Effects of genetically proxied lipid-lowering drugs on acute myocardial infarction: a drug-target mendelian randomization study.

OBJECTIVE: High low-density-lipoprotein (LDL) cholesterol has been associated with an increased risk of coronary artery diseases (CAD) including acute myocardial infarction (AMI). However, whether lipids lowering drug treatment is causally associated with decreased risk of AMI remains largely unknown. We used Mendelian randomization (MR) to evaluate the influence of genetic variation affecting the function of lipid-lowering drug targets on AMI. METHODS: Single-nucleotide polymorphisms (SNPs) associated with lipids as instruments were extracted from the Global Lipids Genetics Consortium (GLGC). The genome-wide association study (GWAS) data for AMI were obtained from UK Biobank. Two sample MR analysis was used to study the associations between high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, and triglycerides (TG) with AMI (n = 3,927). Genetic variants associated with LDL cholesterol at or near drug target gene were used to mimic drug effects on the AMI events in drug target MR. RESULTS: Genetically predicted higher LDL-C (per one SD increase in LDL-C of 38.67 mg/dL, OR 1.006, 95% CI 1.004-1.007) and TG (per one SD increase in TG of 90.72 mg/dL, 1.004, 1.002-1.006) was associated with increased risk of AMI, but decreased risk for higher HDL-C (per one SD increase in HDL-C of 15.51 mg/dL, 0.997, 0.995-0.999) in univariable MR. Association remained significant for LDL-C, but attenuated toward the null for HDL-C and TG in multivariable MR. Genetically proxied lower LDL-C with genetic variants at or near the PCSK9 region (drug target of evolocumab) and NPC1L1 (drug target of ezetimibe) were associated with decreased risk of AMI (0.997, 0.994-0.999 and 0.986, 0.975-0.998, respectively), whereas genetic variants at HMGCR region (drug target of statin) showed marginal association with AMI (0.995, 0.990-1.000). After excluding drug target-related SNPs, LDL-C related SNPs outside the drug target region remained a causal effect on AMI (0.994, 0.993-0.996). CONCLUSIONS: The findings suggest that genetically predicted LDL-C may play a predominant role in the development of AMI. The drug MR results imply that ezetimibe and evolocumab may decrease the risk of AMI due to their LDL-C lowering effect, and there are other non-drug related lipid lowering pathways that may be causally linked to AMI.

Magnesium implantation as a continuous hydrogen production generator for the treatment of myocardial infarction in rats.

Molecular hydrogen is an emerging broad-spectrum antioxidant molecule that can be used to treat myocardial infarction (MI). However, with hydrogen inhalation, the concentration that can be reached within target organs is low and the duration of action is short, which makes it difficult to achieve high dose targeted delivery of hydrogen to the heart, seriously limiting the therapeutic potential of hydrogen for MI. As a result of reactions with the internal environment of the body, subcutaneous implantation of magnesium slices leads to continuous endogenous hydrogen production, leading to a higher hydrogen concentration and a longer duration of action in target organs. In this study, we propose magnesium implant-based hydrogen therapy for MI. After subcutaneous implantation of magnesium slices in the dorsum of rats, we measured hydrogen production and efficiency, and evaluated the safety of this approach. Compared with hydrogen inhalation, it significantly improved cardiac function in rats with MI. Magnesium implantation also cleared free radicals that were released as a result of mitochondrial dysfunction, as well as suppressing cardiomyocyte apoptosis.

Exploring T-cell exhaustion features in Acute myocardial infarction for a Novel Diagnostic model and new therapeutic targets by bio-informatics and machine learning.

BACKGROUND: T-cell exhaustion (TEX), a condition characterized by impaired T-cell function, has been implicated in numerous pathological conditions, but its role in acute myocardial Infarction (AMI) remains largely unexplored. This research aims to identify and characterize all TEX-related genes for AMI diagnosis. METHODS: By integrating gene expression profiles, differential expression analysis, gene set enrichment analysis, protein-protein interaction networks, and machine learning algorithms, we were able to decipher the molecular mechanisms underlying TEX and its significant association with AMI. In addition, we investigated the diagnostic validity of the leading TEX-related genes and their interactions with immune cell profiles. Different types of candidate small molecule compounds were ultimately matched with TEX-featured genes in the "DrugBank" database to serve as potential therapeutic medications for future TEX-AMI basic research. RESULTS: We screened 1725 differentially expressed genes (DEGs) from 80 AMI samples and 71 control samples, identifying 39 differential TEX-related transcripts in total. Functional enrichment analysis identified potential biological functions and signaling pathways associated with the aforementioned genes. We constructed a TEX signature containing five hub genes with favorable prognostic performance using machine learning algorithms. In addition, the prognostic performance of the nomogram of these five hub genes was adequate (AUC between 0.815 and 0.995). Several dysregulated immune cells were also observed. Finally, six small molecule compounds which could be the future therapeutic for TEX in AMI were discovered. CONCLUSION: Five TEX diagnostic feature genes, CD48, CD247, FCER1G, TNFAIP3, and FCGRA, were screened in AMI. Combining these genes may aid in the early diagnosis and risk prediction of AMI, as well as the evaluation of immune cell infiltration and the discovery of new therapeutics.

