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Background: Metabolic re-wiring with preferential fatty acid oxidation has been observed in lung cancer cells. Whether the use of trimetazidine, an anti-anginal agent that inhibits fatty acid oxidation, alters clinical outcomes in ischemic heart disease (IHD) patients with lung cancers is unknown., Methods: We carried out this territory-wide, retrospective cohort study of 279,894 IHD patients prescribed with trimetazidine or long-acting oral nitrates in Hong Kong (population coverage of 7.5 millions, January 1999 - December 2020). A total of 6561 patients with pre-existing or de novo lung cancers were identified. Clinical outcomes of all-cause mortality were longitudinally compared between lung cancer patients who received trimetazidine (n = 547) versus non-users (control, n = 6014)., Results: Over 902.9 ± 1410.6 days, lower incidence of deaths occurred in the trimetazidine group (79.0 %, n = 432/547) compared to controls (90.5 %, n = 5442/6014, P < 0.001). Kaplan-Meier analyses showed that trimetazidine use was associated with significantly higher survival from all-cause mortality in IHD patients (trimetazidine: mean survival = 1840.6 [95 %CI 1596.0-2085.3], versus control: 1056.7 [95 %CI 1011.3-1102.0] days, Log Rank = 69.4, P < 0.001). Cox regression showed that trimetazidine use was significantly associated with reduced risk of all-cause mortality in crude (HR = 0.60 [95 %CI: 0.53 to 0.68], P < 0.001) and multivariable models (HR = 0.65 [95 % CI: 0.57 to 0.74], P < 0.001). Pre-specified analyses amongst patients with pre-existing lung cancers yielded similar findings (HR = 0.49 [95 %CI: 0.35 to 0.67], P < 0.001). Survival benefits related to trimetazidine use was predominantly restricted to non-cardiovascular mortality (P < 0.001)., Conclusions: Trimetazidine use is associated with higher overall survival in IHD patients with lung cancers, particularly from non-cardiovascular death. These findings need to be confirmed by randomized controlled trials., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Qishen Yiqi dropping pills combined with modern medicine have been widely used as a treatment for coronary heart disease with ischemic heart failure. Currently, there have been no robust studies addressing the efficacy and safety of Qishen Yiqi dropping pills combined with modern medicine for coronary heart disease with ischemic heart failure. Therefore, this systematic review and meta-analysis are conducted to fill in the gaps mentioned above., Methods: This systematic review was conducted and reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Relevant studies published from inception to April 17, 2023, in the 5 electronic databases: PubMed, The Cochrane Library, EMBASE, CNKI, and the Wanfang database were comprehensively searched. Weighted mean difference was used as the effect size for the continuous variables. Pooled odd ratios are presented if the results are binary variables. Additionally, we performed subgroup and sensitivity analyses to examine the source of heterogeneity. The funnel plot and the Egger test were used to estimate publication bias., Results: This meta-analysis included 46 studies involving 5843 participants. There is a significant difference in clinical efficacy, the 6-minute walk test (weighted mean difference = 50.10; 95% CI 28.19 to 72.02; I2 = 98.9%, P = .000), the indexes of ultrasonic cardiogram, blood biochemical indexes, and adverse effects (odds ratios = 0.46; 95% CI 0.29 to 0.75; I2 = 35.9%, P = .142). The sensitivity analysis and publication bias have demonstrated the robustness of the results (P = .702)., Conclusion: Qishen Yiqi dropping pills combined with modern medicine could significantly improve clinical efficacy without incasement adverse effects. Further studies are required to identify the more comprise efficacy and safety results., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Purpose of Review: To summarize the recent evidence and guideline recommendations on aspirin or P2Y 12 inhibitor monotherapy in patients with stable ischemic heart disease and provide insights into future directions on this topic, which involves transition to a personalized assessment of bleeding and thrombotic risks., Recent Findings: It has been questioned whether the evidence for aspirin as the foundational component of secondary prevention in patients with coronary artery disease aligns with contemporary pharmaco-invasive strategies. The recent HOST-EXAM study randomized patients who had received dual antiplatelet therapy for 6 to 18 months without ischemic or major bleeding events to either clopidogrel or aspirin for a further 24 months, and demonstrated that the patients in the clopidogrel arm had significantly lower rates of both thrombotic and bleeding complications compared to those in the aspirin arm. The patient-level PANTHER meta-analysis showed that in patients with established coronary artery disease, P2Y 12 inhibitor monotherapy was associated with lower rates of myocardial infarction, stent thrombosis as well as gastrointestinal bleeding and hemorrhagic stroke compared to aspirin monotherapy, albeit with similar rates of all-cause mortality, cardiovascular mortality and major bleeding. Long-term low-dose aspirin is recommended for secondary prevention in patients with stable ischemic heart disease, with clopidogrel monotherapy being acknowledged as a feasible alternative. Dual antiplatelet therapy for six months after percutaneous coronary intervention remains the standard recommendation for patients with stable ischemic heart disease. However, the duration of dual antiplatelet therapy may be shortened and followed by P2Y 12 inhibitor monotherapy or prolonged based on individualized evaluation of the patient's risk profile., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: The prevalence of chronic obstructive pulmonary disease (COPD) in patients with ischemic heart disease (IHD) remains uncertain, and its association with adverse outcomes is frequently overlooked. This study aimed to estimate the prevalence of COPD, and its impact on pharmacological treatment, and clinical outcomes in patients with IHD., Methods: A systematic literature search was conducted in Web of Science, Embase, and PubMed until November 20, 2023. All studies that reported the prevalence of COPD in IHD patients were included, and a random-effects model was employed to calculate the pooled prevalence. Data on cardiovascular risk factors/comorbidities, beta-blockers (BBs) prescription, acute phase outcomes [in-hospital mortality, major adverse cardiovascular events (MACE), acute heart failure (AHF), and cardiogenic shock], and long-term mortality were compared according to COPD status., Results: A total of 82 eligible studies that reported the prevalence of COPD in 18 million IHD patients were included. The pooled prevalence of COPD was 12.0% [95% confidence intervals (CI): 9.9%-14.1%] in patients with IHD. In subgroup analysis, the prevalence of COPD was highest in North America (15.3%), followed by Europe (10.0%), and Asia (8.8%). In addition, COPD was associated with a higher burden of cardiovascular risk factors/comorbidities, but lower BBs prescription [odds ratio (OR) 0.50, 95% CI 0.38-0.66]. Moreover, COPD was linked to an increased risk of in-hospital mortality (OR 1.47, 95% CI 1.37-1.58), MACE (OR 1.81, 95% CI 1.44-2.27), AHF (OR 2.14, 95% CI 1.86-2.46), cardiogenic shock (OR 1.30, 95% CI 1.01-1.68), as well as long-term mortality (OR 1.99, 95% CI 1.80-2.20)., Conclusion: This meta-analysis demonstrated that COPD is prevalent in IHD, involving 12.0% of IHD patients, and is linked to a lower prescription of BBs, an increased burden of comorbidities, and worse acute phase outcomes and long-term mortality., Competing Interests: The authors report no conflicts of interest in this work., (© 2024 Meng et al.)

