Myocardial Infarct Size Research Articles

Microcirculatory Resistance After Primary Percutaneous Coronary Intervention Predicts Residual Myocardial Damage and Scar Formation.

Coronary microvascular dysfunction has been associated with adverse cardiovascular events following acute myocardial infarction. This study evaluates the role of the angiography-derived index of microcirculatory resistance (angio-IMR) in predicting myocardial damage in patients with ST-segment-elevation myocardial infarction undergoing primary percutaneous coronary intervention (PCI). In this post hoc analysis of the CLEVER-ACS (Controlled-Level Everolimus in Acute Coronary Syndromes) trial, the associations between post-PCI angio-IMR of infarct-related coronary arteries (IRAs) and infarct size, microvascular obstruction, and left ventricular ejection fraction at 30 days as assessed by cardiac magnetic resonance were investigated. High post-PCI angio-IMR was defined as ≥40 mm Hg*s . In non-IRAs, angio-IMR was measured before IRA-PCI. A total of 52 IRAs and 94 non-IRAs of 52 patients were analyzed. Post-PCI angio-IMR was 41.5 (interquartile range [IQR], 28.5-55.7) mm Hg*s in IRAs and pre-PCI angio-IMR was 43.7 (IQR, 31.7-54.0) mm Hg*s in non-IRAs (P=0.70). Patients with high post-PCI angio-IMR (52%) exhibited a larger myocardial infarct size (36.0 [IQR, 23.0-52.5] g versus 14.5 [IQR, 6.50-26.5] g, P<0.001) and a lower left ventricular ejection fraction (46.5% [IQR, 39.5%-49.5%] versus 55.0% [IQR, 48.0%-61.4%], P=0.002) at 30 days as compared with those with low post-PCI angio-IMR values. Post-PCI angio-IMR positively correlated with myocardial infarct size (r=0.45, P=0.001) and extent of microvascular obstruction (r=0.40, P=0.004) at 30 days. Post-PCI angio-IMR predicted myocardial infarct size (area under the curve, 0.78 [IQR, 0.65-0.92]; P=0.001) and extent of microvascular obstruction (area under the curve, 0.74 [IQR, 0.60-0.89]; P=0.009) at 30 days. In patients with ST-segment-elevation myocardial infarction, post-PCI angio-IMR was identified as independent predictor of myocardial infarct size and extent of microvascular obstruction. URL: https://clinicaltrials.gov; Unique Identifier: NCT01529554.

GATAD1 is involved in sphingosylphosphorylcholine-attenuated myocardial ischemia-reperfusion injury by modulating myocardial fatty acid oxidation and glucose oxidation

Modulating the equilibrium between glucose metabolism and fatty acid metabolism represents highly promising novel strategies for therapy of myocardial ischemia/reperfusion (I/R) injury. Sphingosylphosphorylcholine (SPC), an intermediate metabolite of sphingolipids, has shown cardioprotective roles during myocardial infarction by regulating the activities of various transcript factors. Gene microarray revealed that SPC significantly upregulated the expression of GATA zinc finger domain protein 1 (GATAD1), which is a vital transcript factor affecting heart development and various heart diseases. However, it remains unclear whether SPC is involved in the regulation of cardiac fatty acid and glucose metabolism via GATAD1. In this study, we found that myocardium-specific Gatad1 knockout (Gatad1 CKO) significantly increased the myocardial infarct size, impaired cardiac function in I/R mice, and disrupted the protective effect of SPC on the hearts of I/R mice. Immunofluorescence experiment and Western blot evaluation of the nuclear-cytoplasmic fractionation sample showed that GATAD1 acted as a transcription factor and was regulated by SPC. Double fluorescence reporting experiment and quantitative polymerase chain reaction (qPCR) revealed that GATAD1 could inhibit the expression of genes involved in fatty acid oxidation (FAO), i.e., acetyl-coenzyme A acyltransferase 2 (Acaa2) and medium-chain acyl-CoA dehydrogenase (Acadm), and promoted the expression of genes involved in glucose oxidation, i.e., pyruvate dehydrogenase E1 α subunit (Pdha1). Small interfering RNA (SiRNA) or overexpression strategies confirmed the pro-apoptotic roles of Acaa2 and Acadm and anti-apoptotic role of Pdha1 in cardiac myocytes challenged with I/R treatment. In summary, our findings suggest that SPC can be used as a candidate to prevent I/R injury by reshaping fatty acid and glucose metabolism. Transcription factor GATAD1 plays a crucial role in regulating fatty acid oxidation and glucose oxidation homeostasis and is involved in SPC-mediated cardioprotection during I/R of the heart. Our study identifies GATAD1 as a new therapeutic target for clinical treatment of myocardial I/R injury.