ß-Blocker Use and Clinical Outcomes in Patients With COPD Following Acute Myocardial Infarction.

Importance: While ß-blockers are associated with decreased mortality in cardiovascular disease (CVD), exacerbation-prone patients with chronic obstructive pulmonary disease (COPD) who received metoprolol in the Beta-Blockers for the Prevention of Acute Exacerbations of Chronic Obstructive Pulmonary Disease (BLOCK-COPD) trial experienced increased risk of exacerbations requiring hospitalization. However, the study excluded individuals with established indications for the drug, raising questions about the overall risk and benefit in patients with COPD following acute myocardial infarction (AMI). Objective: To investigate whether ß-blocker prescription at hospital discharge is associated with increased risk of mortality or adverse cardiopulmonary outcomes in patients with COPD and AMI. Design, Setting, and Participants: This prospective, longitudinal cohort study with 6 months of follow-up enrolled patients aged 35 years or older with COPD who underwent cardiac catheterization for AMI at 18 BLOCK-COPD network hospitals in the US from June 2020 through May 2022. Exposure: Prescription for any ß-blocker at hospital discharge. Main Outcomes and Measures: The primary outcome was time to the composite outcome of death or all-cause hospitalization or revascularization. Secondary outcomes included death, hospitalization, or revascularization for CVD events, death or hospitalization for COPD or respiratory events, and treatment for COPD exacerbations. Results: Among 3531 patients who underwent cardiac catheterization for AMI, prevalence of COPD was 17.1% (95% CI, 15.8%-18.4%). Of 579 total patients with COPD and AMI, 502 (86.7%) were prescribed a ß-blocker at discharge. Among the 562 patients with COPD included in the final analysis, median age was 70.0 years (range, 38.0-94.0 years) and 329 (58.5%) were male; 553 of the 579 patients (95.5%) had follow-up information. Among those discharged with ß-blockers, there was no increased risk of the primary end point of all-cause mortality, revascularization, or hospitalization (hazard ratio [HR], 1.01; 95% CI, 0.66-1.54; P = .96) or of cardiovascular events (HR, 1.11; 95% CI, 0.65-1.92; P = .69), COPD-related or respiratory events (HR, 0.75; 95% CI, 0.34-1.66; P = .48), or treatment for COPD exacerbations (rate ratio, 1.01; 95% CI, 0.53-1.91; P = .98). Conclusions and Relevance: In this cohort study, ß-blocker prescription at hospital discharge was not associated with increased risk of adverse outcomes in patients with COPD and AMI. These findings support use of ß-blockers in patients with COPD and recent AMI.

Peptides Are Cardioprotective Drugs of the Future: The Receptor and Signaling Mechanisms of the Cardioprotective Effect of Glucagon-like Peptide-1 Receptor Agonists.

The high mortality rate among patients with acute myocardial infarction (AMI) is one of the main problems of modern cardiology. It is quite obvious that there is an urgent need to create more effective drugs for the treatment of AMI than those currently used in the clinic. Such drugs could be enzyme-resistant peptide analogs of glucagon-like peptide-1 (GLP-1). GLP-1 receptor (GLP1R) agonists can prevent ischemia/reperfusion (I/R) cardiac injury. In addition, chronic administration of GLP1R agonists can alleviate the development of adverse cardiac remodeling in myocardial infarction, hypertension, and diabetes mellitus. GLP1R agonists can protect the heart against oxidative stress and reduce proinflammatory cytokine (IL-1ß, TNF-α, IL-6, and MCP-1) expression in the myocardium. GLP1R stimulation inhibits apoptosis, necroptosis, pyroptosis, and ferroptosis of cardiomyocytes. The activation of the GLP1R augments autophagy and mitophagy in the myocardium. GLP1R agonists downregulate reactive species generation through the activation of Epac and the GLP1R/PI3K/Akt/survivin pathway. The GLP1R, kinases (PKCε, PKA, Akt, AMPK, PI3K, ERK1/2, mTOR, GSK-3ß, PKG, MEK1/2, and MKK3), enzymes (HO-1 and eNOS), transcription factors (STAT3, CREB, Nrf2, and FoxO3), KATP channel opening, and MPT pore closing are involved in the cardioprotective effect of GLP1R agonists.