Polygonatum cyrtonema Hua and its processed products have demonstrated cardio-protective effects, though the underlying mechanisms remain unclear. In this study, plasma metabolic profiling and pattern recognition were employed to explore the cardio-protective mechanisms of both crude and processed P. cyrtonema in a myocardial ischemia model induced by ligation, using gas chromatography-mass spectrometry. Post-modeling, plasma levels of creatine kinase-MB, lactate dehydrogenase, troponin T, and malondialdehyde were significantly elevated but were notably reduced after treatment. Conversely, plasma levels of glutathione peroxidase and superoxide dismutase, which were significantly decreased post-modeling, were restored following treatment. Hematoxylin-eosin (HE) and Masson staining revealed that both crude and processed P. cyrtonema effectively reduced inflammatory infiltration and fibrosis in cardiac tissue. Metabolic profiling identified 34 differential endogenous metabolites in the treatment groups, with 19 confirmed using standard compounds. The linear correlation coefficients (R2) for these standards ranged from 0.9960 to 0.9996, indicating high accuracy. The method exhibited excellent precision and repeatability, with relative standard deviation (RSD) values below 8.57%. Recovery rates were between 95.02% and 105.15%, and the stability of the standard compounds was confirmed after three freeze-thaw cycles, with RSD values under 4.42%. Both crude and processed P. cyrtonema were found to alleviate myocardial ischemia symptoms by regulating branched-chain amino acid metabolism and energy metabolism. These findings provide a solid foundation for the potential clinical use of this herb and its processed products in treating heart disease., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Activating SIRT1 or promoting SIRT1 expression are both protective against myocardial ischemia. Combining these approaches would be an effective strategy for treating ischemic heart disease. Herein, we identified lead compounds with SIRT1 activation activity through screening the natural product library, and five series of H 2 S donating derivatives were designed and synthesized. Among them, compound 17 exerted an effective cardioprotective effect in vitro and in vivo . The addition of H 2 S scavenger attenuated the protective activity, emphasizing the critical involvement of H 2 S in the myocardial ischemia process. Interestingly, 17 exhibited stronger direct SIRT1 activative ability and induced higher SIRT1 expression capability compared to the lead. Furthermore, 17 attenuates oxidative stress-induced cardiomyocytes apoptosis by activating the SIRT1-PGC1α signaling pathway. Our study validated the promising potential of activating SIRT1 and promoting SIRT1 expression through H 2 S to improve cardiomyocytes function, providing novel insights into the protective mechanisms during the progression of ischemic heart disease.

Introduction: Heart failure (HF) is a complex and heterogeneous syndrome resulting from any diastolic or systolic dysfunction of the cardiac muscle. In addition to comorbid conditions, pressure overload, and myocardial ischemia are associated with cardiac remodeling which manifests as extracellular matrix (ECM) perturbations, impaired cellular responses, and subsequent ventricular dysfunction., Areas Covered: The current review discusses the main aspects of the cyclic guanosine monophosphate (cGMP)-protein kinase G (PKG) pathway (cGMP-PKG) pathway modulators and highlights the promising outcomes of its novel pharmacological boosters., Expert Opinion: Among several signaling pathways involved in the pathogenesis of pressure overload, ischemia and HF with preserved ejection fraction (HFpEF) is cGMP-PKG pathway. This pathway plays a pivotal role in the regulation of cardiac contractility, and modulation of cGMP-PKG signaling, contributing to the development of the diseases. Ventricular cardiomyocytes of HF patients and animal models are known to exhibit reduced cGMP levels and disturbed cGMP signaling including hypophosphorylation of PKG downstream targets. However, restoration of cGMP-PKG signaling improves cardiomyocyte function and promotes cardioprotective effects.

Heart failure (HF) represents the terminal stage of cardiovascular diseases, with limited therapeutic options currently available. Calotropin (CAL), a cardenolide isolated from Calotropis gigantea, exhibits a similar chemical structure and inhibitory effect on Na+/K+-ATPase to digoxin, a positive inotropic drugs used in heart failure treatment. However, the specific effect of calotropin in ischemic HF (IHF) remains unknown. The objective of this study is to assess the anti-HF effect and clarify its underlying mechanisms. The left anterior descending (LAD) artery ligation on Male Sprague-Dawley (SD) rats was used to construct ischemic HF model. Daily administration of CAL at 0.05 mg/kg significantly enhanced ejection fraction (EF) and fractional shortening (FS), while inhibiting cardiac fibrosis in IHF rats. CAL reduced the OGD/R-induced H9c2 cell injury. Furthermore, CAL upregulated the expression of SERCA2a and SIRT1. The cardioprotective effect of CAL against IHF was abrogated in the presence of the SIRT1 inhibitor EX527. Notably, we identified FOXD3 as a pivotal transcription factor mediating CAL-induced SERCA2a regulation. CAL promoted the deacetylation and nuclear translocation of FOXD3 in a SIRT1-dependent manner. In conclusion, our study explores a novel mechanism of calotropin for improving cardiac dysfunction in ischemic heart failure by regulating SIRT1/FOXD3/SERCA2a pathway., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Background: Inflammation and oxidative stress are key players in lung injury stemming from cardiac ischemia (LISCI). Cannabidiol (CBD) demonstrates tissue-protective properties through its antioxidant, anti-inflammatory, and anti-apoptotic characteristics. This study aims to assess the preventive (p-CBD) and therapeutic (t-CBD) effects of CBD on LISCI., Methods: Forty male Wistar Albino rats were divided into four groups: control (CON), LISCI, p-CBD, and t-CBD. The left anterior descending coronary artery was ligated for 30 min of ischemia followed by 30 min of reperfusion. Lung tissues were then extracted for histopathological, immunohistochemical, genetic, and biochemical analyses., Results: Histopathologically, marked hyperemia, increased septal tissue thickness, and inflammatory cell infiltrations were observed in the lung tissues of the LISCI group. Spectrophotometrically, total oxidant status and oxidative stress index levels were elevated, while total antioxidant status levels were decreased. Immunohistochemically, expressions of cyclooxygenase-1 (COX1), granulocyte colony-stimulating factor (GCSF), interleukin-6 (IL6) were increased. In genetic analyses, PERK and CHOP expressions were increased, whereas Nuclear factor erythroid 2-related factor 2 (NRF2) and B-cell leukemia/lymphoma 2 protein (BCL2) expressions were decreased. These parameters were alleviated by both prophylactic and therapeutic CBD treatment protocols., Conclusion: In LISCI-induced damage, both endoplasmic reticulum and mitochondrial stress, along with oxidative and inflammatory markers, were triggered, resulting in lung cell damage. However, both p-CBD and t-CBD treatments effectively reversed these mechanisms, normalizing all histopathological, biochemical, and PCR parameters.

Background: Coronary artery thrombosis and myocardial ischemia caused by giant coronary aneurysms are the main causes of death in children with Kawasaki disease. The use of thrombolytic therapy in children with Kawasaki disease who have coronary thrombosis is a controversial topic, especially with respect to the timing of treatment., Case Presentation: In this article, we report a case of a child aged two years and nine months with Kawasaki disease whose coronary arteries had no involvement in the acute phase. However, by only one week after discharge, the patient returned because we found giant coronary aneurysms complicated by thrombosis via echocardiography. Despite aggressive thrombolytic therapy, the child developed myocardial ischemia during thrombolytic therapy. Fortunately, because of timely treatment, the child's thrombus has dissolved, and the myocardial ischemia has resolved., Conclusions: This case suggests that for patients at high risk of coronary artery aneurysms, echocardiography may need to be reviewed earlier. Low-molecular-weight heparin should be added to antagonize the early procoagulant effects of warfarin when warfarin therapy is initiated. In the case of first-detected coronary thrombosis, aggressive thrombolytic therapy may be justified, particularly during the acute and subacute phases of the disease course., (© 2024. The Author(s).)

Background: Non-cardioembolic ischemic stroke (NCIS) and ischemic heart disease (IHD) require secondary prevention with antiplatelet therapy (APT). We investigated APT prescription status for patients with NCIS and IHD., Research Design and Methods: This retrospective study utilized claims data from patients with NCIS and those who underwent percutaneous coronary intervention for IHD and received antiplatelet drugs. The study included Phases A (2015-2016), B (2017-2018), and C (2019-2020). We evaluated patient characteristics, APT prescription rates (dual [DAPT] and single [SAPT]), and prescriptions by NCIS subtype., Results: In the NCIS cohort, the initial DAPT prescription rate increased over time (Phase A: 14.9%, B: 19.2%, C: 28.0%), but decreased to 6% after 3 months. Subsequently, 25% of patients did not receive APT. For IHD, DAPT duration decreased over time, with 12-month prescription rates of 48.0%, 43.1%, and 32.6% for Phases A, B, and C, respectively. SAPT prescriptions, predominantly aspirin, increased, and use of P2Y12 inhibitors also rose. Few patients (10%) did not receive APT., Conclusions: Shorter DAPT duration/earlier switching to SAPT for NCIS and IHD have gained acceptance in regional medical care. A higher proportion of NCIS vs IHD patients did not receive APT in the chronic phase., Trial Registration: UMIN000052198.