Активація мітохондріальних механізмів кардіопротекції при ішемії-реперфузії ізольованого серця щурів з інсулінорезистентністю

Dysregulation of mitochondrial functions can significantly disrupt energy metabolism in the myocardium. However, mitochondrial mechanisms of cardioprotection and their disruption in metabolic disorders are still insufficiently studied. The aim of the our work was to characterize mitochondrial mechanisms of cardioprotection in ischemia-reperfusion of the rat heart under conditions of insulin resistance and hypoxic preconditioning. Adult male Wistar rats were induced to insulin resistance by consuming a high-fat diet with 58% fat for 14 days. Hypoxic preconditioning was reproduced by exposure to hypobaric hypoxia (360 Torr) in a pressure chamber for 3 hours. To assess the cardioprotective effects, 30-minute ischemia and 40-minute reperfusion of the isolated heart were simulated after 24 hours with isovolumic retrograde perfusion according to the Langendorff method. The size of the myocardial infarction, oxidative stress indicators and the level of expression of the mitochondrial protein PGC-1α were determined. Mitochondria were examined using electron microscopy. In the myocardium of insulin-resistant rats, there was a quantitative increase in all mitochondrial subpopulations, activation of their intracellular connections with other organelles, and an increase in the level of PGC-1α expression in the left ventricle. At the same time, activation of free radical processes in the myocardium was observed with an increase in the content of TBA-AP and activation of antioxidant mechanisms, in particular, the glutathione system. Hypoxic preconditioning increased the level of PGC-1α expression in the right ventricle, led to the activation of energy metabolism, increased mitochondrial dynamics with the elimination of damaged organelles by mitophagy and biogenesis of new mitochondria against the background of a decrease in mitochondrial dysfunction. After ischemia-reperfusion in the myocardium of insulin-resistant rats, limitations in mitochondrial damage and manifestations of their dysfunction were observed. Preconditioning contributed to a decrease in infarct size, enhanced the mitoprotective effect in the ischemic heart. Insulin resistance contributed to the intensification of PGC-1α-dependent mitochondrial mechanisms of protection against ischemic damage in the myocardium. Hypoxic preconditioning enhanced the myoprotective effect in insulin-resistant hearts compared with intact myocardium, leading to a reduction in myocardial infarct size during isolated heart ischemia-reperfusion, but the antioxidant effect was partially lost.

Icariside II attenuates isoproterenol-induced myocardial ischemia by regulating NLRP3/Caspase-1 axis

Abstract Background Epimedii Folium, first recorded in the Shennong’s Classic of Materia Medica (Shen Nong Ben Cao Jing), is a traditional Chinese medicine (TCM) known for its effects of “benefiting Qi and strengthening the heart.” Icariside II (ICS II) is one of the main active components of Epimedii Folium, possessing cardiovascular protective and anti-inflammatory properties. However, the potential mechanisms of ICS II on myocardial ischemia (MI) remain unclear. Objective The aim of the study was to investigate the effects and preliminary molecular mechanisms of ICS II in treating isoproterenol-induced MI in rats. Methods A rat model of MI was established by subcutaneous injection of isoproterenol. Electrocardiography, echocardiography, myocardial enzymes analysis, heart weight index, triphenyltetrazolium chloride staining, histopathology, TUNEL staining, RT-qPCR, and Western blot were employed to evaluate the effects and preliminary molecular mechanisms of ICS II on MI rats. Results Pharmacodynamic studies suggested that ICS II inhibited ST-segment elevation in electrocardiograms, improved cardiac function, reduced heart weight index and myocardial enzyme levels, decreased myocardial infarct size, alleviated cardiac histological damage, and inhibited apoptosis, thereby exerting cardioprotective effects in MI rats. Further studies revealed that ICS II may partially inhibit the expression of NLRP3/Caspase-1 axis-related targets at both protein and mRNA levels. Conclusions O`nary molecular mechanisms may be related to inhibiting the activation of the NLRP3/Caspase-1 axis to alleviate inflammatory responses.

Quercetin Reduces the Susceptibility to Cardiac Reperfusion Arrhythmias in Ovariectomized Rats.

Cardiovascular diseases (CVDs) are the leading cause of death globally. Decrease in female sex hormones during menopause increases the risk of cardiovascular disease, mainly ischemic heart disease (IHD). Quercetin, a flavonoid, has beneficial properties in CVDs due to its antioxidant, anti-inflammatory, and anti-apoptotic effects. The aim of this study was to investigate the effects of quercetin on susceptibility to cardiac reperfusion arrhythmias and mitochondrial function in ovariectomized rats (OVX). Three-month-old Wistar female rats were randomly assigned to the following experimental groups: SHAM-operated, vehicle-treated (DMSO 10% + PBS, 1mLkg-1); OVX (vehicle-treated); and OVX+Q (25mg·kg-1). The three experimental groups were carried out for 4 weeks (five times a week) by oral gavage. Quercetin treatment effectively decreased myocardial infarct size and susceptibility to reperfusion arrhythmias. Quercetin treatment was also effective in preventing mitochondrial swelling, while increased ATP production compared to the OVX group. In conclusion, our results indicate that quercetin could have a therapeutic effect in preventing some of the pathophysiological changes caused by low estrogen levels in the cardiovascular system.