Pyroptosis inhibitors MCC950 and VX-765 mitigate myocardial injury by alleviating oxidative stress, inflammation, and apoptosis in acute myocardial hypoxia.

Acute myocardial infarction (AMI) is a prevalent cardiovascular disease with high morbidity and mortality rates worldwide. Pyroptosis is an inflammatory form of programmed cell death that has been linked to various pathological conditions. However, its exact contribution to the onset and progression of heart injury in AMI has not yet fully elucidated. Herein, we established mouse AMI model by ligating the left anterior descending artery and performed transcriptome analysis during the early phase of AMI. Mouse HL-1 and human AC-16 cardiomyocytes were subjected to hypoxia to simulate ischemic injury in vitro. Our results revealed a significant activation of the inflammatory response at 3 h post-ligation, as confirmed by RNA sequencing. We identified the occurrence of NLRP3 inflammasome-mediated pyroptosis in the cardiac tissues of human cases with AMI, as well as in mouse models of AMI and hypoxia-induced cardiomyocytes, using immunohistochemistry staining and Western blotting assays. Concurrently, pharmacological inhibition of NLRP3 inflammasome-mediated pyroptosis with MCC950 and VX-765 effectively decreased hypoxia-induced cardiomyocytes injury, while mitigating myocardial oxidative stress, apoptosis and inflammation caused by hypoxia. Moreover, the circulating levels of gasdermin D (GSDMD), the pyroptosis executor, were remarkably elevated in the plasma of mice with early AMI and in the supernatant of hypoxia-exposed cardiomyocytes in a time-dependent manner using ELISA and Western blotting. Furthermore, the change in circulating GSDMD positively correlated with Creatine Kinase-MB (CK-MB) in the plasma of early-stage AMI mouse. In summary, these findings indicated a critical role for NLRP3 inflammasome-mediated pyroptosis in the progression of AMI, the administration of MCC950 and VX-765 may be attractive candidate therapeutic approaches for cardiac injury caused by acute hypoxia or even AMI. Additionally, the circulating GSDMD exhibits potential as a newly diagnostic biomarker for AMI.

Progresses and perspectives on natural polysaccharide based hydrogels for repair of infarcted myocardium.

Myocardial infarction (MI) is serious health threat and impairs the quality of life. It is a major causative factor of morbidity and mortality. MI leads to the necrosis of cardio-myocytes, cardiac remodelling and dysfunction, eventually leading to heart failure. The limitations of conventional therapeutic and surgical interventions and lack of heart donors have necessitated the evolution of alternate treatment approaches for MI. Polysaccharide hydrogel based repair of infarcted myocardium have surfaced as viable option for MI treatment. Polysaccharide hydrogels may be injectable hydrogels or cardiac patches. Injectable hydrogels can in situ deliver cells and bio-actives, facilitating in situ cardiac regeneration and repair. Polysaccharide hydrogel cardiac patches reduce cardiac wall stress, and inhibit ventricular expansion and promote angiogenesis. Herein, we discuss about MI pathophysiology and myocardial microenvironment and how polysaccharide hydrogels are designed to mimic and support the microenvironment for cardiac repair. We also put forward the versatility of the different polysaccharide hydrogels in mimicking diverse cardiac properties, and acting as a medium for delivery of cells, and therapeutics for promoting angiogenesis and cardiac repair. The objectives of this review is to summarize the factors leading to MI and to put forward how polysaccharide based hydrogels promote cardiac repair. This review is written to enable researchers understand the factors promoting MI so that they can undertake and design novel hydrogels for cardiac regeneration.

Activation of Cardiac δ2-Opioid Receptors Increases Heart Tolerance to Reperfusion.