Background: Zishenhuoxue decoction (ZSHX), a Chinese herbal medicine, exhibits myocardial and vascular endothelial protective properties. The intricate regulatory mechanisms underlying myocardial ischemic injury and its association with dysfunctional mitochondrial quality surveillance (MQS) remain elusive., Hypothesis/purpose: To study the protective effect of ZSHX on ischemic myocardial injury in mice using a TMBIM6 gene-modified animal model and mitochondrial quality control-related experiments., Study Design: Using model animals and myocardial infarction surgery-induced ischemic myocardial injury TMBIM6 gene-modified mouse models, the pharmacological activity of ZSHX in inhibiting ischemic myocardial injury and mitochondrial homeostasis disorder in vivo was tested., Methods: Our focal point entailed scrutinizing the impact of ZSHX on ischemic myocardial impairment through the prism of TMBIM6. This endeavor was undertaken utilizing mice characterized by heart-specific TMBIM6 knockout (TMBIM6 CKO ) and their counterparts, the TMBIM6 transgenic (TMBIM6 TG ) and VDAC1 transgenic (VDAC1 TG ) mice., Results: ZSHX demonstrated dose-dependent effectiveness in mitigating ischemic myocardial injury and enhancing mitochondrial integrity. TMBIM6 CKO hindered ZSHX's cardio-therapeutic and mitochondrial protective effects, while ZSHX's benefits persisted in TMBIM6 TG mice. TMBIM6 CKO also blocked ZSHX's regulation of mitochondrial function in HR-treated cardiomyocytes. Hypoxia disrupted the MQS in cardiomyocytes, including calcium overload, excessive fission, mitophagy issues, and disrupted biosynthesis. ZSHX counteracted these effects, thereby normalizing MQS and inhibiting calcium overload and cardiomyocyte necroptosis. Our results also showed that hypoxia-induced TMBIM6 blockade resulted in the over-activation of VDAC1, a major mitochondrial calcium uptake pathway, while ZSHX could increase the expression of TMBIM6 and inhibit VDAC1-mediated calcium overload and MQS abnormalities., Conclusions: Our findings suggest that ZSHX regulates mitochondrial calcium homeostasis and MQS abnormalities through a TMBIM6-VDAC1 interaction mechanism, which helps to treat ischemic myocardial injury and provides myocardial protection. This study also offers insights for the clinical translation and application of mitochondrial-targeted drugs in cardiomyocytess., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2023 Elsevier GmbH. All rights reserved.)

Background: Clinically, various diseases cause myocardial ischemia (MI), which further induces severe cardiac injury and leads to high mortality in patients. Ginsenoside Re, one of the major ginsenosides in ginseng, can regulate the level of oxidative stress in the injured myocardium. Thus, it may attenuate MI injury, but the related mechanism has not been comprehensively studied., Purpose: This study aimed to investigate the anti-MI effect and comprehensively mechanisms of Ginsenoside Re., Study Design/methods: Oxygen-glucose deprivation (OGD), oxidative-induced cardiomyocyte injury, and isoproterenol-induced MI mice were used to explore their protective effect of Ginsenoside Re. An integrated approach of network pharmacology, molecular docking, and tandem mass tag proteomics was applied to determine the corresponding common potential targets of Ginsenoside Re against MI, such as target proteins and related pathways. The major anti-MI target proteins and related pathways were validated by immunofluorescence (IF) assay and Western blotting (WB)., Results: Ginsenoside Re (1.32-168.93 µM) had low toxicity to normal cardiomyocytes, and increased the survival of oxidative stress-injured (OGD-induced injury or H 2 O 2 -induced injury) cardiomyocytes in this concentration range. It regulated the reactive oxygen species (ROS) level in OGD-injured cardiomyocytes; stabilized the nuclear morphology, mitochondrial membrane potential (MMP), and mitochondrial function; and reduced apoptosis. Meanwhile, Ginsenoside Re (5-20 mg/kg) alleviated cardiac injury in MI mice and maintained cardiac function. Through network pharmacology and proteomics, the relevant mechanisms revealed several key pathways of Ginsenoside Re anti-MI, including inhibition of MAPK pathway protein phosphorylation, downregulation of phosphorylated PDPK1, AKT, and STAT3, and upregulation of TGF-β3, ferroptosis pathway (upregulation of GPX4 and downregulation of phosphorylation level of MDM2) and AMPK pathway (regulating the synthesis of cholesterol in the myocardium by downregulation of HMGCR). The key proteins of these target pathways were validated by IF and/or WB., Conclusion: Ginsenoside Re may target MAPK, AKT, ferroptosis pathways and AMPK pathway to prevent and/or treat MI injury and protect cardiomyocytes from oxidative damage., Competing Interests: Declaration of competing interest All authors here declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier GmbH.)

Trichosanthes kirilowii-Allium macrostemon (Chinese name Gualou and Xiebai, GLXB), a classical herb pair, has significant clinical efficacy in the treatment of myocardial ischemia (MI). In this study, network pharmacology combined with RNA-seq strategy was employed to predict the targets and pathways of GLXB for MI. GLXB significantly modulated signaling pathways related to the pathology of MI, such as anti-inflammatory and anti-apoptotic signaling pathways such as WNT, PI3K/AKT, and AMPK. GSEA showed that GLXB administration downregulated these key pathways. In addition, Metabolomic analysis demonstrated that GLXB treatment reversed metabolic disorder. Integrative analysis demonstrated three key metabolites (pyruvate, lactate, and palmitate) and three differential genes (Pck1, Cdo1, and Cth) that affected glycolysis or gluconeogenesis and cysteine and methionine metabolism. The results of molecular docking showed that chrysin-7-O-glucuronide and diosmetin-7-O-rutinoside may be the crucial components that exert myocardial protective activity. Western blot showed that GLXB administration reversed the expression levels of Pck1, Cdo1, Cth, Alb, Bcl2, and Ccnd1. This study has elucidated that GLXB could alleviate MI in rats by modulating WNT and PI3K/AKT signaling pathways, thereby reducing inflammation and apoptosis as well as improving energy metabolism., (© 2024 John Wiley & Sons Ltd.)

Ischemic heart disease (IHD) is increasingly recognized as a significant cardiovascular disease with a growing global incidence. Interventions targeting the oxidative microenvironment have long been pivotal in therapeutic strategies. However, many antioxidant drugs face limitations due to pharmacokinetic and delivery challenges, such as short half-life, poor stability, low bioavailability, and significant side effects. Fortunately, nanotherapies exhibit considerable potential in addressing IHD. Nanomedicines offer advantages such as passive/active targeting, prolonged circulation time, enhanced bioavailability, and diverse carrier options. This comprehensive review explores the advancements in nanomedicines for mitigating IHD through oxidative stress regulation, providing an extensive overview for researchers in the field of antioxidant nanomedicines. By inspiring further research, this study aims to accelerate the development of novel therapies for myocardial injury., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

There is insufficient data on systemic embolic events (SSEs) in patients with ischemic left ventricular aneurysm (LVA) concerning the impact of anticoagulation therapy. In this retrospective cohort study with 1043 patients with ischemic LVA, SSEs occurred in 7.2% over 2.4 years. After adjusting for relevant factors, the use of anticoagulants was independently associated with a lower incidence of SSE (3.1% vs. 9.0%, P < 0.001; subdistribution hazard ratios (SHR) 0.21, 95% confidence intervals (CI) 0.10-0.44, P < 0.001), with no significant difference in net adverse clinical events (NACEs) (10.6% vs. 13.3%, P = 0.225). Specifically, anticoagulation in patients with apical segment akinesis significantly reduced SSEs (3.9% vs. 13.6%, P = 0.002) and NACE rates (7.8% vs. 19.4%, P = 0.002). Major bleeding rates did not significantly differ between groups (5.6% vs. 3.5%, P = 0.111). These findings highlight the SSE risk in ischemic LVA and suggest potential benefits of anticoagulation, particularly in those with apical segment akinesis. These findings need to be validated in independent datasets., (© 2024. The Author(s).)