Inhibition of CCR2 attenuates NLRP3-dependent pyroptosis after myocardial ischaemia-reperfusion in rats via the NF-kB pathway.

Myocardial infarction (MI) is a leading cause of mortality worldwide, contributing significantly to long-term cardiac dysfunction and heart failure. Effective therapeutic strategies are urgently needed to mitigate the extensive damage caused by MI and subsequent ischemia-reperfusion (I/R) injury. This study investigates the role of the Chemokine receptor 2 (CCR2) in regulating NLRP3-dependent cardiomyocyte pyroptosis following myocardial ischemia-reperfusion (MIR), elucidating its molecular mechanisms. A myocardial ischemia-reperfusion model was established using 124 Sprague-Dawley rats by ligating the left coronary artery, inducing 30min of ischemia. Following ischemia, RS504393, a selective CCR2 antagonist, was administered intraperitoneally one hour after reperfusion. To further explore the underlying mechanisms, the NF-κB pathway agonist Phorbol 12-myristate 13-acetate (PMA) was administered 1h post-MIR. The results showed a marked increase in CCR2 expression in the heart, peaking on the first day of reperfusion. Treatment with RS504393 significantly improved short-term cardiac function and reduced myocardial infarction size, decreased myocardial pyroptosis and suppressed the expression of NLRP3, GSDMD, Caspase-1, IL-1β, and IL-18 through inhibition of the NF-κB signaling pathway. This effect was reversed with the administration of PMA. In summary, the inhibition of CCR2 shows potential in mitigating myocardial injury following MIR by modulating the NF-κB signaling pathway. These findings highlight CCR2 as a promising therapeutic target for myocardial ischemia-reperfusion injury.

Exploring the Relationship Between Sleep Apnea, Myocardial Infarct Size, and Coronary Collaterals in Acute Myocardial Infarction: A Multidisciplinary Study.

We designed a study investigating the cardioprotective role of sleep apnea (SA) in patients with acute myocardial infarction (AMI), focusing on its association with infarct size and coronary collateral circulation. We recruited adults with AMI, who underwent Level-III SA testing during hospitalization. Delayed-enhancement cardiac magnetic resonance (CMR) imaging was performed to quantify AMI size (percent-infarcted myocardium). Rentrop Score quantified coronary collateralization (scores 0-3, higher scores indicating augmented collaterals). Group differences in Rentrop grade and infarct size were compared using the Wilcoxon Rank-Sum test and Fisher's Exact test as appropriate, with a significance threshold set at p <0.05. Among 33 adults, mean age was 54.4±11.5 and mean BMI was 28.4±5.9. 8 patients (24%) had no SA, and 25 (76%) had SA (mild n=10, moderate n=8, severe n=7). 66% (n=22) underwent CMR, and all patients had Rentrop scores. Median infarct size in the no-SA group was 22% versus 28% in the SA group (p=0.79). While we did not find statistically significant differences, moderate SA had a trend toward a smaller infarct size (median 15.5%; IQR 9.23) compared to the other groups (no SA [22.0%; 16.8,31.8], mild SA [27%; 23.8,32.5], and severe SA [34%; 31.53], p=0.12). A higher proportion of moderate SA patients had a Rentrop grade >0, with a trend toward significance (moderate SA versus other groups: 62.5% versus 28%, p=0.08). Our study did not find statistically significant differences in cardiac infarct size and the presence of coronary collaterals by sleep apnea severity among patients with AMI. However, our results are hypothesis-generating, and suggest that moderate SA may potentially offer cardioprotective benefits through enhanced coronary collaterals. These insights call for future research to explore the heterogeneity in ischemic preconditioning by SA severity and hypoxic burden to guide tailored clinical strategies for SA management in patients with AMI.

Study on the protective mechanism of Xuemaitong Capsule against acute myocardial ischemia rat based on network pharmacology and metabolomics

Xuemaitong Capsule (XMT) is a widely recognized traditional Miao medicine extensively utilized in Chinese clinical settings. Previous studies have demonstrated XMT protective effects against acute myocardial ischemia (AMI). However, the mechanism by which XMT provides protection to AMI rats is yet to be fully understood. The purpose of this study was to investigate the protective mechanism of XMT on AMI rats through network pharmacology, traditional pharmacodynamics and metabolomics. The components and potential targets of XMT were identified through the application of traditional Chinese medicine system pharmacology and traditional Chinese medicine molecular mechanism bioinformatics analysis tools. We constructed herb-composition-target networks and analyzed protein-protein interaction (PPI) networks. The potential mechanism was explored by pathway enrichment analysis. Subsequently, the AMI model was constructed by ligation of the anterior descending branch of the left coronary artery, and XMT protective effects on AMI rats were evaluated by analyzing the myocardial enzyme profiles, electrocardiograms(ECG), Triphenyltetrazolium chloride(TTC) staining, and Hematoxylin-Eosin (HE) staining in AMI rats. Metabolomics based on UHPLC-Q-Exactive Orbitrap MS was used to observe the protective effect of XMT on the serum metabolic profile of AMI, and multivariate statistical analysis further revealed the differential patterns of metabolites after XMT treatment. Finally, integrated pathway analysis was carried out to reveal the biological metabolic mechanism. A total of 392 active components of XMT acted with 624 targets for treating AMI. Pathway enrichment analysis revealed that XMT could treat AMI through TNF, MAPK and PI3K-Akt signaling pathways. Further, XMT could effectively prevent ST-segment elevation in the ECG, reduce the size of myocardial infarction, decrease cardiac weight index and cardiac enzyme levels, and mitigate histological damage in the hearts of AMI rats. In addition, XMT callback 117 metabolites and four metabolic pathways, including taurine and hypotaurine metabolism, phenylalanine metabolism, pyrimidine metabolism and retinol metabolism. Through integrating network pharmacology and metabolomics, we explored the biological mechanism by which XMT treats AMI. It was speculated that the mechanism of XMT is to regulate TNF signaling, PI3K-Akt pathway and MAPK signaling pathway, and participate in cell apoptosis, oxidative stress, immune and inflammatory reaction and other biological processes. XMT plays a protective role in AMI rats by regulating multiple metabolic biomarkers, multiple targets and pathways. Therefore, XMT may provide a potential strategy for the treatment of AMI.