Coronary occlusion (45 min) and reperfusion (120 min) in male Wistar rats in vivo, as well as total ischemia (45 min) of an isolated rat heart followed by reperfusion (30 min) were reproduced. The selective δ2-opioid receptor agonist deltorphin II (0.12 mg/kg and 152 nmol/liter) was administered intravenously 5 min before reperfusion in vivo or added to the perfusion solution at the beginning of reperfusion of the isolated heart. The peripheral opioid receptor antagonist naloxone methiodide and δ2-opioid receptor antagonist naltriben were used in doses of 5 and 0.3 mg/kg, respectively. It was found that the infarct-limiting effect of deltorphin II is associated with the activation of δ2-opioid receptors. We have demonstrated that deltorphin II can improve the recovery of the contractility of the isolated heart after total ischemia.

Chlorthalidone vs Hydrochlorothiazide for Hypertension Treatment After Myocardial Infarction or Stroke: A Secondary Analysis of a Randomized Clinical Trial.

Importance: Patients with prior myocardial infarction (MI) or stroke have a greater risk of recurrent cardiovascular (CV) events. Objective: To evaluate the association of chlorthalidone (CTD) vs hydrochlorothiazide (HCTZ) with CV outcomes and noncancer deaths in participants with and without prior MI or stroke. Design, Setting, and Participants: This was a prespecified secondary analysis of the Diuretic Comparison Project (DCP), a pragmatic randomized clinical trial conducted within 72 participating Veterans Affairs health care systems from June 2016 to June 2021, in which patients aged 65 years or older with hypertension taking HCTZ at baseline were randomized to continue HCTZ or switch to CTD at pharmacologically comparable doses. This secondary analysis was performed from January 3, 2023, to February 29, 2024. Exposures: Pharmacologically comparable daily dose of HCTZ or CTD and history of MI or stroke. Main Outcomes and Measures: Outcome ascertainment was performed from randomization to the end of the study. The primary outcome consisted of a composite of stroke, MI, urgent coronary revascularization because of unstable angina, acute heart failure hospitalization, or noncancer death. Additional outcomes included achieved blood pressure and hypokalemia (potassium level <3.1 mEq/L; to convert to mmol/L, multiply by 1.0). Results: The DCP randomized 13 523 participants to CTD or HCTZ, with a mean (SD) study duration of 2.4 (1.4) years. At baseline, median age was 72 years (IQR, 69-75 years), and 96.8% were male. Treatment effect was evaluated in subgroups of participants with (n = 1455) and without (n = 12 068) prior MI or stroke at baseline. There was a significant adjusted interaction between treatment group and history of MI or stroke. Participants with prior MI or stroke randomized to CTD had a lower risk of the primary outcome than those receiving HCTZ (105 of 733 [14.3%] vs 140 of 722 [19.4%]; hazard ratio [HR], 0.73; 95% CI, 0.57-0.94; P = .01) compared with participants without prior MI or stroke, among whom incidence of the primary outcome was slightly higher in the CTD arm compared with the HCTZ arm (597 of 6023 [9.9%] vs 535 of 6045 [8.9%]; HR, 1.12; 95% CI, 1.00-1.26; P = .054) (P = .01 for interaction). The incidence of a nadir potassium level less than 3.1 mEq/L and hospitalization for hypokalemia differed among those with and without prior MI or stroke when comparing those randomized to CTD vs HCTZ, with a difference only among those without prior MI or stroke (potassium level <3.1 mEq/L: prior MI or stroke, 43 of 733 [5.9%] vs 37 of 722 [5.1%] [P = .57]; no prior MI or stroke, 292 of 6023 [4.9%] vs 206 of 6045 [3.4%] [P < .001]; hospitalization for hypokalemia: prior MI or stroke, 14 of 733 [1.9%] vs 16 of 722 [2.2%] [P = .72]; no prior MI or stroke: 84 of 6023 [1.4%] vs 57 of 6045 [0.9%] [P = .02]). Conclusions and Relevance: Results of this secondary analysis of the DCP trial suggest that CTD may be associated with reduced major adverse CV events and noncancer deaths in patients with prior MI or stroke compared with HCTZ. Trial Registration: ClinicalTrials.gov Identifier: NCT02185417.

Melatonin alleviates myocardial dysfunction through inhibition of endothelial-to-mesenchymal transition via the NF-κB pathway.