Ethnopharmacological Relevance: Optimized New Shengmai Powder (ONSMP) is a sophisticated traditional Chinese medicinal formula renowned for bolstering vital energy, optimizing blood circulation, and mitigating fluid retention. After years of clinical application, ONSMP has shown a significant impact in improving myocardial injury and cardiac function and has a positive effect on treating heart failure. However, many unknowns exist about the molecular biological mechanisms of how ONSMP exerts its therapeutic effects, which require further research and exploration., Aim of the Study: Exploring the potential molecular biological mechanisms by which ONSMP ameliorates cardiomyocyte apoptosis and ferroptosis in ischemic heart failure (IHF)., Materials and Methods: First, we constructed a rat model of IHF by inducing acute myocardial infarction through surgery and using echocardiography, organ coefficients, markers of heart failure, antioxidant markers, and histopathological examination to assess the effects of ONSMP on cardiomyocyte apoptosis and ferroptosis in IHF rats. Next, we used bioinformatics analysis techniques to analyze the active components, signaling pathways, and core targets of ONSMP and calculated the interactions between core targets and corresponding elements. Finally, we detected the positive expression of apoptosis and ferroptosis markers and core indicators of signaling pathways by immunohistochemistry; detected the mean fluorescence intensity of core indicators of signaling pathways by immunofluorescence; detected the protein expression of signaling pathways and downstream effector molecules by western blotting; and detected the mRNA levels of p53 and downstream effector molecules by quantitative polymerase chain reaction., Results: ONSMP can activate the Ser83 site of ASK by promoting the phosphorylation of the PI3K/AKT axis, thereby inhibiting the MKK3/6-p38 axis and the MKK4/7-JNK axis signaling to reduce p53 expression, and can also directly target and inhibit the activity of p53, ultimately inhibiting p53-mediated mRNA and protein increases in PUMA, SAT1, PIG3, and TFR1, as well as mRNA and protein decreases in SLC7A11, thereby inhibiting cardiomyocyte apoptosis and ferroptosis, effectively improving cardiac function and ventricular remodeling in IHF rat models., Conclusion: ONSMP can inhibit cardiomyocyte apoptosis and ferroptosis through the PI3K/AKT/p53 signaling pathway, delaying the development of IHF., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. The authors declare that there is no conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Myocardial ischemia (MI) is a significant contributor to ischemic heart diseases like angina pectoris and myocardial infarction. Reactive oxygen species produced during MI can trigger lipid peroxidation, damaging cell structure and function. Salvia miltiorrhiza (SM) has been widely used clinically in the treatment of cardiovascular diseases. However, in the process of rooting, the aboveground parts of this plant are usually discarded by tons. To make better use of these plant resources, the phenolic acids extracted and purified from the aerial part of SM were studied and chemically transformed, and the potential protective effect and possible mechanism of salvianolic acids containing a higher content of salvianolic acid A on MI were obtained. The transformed products of SM stem-leaves total phenolic acids with 8.16 % salvianolic acid A showed a better protective effect on the isoproterenol (ISO)-induced acute MI injury rat model. It can improve ST segment changes and has good antioxidant, anti-inflammatory and anticoagulant effects. In addition, the dysbiosis of gut microbiota and the related metabolic levels of short chain fatty acids (SCFAs), phenylalanine and glycerophospholipids were improved. This was achieved by reducing the abundance of Bacteroides, Faecalibaculum, and L-phenylalanine levels. In addition, the abundance of probiotics in Butyricoccus, Roseburia, and norank&#95;f&#95;Eubacterium&#95;coprostanoligenes&#95;group, as well as the contents of propionic acid and isobutyric acid, LPCs and PCs were increased. In conclusion, total phenolic acids of SM stem-leaves showed protective effects against ISO-induced rats, especially the strongest effect after conversion, which is a new option for the prevention and treatment of MI., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

β2 adrenergic receptor (β2AR) is a G-protein-coupled receptor involved in cardiac protection. In chronic heart failure (CHF), persistent sympathetic nervous system activation occurs, resulting in prolonged β2AR activation and subsequent receptor desensitization and downregulation. Notoginsenoside R1 (NGR1) has the functions of enhancing myocardial energy metabolism and mitigating myocardial fibrosis. The mechanisms of NGR1 against ischemic heart failure are unclear. A left anterior descending (LAD) artery ligation procedure was performed on C57BL/6 J mice for four weeks. From the 4th week onwards, they were treated with various doses (3, 10, 30 mg/kg/day) of NGR1. Subsequently, the impacts of NGR1 on ischemic heart failure were evaluated by assessing cardiac function, morphological changes in cardiac tissue, and the expression of atrial natriuretic peptide (ANP) and beta-myosin heavy chain (β-MHC). H9c2 cells were protected by NGR1 when exposed to OGD/R conditions. H9c2 cells were likewise protected from OGD/R damage by NGR1. Furthermore, NGR1 increased β2AR levels and decreased β2AR ubiquitination. Mechanistic studies revealed that NGR1 enhanced MDM2 protein stability and increased the expression of MDM2 and β-arrestin2 while inhibiting their interaction. Additionally, under conditions produced by OGD/R, the protective benefits of NGR1 on H9c2 cells were attenuated upon administration of the MDM2 inhibitor SP141. According to these findings, NGR1 impedes the interplay between β-arrestin2 and MDM2, thereby preventing the ubiquitination and degradation of β2AR to improve CHF., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Although both clinical data and animal models suggest cardiovascular benefits following administration of Dipeptidyl Peptidase 4 (DPP-4) inhibitors, the underlying mechanisms remain unclear. We therefore sought to evaluate the effect of the DPP-4 inhibitor sitagliptin on myocardial fibrosis, and insulin signaling in chronic myocardial ischemia using a swine model. An ameroid constrictor placement on the left coronary circumflex artery of thirteen Yorkshire swine to model chronic myocardial ischemia. After two weeks of recovery, swine were assigned to one of two groups: control (CON, n = 8), or sitagliptin 100mg daily (SIT, n = 5). After 5 weeks of treatment, the swine underwent terminal harvest with collection of myocardial tissue. Fibrosis was quantified using Masson's trichrome. Protein expression was quantified by Immunoblotting. Trichrome stain demonstrated a significant decrease in perivascular and interstitial fibrosis in the SIT group relative to CON (all p<0.05). Immunoblot showed a reduction in Jak2, the pSTAT3 to STAT 3 Ratio, pSMAD 2/3, and SMAD 2/3, and an increase in STAT 3 in the SIT group relative to CON (all p<0.05). SIT treatment was associated with increased expression of insulin receptor one and decreased expression of makers for insulin resistance, including phospho-PKC- alpha, RBP-4, SIRT1, and PI3K (p<0.05). Sitagliptin results in a reduction in perivascular and interstitial fibrosis and increased insulin sensitivity in chronically ischemic swine myocardium. This likely contributes to the improved cardiovascular outcomes seen with DPP-4 inhibitors., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Harris et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