Inhibition of Taurine-upregulated Gene 1 Upregulates MiR-34a-5p to Protect against Myocardial Ischemia/Reperfusion via Autophagy Regulation.

Taurine upregulated gene 1 (TUG1) has been identified on long noncoding RNA (lncRNA); however, its function in myocardial cells following ischemia/ reperfusion (I/R) injury has not been explored. This study aimed to investigate the role of LncTUG1 in I/R injury by focusing on its relationship with autophagy induction by regulating miR-34a-5p expression. We established a myocardial I/R model and H9C2 hypoxia-ischemic and reoxygenation (HI/R) conditions to induce I/R injury. TTC, Western blot, CCK-8 assay, quantitative reverse transcription PCR, flow cytometry, and confocal microscopy were used to assess the size of myocardial infarct, level of some apoptotic-related and autophagy-associated proteins, cell viability, the level of LncRNA TUG1, apoptosis, and autophagy, respectively. The results revealed that a TUG1 knockdown protected against I/R-induced myocardial injury by decreasing the impairment in cardiac function. LncRNA TUG1 expression was increased in a myocardial I/R model and HI/R in H9C2 cells. Moreover, inhibition of LncTUG1 enhanced H9C2 cell viability and protected the cells from HI/R-induced apoptosis. Silencing LncRNA TUG1 promoted HI/R-induced autophagy. Furthermore, TUG1 siRNA upregulated the level of miR-34a-5p compared to the HI/R group. The protective effect of LncRNA TUG1 inhibition on H9C2 cells following HI/R was eliminated by blocking autophagy with an miR-34a-5p inhibitor. These findings indicated that inhibiting TUG1 may reduce the extent of myocardial I/R injury by regulating miR-34a-5p. Taken together, these results suggest that LncRNA TUG1 may represent a novel therapeutic target for myocardial I/R injury.

Deptor protects against myocardial ischemia-reperfusion injury by regulating the mTOR signaling and autophagy

Deptor knockout mice were constructed by crossing Deptor Floxp3 mice with myh6 Cre mice, establishing a myocardial ischemia-reperfusion (I/R) model. Deptor knockout mice exhibited significantly increased myocardial infarction size and increased myocardial apoptosis in vivo. ELISA analysis indicated that the expression of CK-MB, LDH, and CtnT/I was significantly higher in the Deptor knockout mice. Deptor siRNA significantly reduced cell activity and increased myocardial apoptosis after I/R-induced in vitro. Deptor siRNA also significantly up-regulated the expression of p-mTOR, p-4EBP1, and p62, and down-regulated the expression of LC3 after I/R induction. Immunofluorescence indicated that LC3 dual fluorescence was weakened by Deptor knockout, and was enhanced after transfection with Deptor-overexpression plasmids. Treatment with OSI027, a co-inhibitor of mTORC1 and mTORC2, in either Deptor knockout mice or Deptor knockout H9C2 cells, resulted in a significant reduction in infarction size and apoptotic cardiomyocytes. ELISA analysis also showed that the expression of CK-MB, LDH, and CtnT/I were significantly down-regulated by treatment with OSI027. CCK-8 cell viability indicated that cell viability was enhanced, and the number of apoptotic cells was decreased in vitro following treatment with OSI027. These results revealed that OSI027 exerts a protective effect on myocardial ischemia/reperfusion injury in both an in vivo and in an in vitro model of I/R. These findings demonstrate that Deptor protects against I/R-induced myocardial injury by inhibiting the mTOR pathway and by increasing autophagy.

Vaspin inhibits ferroptosis: A new hope for treating myocardial ischemia-reperfusion injury.