Endothelial-to-mesenchymal transition (EndMT) is a complex biological process of cellular transdifferentiation by which endothelial cells (ECs) lose their characteristics and acquire mesenchymal properties, leading to cardiovascular remodeling and complications in the adult cardiovascular diseases environment. Melatonin is involved in numerous physiological and pathological processes, including aging, and has anti-inflammatory and antioxidant activities. This molecule is an effective therapeutic candidate for preventing oxidative stress, regulating endothelial function, and maintaining the EndMT balance to provide cardiovascular protection. Although recent studies have documented improved cardiac function by melatonin, the mechanism of action of melatonin on EndMT remains unclear. The present study investigated the effects of melatonin on induced EndMT by transforming growth factor-ß2/interleukin-1ß in both in vivo and in vitro models. The results revealed that melatonin reduced the migratory ability and reactive oxygen species levels of the cells and ameliorated mitochondrial dysfunction in vitro. Our findings indicate that melatonin prevents endothelial dysfunction and inhibits EndMT by activating related pathways, including nuclear factor kappa B and Smad. We also demonstrated that this molecule plays a crucial role in restoring cardiac function by regulating the EndMT process in the ischemic myocardial condition, both in vessel organoids and myocardial infarction (MI) animal models. In conclusion, melatonin is a promising agent that attenuates EC dysfunction and ameliorates cardiac damage compromising the EndMT process after MI.

Integrated serum pharmacochemistry with network pharmacology and pharmacological validation to elucidate the mechanism of yiqitongmai decoction (YQTMD) against myocardial infarction.

ETHNOPHARMACOLOGICAL RELEVANCE: Yiqitongmai decoction (YQTMD), a classic TCM, has been widely used in clinical treatment for MI. However, it is still difficult to clarify the potential active compounds and pharmacological mechanisms of it in treating MI. AIM OF THE STUDY: To explore the active ingredients, pharmacological effects, potential targets and mechanisms of YQTMD against MI. MATERIALS AND METHODS: Serum pharmacochemistry by UPLC-MS/MS was applied to analyze the phytochemical components in serum from YQTMD. These components were then used to predict the potential targets using network pharmacology approach and molecular dynamics simulations, and then the protective effect of them on H9c2 cells following hypoxic conditions was assessed. Afterwards, the pharmacological effects of YQTMD on MI in mice were tested by determining electrocardiogram (ECG), echocardiography, cardiac biomarkers, oxidative stress, inflammation and pathophysiological changes. The protein levels involving STAT3 signal were detected using Western blot and immunofluorescence assays. Furthermore, STAT3 inhibitor Sttatic was employed to further elucidate the underlying mechanisms. RESULTS: Totally, 26 compounds derived from YQTMD were identified in mice serum, and 201 genes associated with the compounds were collected. The compounds including safflomin A, ferulic acid, gypenoside XVII, ginsenoside Rg1 and glycyrrhizic acid were identified as the critical compounds of YQTMD to regulate STAT3 pathway. In vitro, compounds combination significantly enhanced the viability of H9c2 cells and reduced ROS level compared to model cells. The in vivo results showed that YQTMD effectively reduced myocardial injury, as evidenced by the decreased serum cardiac injury markers, reduction in the size of myocardial infarct, restoration of abnormal alterations in ECG and decrease in cardiomyocyte apoptosis. Additionally, YQTMD attenuated MI-induced cardiac dysfunction, alleviated pathological changes, reduced MDA levels, and enhanced SOD and GSH levels compared with model mice. Significantly, the levels of IL-6, IL-1ß, and TNF-α were observed to decrease in the YQTMD group. The expression levels of key proteins (p-STAT3, HIF-1α, NOX2, TLR5 and Caspase3) in STAT3 pathway were also regulated by YQTMD. However, the cardioprotective effects of YQTMD on MI were attenuated by STAT3 inhibitor Sttatic. CONCLUSIONS: This study investigated the active ingredients and potential mechanisms of YQTMD for MI treatment based on serum pharmacochemistry and network pharmacology approaches, revealing that YQTMD exerts its therapeutic effects on MI by alleviating oxidative stress, inflammation and apoptosis through adjusting STAT3 signaling pathway.

Vericiguat suppresses ventricular tachyarrhythmias inducibility in a rabbit myocardial infarction model.