This study aimed to compare the 2-year cardio-cerebrovascular adverse outcomes of patients with influenza with and without preexisting cardiovascular disease (preCVD) treated with oral antiviral agents in the outpatient clinic. Oral antiviral agents are routinely prescribed to treat influenza infection with a positive rapid-antigen test in the outpatient clinic; however, influenza-associated cardio-cerebrovascular outcomes have not yet been characterized in patients with preCVD treated with oral antiviral agents. Data between 2006 and 2016 were extracted from the National Health Database of South Korea. A total of 865,522 patients with influenza treated with oral antiviral agents were selected in South Korea and classified as preexisting ischemic heart disease (IHD), heart failure (HF), or atrial fibrillation (AF), and 2-year cardio-cerebrovascular outcomes were analyzed using a Cox proportional hazard regression model. Among the participants, 96,433 had preCVD (11.1%; mean age, 46 years) including IHD (86.4%), HF (23.1%), and AF (12.5%). The incidence of new-onset IHD, AF, HF, and death was similar between patients with influenza with and without preCVD. The incidences of IHD and stroke were 0.489 and 0.047 per 100-person year in the preCVD group, respectively. The incidence of cardiovascular mortality was 0.489 per 100-person year in the preCVD group, and the hazard ratio for cardiovascular mortality in the preCVD group was not significantly different from that in patients without preCVD. Based on the national health data, 2-year cardio-cerebrovascular adverse outcomes were not significantly different between patients with and without preCVD treated with oral antiviral agents., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Aims: Large outcome trials have demonstrated cardiovascular benefits of selected glucagon-like peptide-1 (GLP-1) receptor agonists. We examined coronary disease outcomes in the Harmony Outcomes trial of the GLP-1 receptor agonist albiglutide., Methods and Results: Harmony Outcomes was an event-driven, multicenter, double-blind, and placebo-controlled trial involving 9463 patients >40 years of age with type-2 diabetes and established atherosclerotic cardiovascular disease. It tested the effects of albiglutide on the occurrence of a composite primary endpoint, consisting of cardiovascular death, myocardial infarction (MI), or stroke. Within this post-hoc analysis, the effects of albiglutide on MI subtypes and other ischaemic endpoints were analysed.During the median-follow up of 1.6 years, a total of 421 patients (4.5%) experienced at least one MI, with 72 patients having more than one event. Treatment with albiglutide reduced both first events [hazard ratio (HR) 0.75 (0.62-0.91)] and overall events [HR 0.75 (0.61-0.91)] as well as first type 1 [HR 0.73 (0.57-0.92)] and type 2 myocardial infarctions [HR 0.65 (0.46-0.92)]. The effect of albiglutide treatment was consistent for ST-segment elevation [HR 0.69 (0.38-1.26)] and non-ST elevation (HR 0.86 (0.66-1.2) MI., Conclusion: Treatment with the GLP-1 receptor agonist albiglutide resulted in a 25% relative risk reduction in MI that was consistent for type of infarction and presence or absence of ST elevation. Our findings add novel information about the effects of GLP-1 receptor agonists on ischaemic events in patients with type 2 diabetes., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Ethnopharmacological Relevance: Ischemic heart diseases (IHD), characterized by metabolic dysregulation, contributes majorly to the global morbidity and mortality. Glucose, lipid and amino acid metabolism are critical energy production for cardiomyocytes, and disturbances of these metabolism lead to the cardiac injury. Traditional Chinese medicine (TCM), widely used for treating IHD, have been demonstrated to effectively and safely regulate the cardiac metabolism reprogramming., Aim of the Review: This study discussed and analyzed the disturbed cardiac metabolism induced by IHD and development of formulas, extracts, single herb, bioactive compounds of TCM ameliorating IHD injury via metabolism regulation, with the aim of providing a basis for the development of clinical application of therapeutic strategies for TCM in IHD., Materials and Methods: With "ischemic heart disease", "myocardial infarction", "myocardial ischemia", "metabolomics", "Chinese medicine", "herb", "extracts" "medicinal plants", "glucose", "lipid metabolism", "amino acid" as the main keywords, PubMed, Web of Science, and other online search engines were used for literature retrieval., Results: IHD exhibits a close association with metabolism disorders, including but not limited to glycolysis, the TCA cycle, oxidative phosphorylation, branched-chain amino acids, fatty acid β-oxidation, ketone body metabolism, sphingolipid and glycerol-phospholipid metabolism. The therapeutic potential of TCM lies in its ability to regulate these disturbed cardiac metabolisms. Additionally, the active ingredients of TCM have depicted wonderful effects in cardiac metabolism reprogramming in IHD., Conclusion: Drawing from the principles of TCM, we have pinpointed specific herbal remedies for the treatment of IHD, and leveraged advanced metabolomics technologies to uncover the effect of these TCMs on metabolomics alteration. In the future, further clinical experimental studies should be included to explore whether more TCM medicines can play a therapeutic role in IHD by reversing cardiac metabolism disorders; multi-omics would be conducted to explore more pathways and genes targeting such metabolism reprogramming by TCMs, and to seek more TCM therapies for IHD., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Clinical efficacy and mechanism of Qishen Yiqi Dripping Pills(QSYQ) have been well researched, but the compatibility mechanism underlying its therapeutic effect still requires further analysis. This study aims to explore the compatibility mechanism of QSYQ in treating myocardial ischemia. UPLC-Q-Exactive Orbitrap-MS technique was used to obtain the absorbed blood components of QSYQ. Target proteins of the absorbed components were collected and screened using TCMSP, TCMIP, and SwissTargetPrediction databases. Disease proteins related to myocardial ischemia were obtained through GeneCards, OMIM, and DisGeNET databases. Core targets and core components were obtained using online plotting software Venny 2.1.0, STRING, and Cytoscape 3.9.1 software. David database was used for GO functional annotation and KEGG pathway enrichment of core targets, obtaining the main pathways of QSYQ in treating myocardial ischemia and drawing visualized network diagrams. The compatibility mechanism was analyzed based on &quot;component-target&quot;, &quot;drug-pathway&quot;, and &quot;PI3K-AKT&quot; characteristic pathways, and molecular docking was used for validation. This study obtained 42 absorbed blood components of QSYQ, 556 component targets, 1 980 disease targets, 69 core targets, and 15 core components. QSYQ can exert therapeutic effects on myocardial ischemia by regulating proteins such as MAPK1, RELA, SRC, JUN, and STAT3, acting on signaling pathways such as HIF-1, PI3K-AKT, Toll-like, MAPK, VEGF, etc. The interaction network diagrams of &quot;component-target&quot; and &quot;drug-pathway&quot; preliminarily elucidated the synergy among the four drugs in this prescription at the level of targets and pathways. The PI3K-AKT characteristic pathway indicated that the sovereign drug Huangqi(Astragali Radix) and minister drug Danshen(Salviae Miltiorrhizae Radix et Rhizoma) could regulate most targets in this pathway, while the assistant drug Sanqi(Notoginseng Radix et Rhizoma) cooperated with Huangqi and Danshen on IL6 and AKT proteins, and the envoy drug Jiangxiang(Dalbergiae Odoriferae Lignum) acted on AKT and RXRA proteins, with all drugs acting synergistically on proteins such as AKT, RXRA, NFKB to regulate cell survival and promote angiogenesis. Molecular docking indicated that hydrogen bonding and hydrophobic interactions might be the main forms of action, also validating the distribution of binding energy of the PI3K-AKT signaling pathway. This study analyzed the compatibility connotation of QSYQ from multiple dimensions including drugs, components, targets, and pathways, providing reference basis for the study of the mechanism of action and compatibility rules of QSYQ.