Myocardial ischemia-reperfusion injury (MIRI) is a critical pathological basis for cardiovascular diseases. In recent years, the effect of ferroptosis on MIRI has attracted extensive attention. Vaspin, an adipose tissue-derived serine protease inhibitor, has multiple biological functions, including anti-inflammatory and antioxidant effects. This study aims to investigate the molecular mechanism by which vaspin alleviates MIRI by regulating hypoxia-inducible factor-1α (HIF-1α) and ferroptosis signaling pathways. A mouse model of myocardial ischemia/reperfusion (I/R) and a hypoxia/reoxygenation (H/R) model was used to evaluate the protective effects of vaspin on MIRI. The mechanism by which ferroptosis is modulated by the vaspin/HIF-1α signaling pathway was investigated by constructing a vaspin overexpression adenoviral vector. Myocardial infarct size and histological changes were assessed using triphenyltetrazolium chloride and hematoxylin-eosin staining. Ferroptosis-related proteins were detected by Western blot assay, and apoptosis and reactive oxygen species levels were analyzed by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling. Iron content in myocardial tissue and cells was measured by enzyme-linked immunosorbent assay. Myocardial I/R increased myocardial infarct size and serum lactate dehydrogenase (LDH) levels compared with the control group, indicating severe myocardial injury. Western blot results showed that MIRI reduced endogenous vaspin and HIF-1α levels and inhibited glutathione peroxidase 4. In vivo and in vitro vaspin overexpression treatment reduced infarct size, decreased LDH levels, inhibited ferroptosis pathway activity, and alleviated oxidative stress levels in myocardial tissues. In the H/R model, vaspin overexpression upregulated HIF-1α, inhibited ferroptosis markers, and reduced apoptosis and iron deposition. However, inhibiting HIF-1α reversed the cardioprotective and anti-ferroptotic effects of vaspin. Vaspin inhibits ferroptosis and upregulates the HIF-1α signaling pathway to mitigate myocardial I/R injury. The vaspin/HIF-1α pathway could be a potential target for MIRI prevention and treatment and offers fresh perspectives on ischemic heart disease management. Vaspin could be a novel cardioprotective agent that plays a significant role in the prevention and treatment of cardiovascular diseases.

Snowflake‐Like RuMn Branched Nanosheets Enable Topocatalytic Therapy of Cardiac Ischemia/Reperfusion Injury via Resisting Inflammatory Cascade and Neutrophil Invasion

AbstractMyocardial ischemia/reperfusion (I/R) injury is the main cause for limited response to treatment after clinical revascularization. The primary mechanisms are over production of reactive oxygen and nitrogen species (RONS) and severe inflammatory response, leading to irreversible damage to cardiac tissue. Herein, this work proposes the concept of topocatalytic nanomedicine and reports a distinctive class of snowflake‐like ultrathin manganese‐doped ruthenium branched nanosheets with PEGylation (RuMn BNSP) that could overcome complex biological conditions to attenuate myocardial I/R injury. The snowflake‐like RuMn BNSP mimic the function of antioxidative enzymes to effectively scavenge RONS, thereby enabling the excellent cellular protection against oxidative stress. In addition, in an oxidized environment, the snowflake‐like RuMn BNSP could maintain mitochondrial function by preventing mitochondrial membrane potential depolarization and mitochondrial permeability transition pore opening. In a myocardial I/R murine model, a single intravenous bolus of RuMn BNSP prevents the recruitment of inflammatory neutrophils and amplification of inflammatory responses in cardiac tissue, thereby reducing the size of myocardial infarction and improving the cardiac function. These findings validate the rational design of snowflake‐like RuMn BNSP to effectively scavenge toxic RONS and reduce neutrophil infiltration on myocardial I/R injury, providing strong evidence for the application of RuMn BNSP in other oxidative stress‐related diseases.

The size of myocardial infarction and peri-infarction edema are not major determinants of diastolic impairment after acute myocardial infarction

To study the relationship between myocardial infarction size (IS), myocardial edema, and diastolic dysfunction after acute myocardial infarction (MI) both in the acute phase, and in the development of diastolic dysfunction in the follow-up setting. A further purpose is to study diastolic function using a mechanistic model as well as conventional parameters. Patients underwent cardiovascular magnetic resonance (CMR) imaging and echocardiography including mechanistic analysis using the parameterized diastolic filling method within 4–7 days (acute) and 6 months after a first acute anterior MI (n = 74). Linear regression modeling of echocardiographic diastolic parameters using CMR IS with and without inclusion of the myocardium at risk (MAR) and model comparisons with likelihood ratio tests were performed. Diastolic parameters at 6 months follow-up were modelled using final IS. For most parameters there was no association with acute IS, except for deceleration time (R2 = 0.24, p < 0.001), left atrial volume index (R2 = 0.13, p = 0.01) and the mechanistic stiffness parameter (R2 = 0.21, p < 0.001). Adding MAR improved only the e′ model (adjusted R2 increase: 0.08, p = 0.02). At 6 months follow-up, final IS was only associated with viscoelastic energy loss (R2 = 0.22, p = 0.001). In acute MI, both IS and MAR are related to diastolic function but only to a limited extent. At 6 months after infarction, increasing IS is related to less viscoelastic energy loss, albeit also to a limited extent. The relationship between IS and diastolic dysfunction seems to be mediated by mechanisms beyond simply the spatial extent of ischemia or infarction.

