects on alleviation of MI/RI. In the present study, bioinformatics method was used to screen potential therapeutic targets of miR-24 associated with MI/RI. Three days before ischemia/reperfusion surgery, rats in the ischemia/reperfusion, miR-24, and adenovirus-negative control groups were injected with saline, miR-24, and adenovirus-negative control (0.1 mL of 5 × 109 PFU/mL), respectively. Myocardial enzymes, myocardial infarct size, cardiac function, and the possible molecular mechanism were subsequently analyzed. In contrast to the level of S100A8, the level of miR-24 in myocardial tissue was significantly reduced after 30 minutes of ischemia followed by reperfusion for 2 hours. Overexpression of miR-24 reduced the myocardial infarction area and improved the heart function of rats 3 days after MI/RI. Moreover, miR-24 inhibited infiltration of inflammatory cells in the peri-infarction area and decreased creatine kinase myocardial band and lactate dehydrogenase release. Interestingly, miR-24 upregulation reduced S100A8 expression, followed by inhibition of toll-like receptor 4/MyD-88/nuclear factor-k-gene binding signaling activation. In conclusion, miR-24 can alleviate MI/RI via inactivation of the S100A8/toll-like receptor 4/MyD-88/nuclear factor-k-gene binding signaling pathway.