The aim of this study was to investigate the potential mechanism by which cryptotanshinone(CTS) may exert its anti-myo-cardial ischemic effect through the regulation of macrophage polarization via the dendritic cell-associated C-type lectin 1(Dectin-1) signaling pathway. Male C57BL/6 mice, aged six weeks, were utilized to establish myocardial ischemia models and were subsequently divided into five groups: sham, model, CTS low-dose(21 mg·kg~(-1)·d~(-1)), CTS high-dose(84 mg·kg~(-1)·d~(-1)), and dapagliflozin(0.14 mg·kg~(-1)·d~(-1)). The cardiac function, serum enzyme levels, Dectin-1 expression, macrophage polarization, and neutrophil infiltration in the myocardial infarction area were assessed in each group. An in vitro model of M1-type macrophages was constructed using lipopolysaccharide/interfe-ron-γ(LPS/IFN-γ) stimulated RAW264.7 cells to investigate the impact of CTS on macrophage polarization and to examine alterations in key proteins within the Dectin-1 signaling pathway. In the CTS group, compared to the model group mice, there was a significant improvement in the cardiac function and myocardial injury, along with a notable increase in the ratio of M2/M1-type macrophages in the myocardial infarcted area and a decrease in neutrophil infiltration. Additionally, Dectin-1 exhibited low expression. The results of in vitro experiments demonstrated that CTS can decrease the expression of M1-type marker genes and increase the expression of M2-type marker genes. Besides, it can decrease the levels of Dectin-1 and the phosphorylation of its associated proteins, including spleen tyrosine kinase(Syk), protein kinase B(Akt), nuclear factor-kappaB p65(NF-κB p65), and extracellular signal-regulated protein kinases(ERK1/2). Additionally, CTS was found to enhance the phosphorylation of signal transducer and activator of transcription-6(STAT6). The above results suggest that CTS exerts its anti-myocardial ischemic injury effect by regulating macrophage polarization through the Dectin-1 signaling pathway.

Patients with myocardial ischemia and infarction are at increased risk of arrhythmias, which in turn, can exacerbate the overall risk of mortality. Despite the observed reduction in recurrent arrhythmias through antiarrhythmic drug therapy, the precise mechanisms underlying their effectiveness in treating ischemic heart disease remain unclear. Moreover, there is a lack of specialized drugs designed explicitly for the treatment of myocardial ischemic arrhythmia. This study employs an electrophysiological simulation approach to investigate the potential antiarrhythmic effects and underlying mechanisms of various pharmacological agents in the context of ischemia and myocardial infarction (MI). Based on physiological experimental data, computational models are developed to simulate the effects of a series of pharmacological agents (amiodarone, telmisartan, E-4031, chromanol 293B, and glibenclamide) on cellular electrophysiology and utilized to further evaluate their antiarrhythmic effectiveness during ischemia. On 2D and 3D tissues with multiple pathological conditions, the simulation results indicate that the antiarrhythmic effect of glibenclamide is primarily attributed to the suppression of efflux of potassium ion to facilitate the restitution of [K+]o, as opposed to recovery of IKATP during myocardial ischemia. This discovery implies that, during acute cardiac ischemia, pro-arrhythmogenic alterations in cardiac tissue's excitability and conduction properties are more significantly influenced by electrophysiological changes in the depolarization rate, as opposed to variations in the action potential duration (APD). These findings offer specific insights into potentially effective targets for investigating ischemic arrhythmias, providing significant guidance for clinical interventions in acute coronary syndrome., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Li et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

In a translational study involving animal models and human subjects, Lv et al. demonstrate that arachidonic acid (AA) exhibits cardioprotective effects in diabetic myocardial ischemia, suggesting a departure from its known role in promoting ferroptosis-a form of cell death characterized by iron-dependent lipid peroxidation. However, the study does not address how underlying diabetic conditions might influence the metabolic pathways of AA, which are critical for fully understanding its impact on heart disease. Diabetes can significantly alter lipid metabolism, which in turn might affect the enzymatic processes involved in AA's metabolism, leading to different outcomes in the disease process. Further examination of the role of diabetes in modulating AA's effects could enhance the understanding of its protective mechanism in ischemic conditions. This could also lead to more targeted and effective therapeutic strategies for managing myocardial ischemia in diabetic patients, such as optimizing AA levels to prevent heart damage while avoiding exacerbating factors like ferroptosis., (© 2024. The Author(s).)

Concomitant presence of atrial fibrillation and coronary artery disease requiring percutaneous coronary intervention is a frequent occurrence. The choice of optimal antithrombotic therapy, in this context, is still challenging. To offer the best protection both in terms of stroke and stent thrombosis, triple therapy with oral anticoagulation and dual antiplatelet therapy would be required. Several drug combinations have been tested in recent years, including direct oral anticoagulants, with the aim of balancing ischemic and bleeding risk. Both pharmacokinetic aspects of the molecules and patient's characteristics should be analyzed in choosing oral anticoagulation. Then, as suggested by guidelines, triple therapy should start with a seven-day duration and the aim to prolong to thirty days in high thrombotic risk patients. Dual therapy should follow to reach twelve months after coronary intervention. Even not fully discussed by the guidelines, in order to balance ischemic and bleeding risk it should also be considered: 1) integrated assessment of coronary artery disease and procedural complexity of coronary intervention; 2) appropriateness to maintain the anticoagulant drug dosage indicated in technical data sheet; the lack of data on the suspension of antiplatelet drugs one year after percutaneous intervention; 3) the possibility of combination therapy with ticagrelor; and 4) the need to treat the occurrence of paroxysmal atrial fibrillation during acute coronary syndrome. With data provided clinician should pursue a therapy as personalized as possible, both in terms of drug choice and treatment duration, in order to balance ischemic and bleeding risk.

Aims: To compare statin utilization and ischemic heart disease (IHD) mortality trends in Lithuania and Sweden and to assess correlations between the total utilization of statins and IHD mortality., Methods: An ecological study assessing time trends in statin utilization (DDDs per 1000 inhabitants per day; DDD/TID) and IHD mortality in Lithuania and Sweden between 2000 and 2020. Statin utilization data in Lithuania were wholesale trade data, and Swedish data were drugs dispensed at pharmacies. IHD mortality data were extracted from national databases as rates per 100 000 inhabitants. Associations between statin utilization and IHD mortality in Lithuania and Sweden were examined using Spearman's rank and Pearson's correlation coefficients, respectively., Results: Statin utilization increased from 16.8 to 135.8 DDD/TID in Sweden and from 0.2 to 61.8 DDD/TID in Lithuania between 2000 and 2020. Medium intensity was the most common statin dosage in Lithuania, while Sweden used more high intensity than moderate-intensity statins from 2017. IHD mortality in Lithuania remained high between 2000 and 2020 (from 359.1 to 508.8 deaths per 100 000 population), while it decreased markedly in Sweden (from 226.87 to 88.7 deaths per 100 000 population). IHD mortality and statin utilization were inversely correlated in Sweden (r = -0.993, P < 0.001), while a positive correlation was found in Lithuania (rs = 0.871, P < 0.001)., Conclusion: Despite the growing statin utilization in both countries, Lithuania recorded a slight increase in IHD mortality rates unlike the situation in Sweden. This indicates room for improvement in the management of modifiable cardiovascular risk factors in Lithuania including how statins are prescribed and used in clinical practice., Competing Interests: The authors declare no conflict of interest., (© 2024 The Author(s).)