Transcoronary cooling and dilution for cardioprotection during revascularisation for ST-segment elevation myocardial infarction: Design and rationale of the STEMI-Cool study.

ST-segment elevation myocardial infarction (STEMI) is treated with immediate primary percutaneous coronary intervention (pPCI) to restore coronary blood flow in the acutely ischaemic territory, but is associated with reperfusion injury limiting the benefit of the therapy. No treatment has proven effective in reducing reperfusion injury. Transcoronary hypothermia has been tested in clinical studies and is well tolerated, but is generally established after crossing the occlusion with a guidewire therefore after initial reperfusion, which might have contributed to the neutral outcomes. Transcatheter strategies may also offer additional benefit through haemodilution and the resultant controlled reperfusion, but this has not been fully investigated for pPCI. STEMI-Cool is a pragmatic, registry-based randomised clinical pilot trial to test the recruitment rate, feasibility, and safety of a simple transcoronary cooling and dilution protocol. Sixty STEMI patients undergoing pPCI will be randomised 1:1 to standard of care or continuous infusion of room temperature saline through the guiding catheter to achieve intracoronary temperature reductions of 6 to 8°C, commencing before crossing the coronary occlusion with a guidewire. Mechanistic outcome measures will include microvascular resistance, biomarkers of inflammation before infusion and at 24 hour, and magnetic resonance imaging of myocardial salvage and infarct size. STEMI-Cool will investigate the recruitment rate, feasibility and safety of an innovative and simple cooling and diluting strategy for cardioprotection before and during reperfusion with pPCI, aiming to address limitations faced in other studies. Mechanistic outcome measures will allow insight into inflammatory, microvascular and structural changes induced by transcoronary cooling and dilution.

Andrographolide Attenuates Myocardial Ischemia-Reperfusion Injury in Mice by Up-Regulating PPAR-α.

Andrographolide (AGP), a bioactive diterpene lactone, is an active constituent extracted from Andrographis paniculata. It has many biological activities, such as antioxidant, antitumor, antivirus, anti-inflammation, hepatoprotection, and cardioprotection. The aim of the present study is to investigate the cardioprotective effects of AGP in a mouse model of myocardial ischemia-reperfusion injury (MIRI). Adult male C57BL/6J mice were pre-treated orally with AGP (25mg/kg) for six days. After 30min of the left anterior descending coronary artery occlusion followed by 24h of reperfusion, mice received an additional dose of AGP. The results showed that: (i) AGP pretreatment significantly reduced myocardial infarct size and cardiac injury biomarkers in MIRI mice and improved left ventricular ejection fraction (EF) and fractional shortening (FS); (ii) AGP pretreatment attenuated MIRI-induced oxidative stress imbalance in MIRI mice by increasing total antioxidant capacity (T-AOC) and reducing the levels of hydrogen peroxide (H2O2), nitric oxide (NO), malondialdehyde (MDA), and dihydroethidium (DHE); (iii) AGP pretreatment increased Bcl-2 expression and decreased caspase-3 and Bax expression in ischemic myocardial tissue, along with a reduction in TUNEL-positive cells. Further analysis showed that stimulation by I/R decreased peroxisome proliferator-activated receptor-α (PPAR-α) expression in ischemic cardiac tissue, which was prevented by AGP administration. Moreover, administration of the PPAR-α antagonist GW6471 (1mg/kg) abolished the protective effect of AGP on oxidative stress and apoptosis in the ischemic heart tissue of mice stimulated by ischemia-reperfusion. Taken together, these results suggest that AGP attenuates MIRI-induced cardiac injury by up-regulating PPAR-α expression, thereby preventing oxidative stress and cellular apoptosis.

Qingre Huoxue decoction attenuates myocardial ischemia‒reperfusion injury by regulating the autophagy‒endoplasmic reticulum stress axis via FAM134B-mediated ER-phagy.