BACKGROUND: The VICTORIA trial demonstrated a significant decrease in cardiovascular events through vericiguat therapy. This study aimed to assess the potential mechanisms responsible for the reduction of cardiovascular events with vericiguat therapy in a rabbit model of myocardial infarction (MI). METHODS: A chronic MI rabbit model was created through coronary artery ligation. Following 4 weeks, the hearts were harvested and Langendorff perfused. Subsequently, electrophysiological examinations and dual voltage-calcium optical mapping studies were conducted at baseline and after administration of vericiguat at a dose of 5 µmol/L. RESULTS: Acute vericiguat therapy demonstrated a significant reduction in premature ventricular beat burden and effectively suppressed ventricular arrhythmic inducibility. The electrophysiological influences of vericiguat therapy included an increased ventricular effective refractory period, prolonged action potential duration, and accelerated intracellular calcium (Cai) homeostasis, leading to the suppression of action potential and Cai alternans. The pacing-induced ventricular arrhythmias exhibited a reentrant pattern, attributed to fixed or functional conduction block in the peri-infarct zone. Vericiguat therapy effectively mitigated the formation of cardiac alternans as well as the development of reentrant impulses, providing additional anti-arrhythmic benefits. CONCLUSIONS: In the MI rabbit model, vericiguat therapy demonstrates anti-ventricular arrhythmia effects. The vericiguat therapy reduces ventricular ectopic beats, inhibiting the initiation of ventricular arrhythmias. Furthermore, the therapy successfully suppresses cardiac alternans, preventing conduction block and, consequently, the formation of reentry circuits.

Prehospital crushed versus integral prasugrel loading dose in STEMI patients with a large myocardial area.

BACKGROUND: The effect of administering a crushed prasugrel loading dose is uncertain in patients presenting with a large myocardial infarction and ST-segment elevation myocardial infarction (STEMI). AIMS: The aim of this study was to investigate if patients with a large myocardial infarction may benefit from prehospital administration of a crushed prasugrel loading dose. METHODS: Patients from the CompareCrush trial with an available ambulance electrocardiography (ECG) were included in the study. An independent core laboratory confirmed a prehospital large myocardial area. We compared pre- and postprocedural angiographic markers, including Thrombolysis in Myocardial Infarction (TIMI) 3 flow in the infarct-related artery, high thrombus burden, and myocardial blush grade 3, in STEMI patients with and without a prehospital large myocardial area. RESULTS: Ambulance ECG was available for 532 patients, of whom 331 patients were identified with a prehospital large myocardial area at risk. Crushed prasugrel significantly improved postprocedural TIMI 3 flow rates in STEMI patients with a prehospital large myocardial area at risk (92% vs 79%, odds ratio [OR] 3.00, 95% confidence interval [CI]: 1.50-6.00) but not in STEMI patients without a prehospital large myocardial area at risk (91% vs 95%, OR 0.47, 95% CI: 0.14-1.57; pinteraction=0.009). CONCLUSIONS: Administration of crushed prasugrel may improve postprocedural TIMI 3 flow in STEMI patients with signs of a large myocardial area at risk on the ambulance ECG. The practice of crushing tablets of prasugrel loading dose might, therefore, represent a safe, fast and cost-effective strategy to improve myocardial reperfusion in this high-risk STEMI subgroup undergoing primary percutaneous coronary intervention.

Carbon Dots Derived from Curcumae Radix and Their Heartprotective Effect.

Background: Acute myocardial infarction (AMI) is a common cardiovascular disease in clinic. Currently, there is no specific treatment for AMI. Carbon dots (CDs) have been reported to show excellent biological activities, which hold promise for the development of novel nanomedicines for the treatment of cardiovascular diseases. Methods: In this study, we firstly prepared CDs from the natural herb Curcumae Radix Carbonisata (CRC-CDs) by a green, simple calcination method. The aim of this study is to investigate the cardioprotective effect and mechanism of CRC-CDs on isoproterenol (ISO) -induced myocardial infarction (MI) in rats. Results: The results showed that pretreatment with CRC-CDs significantly reduced serum levels of cardiac enzymes (CK-MB, LDH, AST) and lipids (TC, TG, LDL) and reduced st-segment elevation and myocardial infarct size on the ECG in AMI rats. Importantly, cardiac ejection fraction (EF) and shortening fraction (FS) were markedly elevated, as was ATPase activity. In addition, CRC-CDs could significantly increase the levels of superoxide dismutase (SOD), reduced glutathione (GSH), catalase (CAT), and reduce the levels of malondialdehyde (MDA) and reactive oxygen species (ROS) in myocardial tissue, thereby exerting cardioprotective effect by enhancing the antioxidant capacity of myocardial tissue. Moreover, the TUNEL staining image showed that positive apoptotic cells were markedly declined after CRC-CDs treatment, which indicate that CRC-CDs could inhibit cardiomyocyte apoptosis. Importantly, The protective effect of CRC-CDs on H2O2 -pretreated H9c2 cells was also verified in vitro. Conclusion: Taken together, CRC-CDs has the potential for clinical application as an anti-myocardial ischemia drug candidate, which not only provides evidence for further broadening the biological application of cardiovascular diseases, but also offers potential hope for the application of nanomedicine to treat intractable diseases.