DangGui-KuShen (DK) is a well-known classic traditional Chinese medicine recipe that improves blood circulation, eliminates moisture, and detoxifies, and is frequently used in the treatment of cardiovascular problems. Some protective effects of DK on cardiovascular disease have previously been identified, but its precise mechanism remains unknown. The goal of this study is to combine metabolomics and network pharmacology to investigate DK's protective mechanism in Ischemic Heart Disease(IHD) rat models. A combination of metabolomics and network pharmacology based on UPLC-Q-TOF/MS technology was used in this study to verify the effect of DK on IHD through enzyme-linked immunosorbent assay, HE staining, and electrocardiogram, and it was determined that DK improves the synergistic mechanism of IHD. In total, 22 serum differential metabolites and 26 urine differential metabolites were discovered, with the majority of them involved in phenylalanine, tyrosine, and tryptophan biosynthesis, glycine, serine, and threonine metabolism, arginine and proline metabolism, aminoacyl-tRNA biosynthesis, purine metabolism, and other metabolic pathways. Furthermore, using network pharmacology, a composite target pathway network of DangGui and KuShen for treating IHD was created, which is primarily associated to the tumor necrosis factor (TNF) signaling pathway, P53 signaling, and HIF-1 signaling pathways. The combined research indicated that the NF-B signaling pathway and the HIF-1 signaling pathway are critical in DK treatment of IHD. This study clearly confirms and expands on current knowledge of the synergistic effects of DG and KS in IHD., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Hypertension and dyslipidemia are 2 highly prevalent and modifiable risk factors in patients with stable ischemic heart disease. Multiple lines of evidence demonstrate that lowering blood pressure and low-density lipoprotein cholesterol improves clinical outcomes in patients with ischemic heart disease. Accordingly, clinical guidelines recommend intensive treatment targets for these high-risk patients. This article summarizes the pathophysiology, supporting evidence, and treatment recommendations for management of hypertension and dyslipidemia among patients with manifest ischemic heart disease and points to future research and unmet clinical needs., Competing Interests: Disclosure T. Abrahams has no disclosures. S.J. Nicholls has received research support from AstraZeneca, United Kingdom, Amgen, United States, Anthera, CSL Behring, United States, Cerenis, Eli Lilly, Esperion, United States, Resverlogix, Novartis, Switzerland, InfraRedx, United States, and Sanofi-Regeneron; and is a consultant for Amgen, Akcea, AstraZeneca, Boehringer Ingelheim, CSL Behring, Eli Lilly, Esperion, Kowa, Merck, Takeda, Pfizer, Sanofi-Regeneron, Novo Nordisk, CSL Sequiris, and Vaxxinity. A.J. Nelson has received research support from Amgen, Eli Lilly, Novartis and Boehringer Ingelheim; and is a consultant for Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Merck, Sanofi, Novo Nordisk, CSL Sequiris, and Vaxxinity., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Patients with type 2 diabetes and/or obesity and established cardiovascular disease are at increased risk for recurrent cardiovascular events. The indications of glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter-2 inhibitors have been expanded in the last decade due to benefit in cardiovascular outcome trials and are now considered guideline-recommended therapy for patients with type 2 diabetes and cardiovascular disease. Emerging data have begun to suggest that GLP-1RAs can decrease major adverse cardiovascular events among patients with obesity without diabetes. Overall, prescription of these agents remains low, despite being key to improve disparities in recurrent cardiovascular events. In this review, we discuss optimal medical therapy for secondary prevention for stable ischemic heart disease., Competing Interests: Disclosure N. Osude: NIH, United States funded grant T32HL069749. N.J. Pagidipati: Research support from Alnylam, Amgen, United States, Boehringer Ingelheim, Germany, Eggland’s Best, Eli Lilly, Novartis, Switzerland, Novo Nordisk, Denmark, Verily Life Sciences, United States. Consultation/Advisory Panels for Bayer, Boehringer Ingelheim, CRISPR Therapeutics, Eli Lilly, Esperion, AstraZeneca, Merck, Novartis, and Novo Nordisk. Executive Committee member for trials sponsored by Novo Nordisk and by Amgen. DSMB for trials sponsored by J+J and Novartis. Medical advisory board for Miga Health., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Increasing global overweight and obesity rates not only increase the prevalence of myocardial infarction (MI), but also exacerbate ischemic injury and result in worsened prognosis. Currently, there are no drugs that can reverse myocardial damage once MI has occurred, therefore discovering drugs that can potentially limit the extent of ischemic damage to the myocardium is critical. Resveratrol is a polyphenol known for its antioxidant properties, however whether prolonged daily intake of resveratrol during obesity can protect against MI-induced damage remains unexplored., Methods: We established murine models of obesity via high-fat/high-fructose diet, along with daily administrations of resveratrol or vehicle, then performed surgical MI to examine the effects and mechanisms of resveratrol in protecting against myocardial ischemic injury., Results: Daily administration of resveratrol in obese mice robustly protected against myocardial ischemic injury and improved post-MI cardiac function. Resveratrol strongly inhibited oxidative and DNA damage via activating SIRT3/FOXO3a-dependent antioxidant enzymes following MI, which were completely prevented upon administration of 3-TYP, a selective SIRT3 inhibitor. Hence, the cardioprotective effects of prolonged resveratrol intake in protecting obese mice against myocardial ischemic injury was due to reestablishment of intracellular redox homeostasis through activation of SIRT3/FOXO3a signaling pathway., Conclusion: Our findings provide important new evidence that supports the daily intake of resveratrol, especially in those overweight or obese, which can robustly decrease the extent of ischemic damage following MI. Our study therefore provides new mechanistic insight and suggests the therapeutic potential of resveratrol as an invaluable drug in the treatment of ischemic heart diseases., Competing Interests: Declaration of Competing Interest The authors confirm that there are no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Chronic coronary disease (CCD) is a major cause of morbidity and mortality worldwide. The most common symptom of CCD is exertional angina pectoris, a discomfort in the chest that commonly occurs during activities of daily life. Patients are dismayed by recurring episodes of angina and seek medical help in preventing or minimizing episodes. Angina occurs when the coronary arteries are unable to supply sufficient blood flow to the cardiac muscle to meet the metabolic needs of the left ventricular myocardium. While lifestyle changes and aggressive risk factor modification play a critical role in the management of CCD, management of angina usually requires pharmacologic therapy. Medications such as beta-blockers, calcium channel blockers, nitrates, ranolazine, and others ultimately work to improve the mismatch between myocardial blood flow and metabolic demand. This manuscript briefly describes the pathophysiologic basis for symptoms of angina, and how currently available anti-anginal therapies contribute to preventing or minimize the occurrence of angina., Competing Interests: Disclosures All authors have no conflicts of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Myocardial ischemia is the leading cause of health loss from cardiovascular disease worldwide. Myocardial ischemia and hypoxia during exercise trigger the risk of sudden exercise death which, in severe cases, will further lead to myocardial infarction. The Nrf2 transcription factor is an important antioxidant regulator that is extensively engaged in biological processes such as oxidative stress, inflammatory response, apoptosis, and mitochondrial malfunction. It has a significant role in the prevention and treatment of several cardiovascular illnesses, since it can control not only the expression of several antioxidant genes, but also the target genes of associated pathological processes. Therefore, targeting Nrf2 will have great potential in the treatment of myocardial ischemic injury. Natural products are widely used to treat myocardial ischemic diseases because of their few side effects. A large number of studies have shown that the Nrf2 transcription factor can be used as an important way for natural products to alleviate myocardial ischemia. However, the specific role and related mechanism of Nrf2 in mediating natural products in the treatment of myocardial ischemia is still unclear. Therefore, this review combs the key role and possible mechanism of Nrf2 in myocardial ischemic injury, and emphatically summarizes the significant role of natural products in treating myocardial ischemic symptoms, thus providing a broad foundation for clinical transformation., Competing Interests: The authors declare that they have no conflicts of interest.