Autophagy‒endoplasmic reticulum (ER) stress axis dysregulation is linked to myocardial ischemia‒reperfusion injury (MIRI), which counteracts the benefits of acute myocardial infarction (AMI) reperfusion therapy. Qingre Huoxue decoction (QRHX) improves the short- and long-term prognosis of AMI after percutaneous coronary intervention and alleviates myocardial injury in AMI rats by stimulating autophagy via the PI3K/Akt pathway. We aimed to further explore the efficacy of QRHX in treating MIRI and its regulatory relationship with FAM134B-mediated ER-phagy. Rats were administered different concentrations of QRHX for 2 weeks, and then MIRI was induced. Ultra-performance liquid chromatography‒tandem mass spectrometry (UPLC‒MS) was used to examine the levels of the main pharmacological metabolites of the serum of rats treated with QRHX. H9c2 cells were pretreated with QRHX-mediating serum (QRHX-MS) for 24h before being exposed to hypoxia/reoxygenation (H/R). The mechanisms underlying the effects of QRHX-MS were further studied via rescue experiments involving FAM134B knockdown. The myocardial infarct size, cardiac function, morphology and the expression of apoptosis-, autophagy-, and ER stress-related proteins and genes were assessed. The colocalization of autophagosomes with lysosomes and the localization of proteins involved in ER-phagy or autophagic flux was examined. QRHX decreased the myocardial infarct size and oxidative stress, improved cardiac function and alleviated morphological changes in a dose-dependent manner in MIRI rats by promoting autophagic flux to inhibit ER stress and ER stress-related apoptosis, which was related to FAM134B-mediated ER-phagy, as revealed by autophagy analysis. UPLC‒MS analysis of QRHX-MS revealed 20 major active metabolites of QRHX-MS, including baicalin, cryptotanshinone, 3,4-dihydroxybenzaldehyde and caffeic acid. QRHX-MS attenuated H/R-induced cardiomyocyte injury and apoptosis by increasing autophagic flux to suppress ER stress and ER stress-related apoptotic protein and gene expression. When autophagic flux was inhibited or FAM134B was knocked down in H9c2 cells followed by QRHX-MS pretreatment, the protective effect of QRHX was partially reversed. QRHX alleviates myocardial injury, apoptosis and infarct size expansion in MIRI by regulating the autophagy‒ER stress axis via FAM134B-mediated ER-phagy.

Long-term FXa inhibition attenuates thromboinflammation after acute myocardial infarction and stroke by platelet proteome alteration

Immediate activated factor (F)X (FXa) inhibition exerts direct antiplatelet effects in the context of arterial thrombosis but little is known about the impact of long-term therapy on platelet function in ischemic cardiovascular diseases. Therefore, we analyzed platelet-derived effects of long-term FXa inhibition in the setting of acute myocardial infarction (AMI) and stroke. We evaluated the effect of acute versus chronic FXa inhibition on thromboinflammation following AMI and stroke in mice invivo. Mechanistically, we identified changes in platelet gene expression and proteome under chronic FXa nonvitamin K antagonist oral anticoagulant treatment and characterized its functional consequence on platelet physiology. In a prospectively recruited cohort of patients with AMI, we determined cardiovascular magnetic resonance based cardiac endpoints under FXa nonvitamin K antagonist oral anticoagulant effects on clinical endpoints in a cohort of patients with AMI. Chronic but not acute FXa inhibition reduced cerebral and myocardial infarct size and improved cardiac function 24 hours after AMI in mice. Mechanistically, we identified an attenuated thromboinflammatory response with reduced neutrophil extracellular trap formation in mice and patient samples. Proteome and RNA expression analysis of FXa inhibitor treated patients revealed a reduction of key regulators within the membrane trafficking and secretion machinery hampering platelet α and dense granule release. Subsequent, thromboinflammatory neutrophil extracellular trap density in thrombi isolated from stroke and myocardial infarction patients was reduced. Patients with AMI treated with FXa inhibitors showed decreased infarct size after myocardial infarction compared to patients without anticoagulation treatment. Long-term FXa inhibition induces antithromboinflammatory proteome signatures in platelets, improving infarct size after myocardial infarction and stroke.

Salvianolic acid B alleviated myocardial ischemia-reperfusion injury via modulating SIRT3-mediated crosstalk between mitochondrial ROS and NLRP3

Mitochondrial ROS (mtROS) accumulation and NLRP3 inflammasome activation are critical in the pathogenesis of myocardial ischemia-reperfusion injury (MIRI). However, their upstream regulatory mechanisms and interaction remain inadequately understood. The study aims to investigate the therapeutic effect of Salvianolic acid B (Sal B) on MIRI and elucidate its potential molecular mechanism, mainly focusing on the role of SIRT3. SIRT3 was knocked down (SIRT3KD) and overexpressed (SIRT3OE) using small interfering RNA and plasmid, respectively. The role of SIRT3 in the cardioprotective effect of Sal B was explored using MIRI rat models and H9c2 cell hypoxia/reoxygenation (H/R) models. SIRT3, NLRP3 inflammasome proteins, and MnSOD expression were analyzed by Western blot and immunofluorescence staining. MtROS levels were assessed with mitochondrial superoxide indicators (MitoSOX™ Red). ELISA was utilized to measure the levels of LDH, CK-MB, cTnT, and markers of inflammation and oxidative stress. The interaction between SIRT3 and Sal B was studied through biolayer interferometry, cellular thermal shift assay and molecular docking. Our findings revealed significantly decreased SIRT3 level, enhanced MnSOD acetylation, and activated NLRP3 inflammasome in myocardium after MIRI and H9c2 cardiomyocytes exposed to H/R conditions. SIRT3KD promoted MnSOD acetylation and NLRP3 expression, aggravating mtROS accumulation and inflammation. Conversely, SIRT3OE significantly inhibited MnSOD acetylation and NLRP3 inflammasome activation. In vitro studies confirmed the crosstalk between mtROS and NLRP3, demonstrating that mtROS scavenger inhibited NLRP3 inflammasome activation induced by H/R and SIRT3KD, and the NLRP3 inhibitor suppressed MnSOD acetylation in H/R and SIRT3KD cardiomyocytes. Interestingly, Sal B was found to bind and upregulate SIRT3, reduce the expression of Acy-MnSOD, NLRP3, ASC, Caspase-1, and GSDMD, inhibit oxidative stress and inflammatory response, decrease myocardial infarct size and ST-segment elevation, and restore myocardial morphology. However, the protective effect of Sal B against MIRI was nullified by a specific SIRT3 inhibitor. This study unveils that the SIRT3-mediated interplay between mtROS and the NLRP3 inflammasome is pivotal in the pathogenesis of MIRI. Furthermore, it highlights Sal B as a novel therapeutic agent that alleviates MIRI by targeting SIRT3, offering new insights into MIRI treatment.