Construction of preclinical evidence for propofol in the treatment of reperfusion injury after acute myocardial infarction: A systematic review and meta-analysis.

Propofol, a commonly used intravenous anesthetic, has demonstrated potential in protecting against myocardial ischemia/reperfusion injury (MIRI) based on preclinical animal studies. However, the clinical benefits of propofol in this context are subject to debate. We conducted a systematic search across eight databases to identify all relevant animal studies investigating the preventive effects of propofol on MIRI until October 30, 2023. We assessed the methodological quality of the included studies using SYRCLE's bias risk tool. Statistical analysis was performed using STATA 15.1. The primary outcome measures analyzed in this study were myocardial infarct size (IS) and myocardial injury biomarkers. This study presents a comprehensive analysis of 48 relevant animal studies investigating propofol's preventive effects on MIRI. Propofol administration demonstrated a reduction in myocardial IS and decreased levels of myocardial injury biomarkers (CK-MB, LDH, cTnI). Moreover, propofol improved myocardial function parameters (+dp/dtmax, -dP/dtmax, LVEF, LVFS), exhibited favorable effects on inflammatory markers (IL-6, TNF-α) and oxidative stress markers (SOD, MDA), and reduced myocardial cell apoptotic index (AI). These findings suggest propofol exerts cardioprotective effects by reducing myocardial injury, decreasing infarct size, and improving heart function. However, the absence of animal models that accurately represent comorbidities such as aging and hypertension, as well as inconsistent administration methods that align with clinical practice, may hinder its clinical translation. Further robust investigations are required to validate these findings, elucidate the underlying mechanisms of propofol, and facilitate its potential translation into clinical practice.

Diosgenin improves post-myocardial infarction cardiac function via HAND2-induced angiogenesis.

While diosgenin has been demonstrated effective in various cardiovascular diseases, its specific impact on treating heart attacks remains unclear. Our research revealed that diosgenin significantly improved cardiac function in a myocardial infarction (MI) mouse model, reducing cardiac fibrosis and cell apoptosis while promoting angiogenesis. Mechanistically, diosgenin upregulated the Hand2 expression, promoting the proliferation and migration of endothelial cells under hypoxic conditions. Acting as a transcription factor, HAND2 activated the angiogenesis-related gene Aggf1. Conversely, silencing Hand2 inhibited the diosgenin-induced migration of hypoxic endothelial cells and angiogenesis. In summary, these findings provide new insights into the protective role of diosgenin in MI, validating its effect on angiogenic activity and providing a theoretical basis for clinical treatment strategies.

Influence of sex on the timing of coronary angiography and the prescription of antiplatelet therapy in patients with nonST-segment elevation myocardial infarction. / Impacto del sexo en los tiempos de cateterismo y en el uso de pretratamiento antiagregante plaquetario en pacientes con síndrome coronario agudo sin elevación del segmento ST (SCASEST).

OBJECTIVES: To assess differences in the clinical management of nonST-segment elevation myocardial infarction (NSTEMI), including in-hospital events, according to biological sex. MATERIAL AND METHODS: Prospective observational multicenter study of patients diagnosed with NSTEMI and atherosclerosis who underwent coronary angiography. RESULTS: We enrolled 1020 patients in April and May 2022; 240 (23.5%) were women. Women were older than men on average (72.6 vs 66.5 years, P .001), and more women were frail (17.1% vs 5.6%, P .001). No difference was observed in pretreatment with any P2Y12 inhibitor (prescribed in 68.8% of women vs 70.2% of men, P = .67); however, more women than men were prescribed clopidogrel (56% vs 44%, P = .009). Women prescribed clopidogrel were more often under the age of 75 years and not frail. Coronary angiography was performed within 24 hours less corooften in women (29.8% vs 36.9%, P = .03) even when high risk was recognized. Frailty was independently associated with deferring coronary angiography in the adjusted analysis; biological sex by itself was not related. The frequency and type of revascularization were the same in both sexes, and there were no differences in in-hospital cardiovascular events. CONCLUSION: Women were more often prescribed less potent antithrombotic therapy than men. Frailty, but not sex, correlated independently with deferral of coronary angiography. However, we detected no differences in the frequency of coronary revascularization or in-hospital events according to sex.