LncRNA DANCR suppresses acute myocardial infarction in mice via mediating p-RXRA/TRAF2/NIK/IKK/NF-κB signaling pathway.

This study aimed to investigate the role of LncRNA differentiation antagonizing non-protein coding RNA (DANCR) in acute myocardial infarction (AMI). A mouse model of AMI was established, and the cardiac contractile function was detected. Next, cardiomyocytes treated with oxygen-glucose deprivation (OGD) were used for gain- and loss-function experiments in vitro. RIP analysis was used to verify the binding of DANCR and Retinoid X receptor alpha (RXRA), and Co-IP assay was used to measure the binding of phosphorylated RXRA to TNF receptor associated factor 2 (TRAF2). The expression of DANCR in myocardial tissues of AMI mice were significantly downregulated. Overexpression of DANCR decreased myocardial infarct size and enhanced cardiac contractile function in AMI mice. Moreover, overexpression of DANCR promoted proliferation and inhibited apoptosis in OGD-induced cardiomyocytes. Mechanism studies demonstrated that DANCR interacted with RXRA and promoted glycogen synthase kinase 3beta (GSK3β)-mediated phosphorylation of RXRA, and phosphorylated RXRA interacted with TRAF2 protein to downregulate TRAF2 protein level. Bexarotene (Bex), an activator of RXRA, inhibited TRAF2 protein expression, while RXRA overexpression had no effect on TRAF2 protein expression. Bex treatment or silencing TRAF2 promoted proliferation and inhibited apoptosis in cardiomyocytes. In addition, silencing DANCR inhibited cardiomyocyte proliferation and induced apoptosis by activating the NIK/IKK/NF-κB pathway, while B022, an inhibitor of NIK, counteracted the effects of DANCR silencing on cardiomyocytes. Studies demonstrated that DANCR suppressed AMI in mice by mediating p-RXRA/TRAF2/NIK/IKK/NF-κB pathway.

Pretreatment with Notoginsenoside R1 enhances the efficacy of neonatal rat mesenchymal stem cell transplantation in model of myocardial infarction through regulating PI3K/Akt/FoxO1 signaling pathways

BackgroundAlthough stem cell transplantation is a promising approach for the treatment of myocardial infarction (MI), there are still some problems faced such as the low survival rate of stem cells. Here, we investigated the role of Notoginsenoside R1 (NGR1) pretreatment in improving the effects of neonatal rat bone marrow mesenchymal stem cell (MSC) transplantation for treatment of MI.MethodsCardiac functions were detected by echocardiography and the myocardial infarct size was determined by Masson’s trichrome staining in a rat model of MI. The cardioprotective effects of NGR1/LY294002 co-pretreated MSCs was evaluated to explore the underlying mechanism. The angiogenesis was determined by vWF and α-SMA immunofluorescence staining and cell apoptosis was detected by TUNEL. In vitro, the effects of NGR1 on stem cell proliferation was examined by CCK-8 and levels of P-Akt, P-CREB, P-FoxO1 were detected by western blot. Apoptosis, ROS content, and cytokine levels were examined by DAPI and TUNEL staining, a ROS assay kit, and ELISA, respectively.ResultsNGR1 elevated the therapeutic effect of MSC transplantation on infarction by preserving cardiac function, increasing angiogenesis and expressions of IGF-1, VEGF, and SDF-1, and reducing cell apoptosis, whereas the addition of LY294002 prior to NGR1 treatment significantly counteracted the foregoing effects of NGR1. NGR1 pretreatment and SC79 pretreatment were similar in that both significantly increased P-Akt and P-FoxO1 levels in MSC and did not affect P-CREB levels. Besides, both NGR1 and SC79 promoted VEGF, SCF and bFGF levels in MSC cultures, and significantly reduced ROS accumulation and the attenuated cell apoptosis in MSC triggered by H2O2. Similarly, addition of LY294002 before NGR1 treatment significantly counteracted the aforementioned effects of NGR1 in vitro.ConclusionsNGR1 pretreatment enhances the effect of MSC transplantation for treatment of MI through paracrine signaling, and the mechanism underlying this effect may be associated with PI3K/Akt/FoxO1 signaling pathways.