OBJETIVO: Evaluar las diferencias en el manejo clínico y eventos intrahospitalarios en una cohorte de pacientes con síndrome coronario agudo sin elevación del segmento ST (SCASEST) en función del sexo. METODO: Estudio observacional, prospectivo y multicéntrico que incluyó pacientes consecutivos con diagnóstico de SCASEST sometidos a coronariografía con enfermedad ateroesclerótica responsable. RESULTADOS: Entre abril y mayo de 2022 se incluyeron 1.020 pacientes; de ellos, 240 eran mujeres (23,5%). En comparación con los hombres, las mujeres fueron mayores (72,6 años vs 66,5 años; p 0,001) y más frágiles (17,1% vs 5,6%; p 0,001). No hubo diferencias en el pretratamiento con un inhibidor del receptor P2Y12 (68,8% vs 70,2%, p = 0,67), aunque las mujeres recibieron más pretratamiento con clopidogrel (56% vs 44%, p = 0,009), principalmente aquellas de edad 75 años y sin fragilidad. En las mujeres se realizaron menos coronariografías precoces (# 24 h) (29,8% vs 36,9%; p = 0,03) a pesar de presentar la misma indicación (criterios de alto riesgo). En el análisis ajustado, la fragilidad, pero no el sexo, se asoció de forma independiente con la realización de una coronariografía diferida. La tasa y el tipo de revascularización fue igual en ambos sexos, y no hubo diferencias en los eventos cardiovasculares intrahospitalarios. CONCLUSIONES: Las mujeres recibieron con mayor frecuencia un tratamiento antitrombótico menos potente. La fragilidad y no el sexo se asoció con la realización de coronariografía diferida. Sin embargo, no hubo diferencias en la tasa de revascularización coronaria ni en los eventos intrahospitalarios en función del sexo.

[Mechanism of Guizhi Gancao Decoction against myocardial ischemia-reperfusion injury based on network pharmacology and experimental verification].

This study employed network pharmacology to investigate the effect of Guizhi Gancao Decoction(GGD) on myocardial ischemia-reperfusion injury(MI/RI) in rats and decipher the underlying mechanism. Firstly, the chemical components and targets of GGD against MI/RI were searched against the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform(TCMSP), SwissTargetPrediction, and available articles. STRING and Cytoscape 3.7.2 were used to establish the protein-protein interaction(PPI) network for the common targets, and then Gene Ontology(GO) and Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway enrichment analyses were carried out for the core targets. The "drug-active component-target-pathway" network was built. Furthermore, molecular docking between key active components and targets was conducted in AutoDock Vina. Finally, the rat model of MI/RI was established, and the myocardial infarction area was measured. Hematoxylin-eosin(HE) staining and transmission electron microscopy(TEM) were employed to detect cardiomyocyte pathology and ultrastructural changes. Western blot was employed to determine the expression of related proteins in the myocardial tissue. A total of 75 chemical components of GGD were screened out, corresponding to 318 targets. The PPI network revealed 46 core targets such as tumor protein p53(TP53), serine/threonine kinase 1(AKT1), signal transducer and activator of transcription 3(STAT3), non-receptor tyrosine kinase(SRC), mitogen-activated protein kinase 1(MAPK1), MAPK3, and tumor necrosis factor(TNF). According to GO and KEGG enrichment analyses, the core targets mainly affected the cell proliferation and migration, signal transduction, apoptosis, and transcription, involving advanced glycation end products-receptor(AGE-RAGE), MAPK and other signaling pathways in cancers and diabetes complications. The molecular docking results showed that the core components of GGD, such as licochalcone A,(+)-catechin, and cinnamaldehyde, had strong binding activities with the core target proteins, such as MAPK1 and MAPK3. The results of animal experiments showed that compared with the model group, GGD significantly increase superoxide dismutase, decreased malondialdehyde, lactate dehydrogenase, and creatine kinase-MB, and reduced the area of myocardial infarction. HE staining and TEM results showed that GGD pretreatment restored the structure of cardiomyocytes and alleviated the pathological changes and ultrastructural damage of mitochondria in the model group. In addition, GGD significantly down-regulated the phosphorylation of c-Jun N-terminal kinase and p38 and up-regulate that of extracellular regulated kinases 1/2 in the myocardial tissue. The results suggested that GGD may exert the anti-MI/RI effect by regulating the MAPK signaling pathway via the synergistic effects of Cinnamomi Ramulus and Glycyrrhizae Radix et Rhizoma.