In this study, nanoparticles loaded with active components from Polygonum orientale L. (PO), a traditional Chinese herb known for its anti-myocardial ischemic properties, were investigated for cardio-protective properties. Specifically, OVQ-Nanoparticles (OVQ-NPs) with Orientin (Ori), Vitexin (Vit), and Quercetin (Que) was obtained by double emulsion-solvent evaporation method. The OVQ-NPs exhibited a spherical shape, with a uniform size distribution of 136.77 ± 3.88 nm and a stable ζ-potential of -13.40 ± 2.24 mV. Notably, these nanoparticles exhibited a favorable sustained-release characteristic, resulting in an extended circulation time within the living organism. Consequently, the administration of these nanoparticles resulted in significant improvements in electrocardiograms and heart mass index of myocardial ischemic rats induced by isoproterenol, as well as decreased serum levels of CK, LDH, and AST. Furthermore, the results of histopathological examination, such as H&E staining and TUNEL staining, confirmed a reduced level of cardiac tissue pathology and apoptosis. Moreover, the quantification of biochemical indicators (SOD, MDA, GSH, NO, TNF-α, and IL-6) demonstrated that OVQ-NPs effectively mitigated myocardial ischemia by regulating oxidative stress and inflammatory pathways. In conclusion, OVQ-NPs demonstrate promising therapeutic potential as an intervention for myocardial ischemia, providing a new perspective on traditional Chinese medicine treatment in this area., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Flavonoids are extensively present in fruits, vegetables, grains, and medicinal plants. Myocardial ischemia and reperfusion (MI/R) comprise a sequence of detrimental incidents following myocardial ischemia. Research indicates that flavonoids have the potential to act as cardioprotective agents against MI/R injuries. Several specific flavonoids, e.g., luteolin, hesperidin, quercetin, kaempferol, and puerarin, have demonstrated cardioprotective activities in animal models., Purpose: The objective of this review is to identify the cardioprotective flavonoids, investigate their mechanisms of action, and explore their application in myocardial ischemia., Methods: A search of PubMed database and Google Scholar was conducted using keywords "myocardial ischemia" and "flavonoids". Studies published within the last 10 years reporting on the cardioprotective effects of natural flavonoids on animal models were analyzed., Results: A total of 55 natural flavonoids were identified and discussed within this review. It can be summarized that flavonoids regulate the following main strategies: antioxidation, anti-inflammation, calcium modulation, mitochondrial protection, ER stress inhibition, anti-apoptosis, ferroptosis inhibition, autophagy modulation, and inhibition of adverse cardiac remodeling. Additionally, the number and position of OH, 3'4'-catechol, C2=C3, and C4=O may play a significant role in the cardioprotective activity of flavonoids., Conclusion: This review serves as a reference for designing a daily diet to prevent or reduce damages following ischemia and screening of flavonoids for clinical application., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier GmbH.)

Oxidative stress (OS) plays a key role in the development of cardiovascular diseases (CVD) in three major ways: reactive oxygen species (ROS)-induced reduction of nitric oxide (NO) bioavailability, ROS-induced inflammation and ROS-induced mitochondrial dysfunction. Oxidation of lipid molecules under the action of ROS leads to damage to membrane structures, changes the functioning of membrane-bound enzymes, and impairs membrane permeability and stability. An increase in OS results in the occurrence of endothelial dysfunction and drug tolerance, side effects, requiring discontinuation of drugs. All of these are significant problems of cardiotherapy. Therefore, the search for new alternative NO donors continues. The present research was aimed at studying the protective effect of 2-ethyl-3-hydroxy-6-methylpyridinium 2-nitroxysuccinate (NS) on the cardiovascular system on mouse myocardial ischemia (MI) model. The NS hybrid molecule includes a synthetic vitamin B6 analog 2-ethyl-3-hydroxy-6-methylpyridine (an antioxidant) and 2-nitroxysuccinic acid (a source of nitric oxide). Using the electron paramagnetic resonance (EPR) method and biochemical methods, we showed that the pronounced ability of NS to release NO is favorably combines with the capacity to prevent OS due to mechanisms such as suppression of the lipid peroxidation (LPO) process, antiradical activity and inhibition of the mitochondrial membrane-bound monoamine oxidase A (MAO-A). Using histological methods, we established that the administration of NS (10 mg/kg, i.p.) reduces the number of ischemic fibers and protects cardiomyocytes against ischemia injury. Thus, the complex protective effect allows us to consider NS as an alternative NO donor and a candidate for the development of a new pharmaceutical agent for the treatment of CVD., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Allopurinol is a xanthine oxidase inhibitor that lowers serum uric acid and is used to prevent acute gout flares in patients with gout. Observational and small interventional studies have suggested beneficial cardiovascular effects of allopurinol., Objective: To determine whether allopurinol improves major cardiovascular outcomes in patients with ischaemic heart disease., Design: Prospective, randomised, open-label, blinded endpoint multicentre clinical trial., Setting: Four hundred and twenty-four UK primary care practices., Participants: Aged 60 years and over with ischaemic heart disease but no gout., Interventions: Participants were randomised (1 : 1) using a central web-based randomisation system to receive allopurinol up to 600 mg daily that was added to usual care or to continue usual care., Main Outcome Measures: The primary outcome was the composite of non-fatal myocardial infarction, non-fatal stroke or cardiovascular death. Secondary outcomes were non-fatal myocardial infarction, non-fatal stroke, cardiovascular death, all-cause mortality, hospitalisation for heart failure, hospitalisation for acute coronary syndrome, coronary revascularisation, hospitalisation for acute coronary syndrome or coronary revascularisation, all cardiovascular hospitalisations, quality of life and cost-effectiveness. The hazard ratio (allopurinol vs. usual care) in a Cox proportional hazards model was assessed for superiority in a modified intention-to-treat analysis., Results: From 7 February 2014 to 2 October 2017, 5937 participants were enrolled and randomised to the allopurinol arm ( n = 2979) or the usual care arm ( n = 2958). A total of 5721 randomised participants (2853 allopurinol; 2868 usual care) were included in the modified intention-to-treat analysis population (mean age 72.0 years; 75.5% male). There was no difference between the allopurinol and usual care arms in the primary endpoint, 314 (11.0%) participants in the allopurinol arm (2.47 events per 100 patient-years) and 325 (11.3%) in the usual care arm (2.37 events per 100 patient-years), hazard ratio 1.04 (95% confidence interval 0.89 to 1.21); p = 0.65. Two hundred and eighty-eight (10.1%) participants in the allopurinol arm and 303 (10.6%) participants in the usual care arm died, hazard ratio 1.02 (95% confidence interval 0.87 to 1.20); p = 0.77. The pre-specified health economic analysis plan was to perform a 'within trial' cost-utility analysis if there was no statistically significant difference in the primary endpoint, so NHS costs and quality-adjusted life-years were estimated over a 5-year period. The difference in costs between treatment arms was +£115 higher for allopurinol (95% confidence interval £17 to £210) with no difference in quality-adjusted life-years (95% confidence interval -0.061 to +0.060). We conclude that there is no evidence that allopurinol used in line with the study protocol is cost-effective., Limitations: The results may not be generalisable to younger populations, other ethnic groups or patients with more acute ischaemic heart disease. One thousand six hundred and thirty-seven participants (57.4%) in the allopurinol arm withdrew from randomised treatment, but an on-treatment analysis gave similar results to the main analysis., Conclusions: The ALL-HEART study showed that treatment with allopurinol 600 mg daily did not improve cardiovascular outcomes compared to usual care in patients with ischaemic heart disease. We conclude that allopurinol should not be recommended for the secondary prevention of cardiovascular events in patients with ischaemic heart disease but no gout., Future Work: The effects of allopurinol on cardiovascular outcomes in patients with ischaemic heart disease and co-existing hyperuricaemia or clinical gout could be explored in future studies., Trial Registration: This trial is registered as EU Clinical Trials Register (EudraCT 2013-003559-39) and ISRCTN (ISRCTN 32017426)., Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 11/36/41) and is published in full in Health Technology Assessment ; Vol. 28, No. 18. See the NIHR Funding and Awards website for further award information.

Background: Myocardial ischemia/reperfusion injury (MIRI) poses a formidable challenge to cardiac reperfusion therapy due to the absence of effective clinical interventions. Methylation of N6-methyladenosine (m 6 A), which is the most common post-transcriptional modifications occurring within mammalian mRNA, is believed to be involved in MIRI by modulating autophagy. MicroRNAs (miRNAs) play a crucial role in regulating gene expression at the post-transcriptional level and have been implicated in the regulation of m 6 A methylation. Suxiao Jiuxin Pill (SJP) is extensively used in China for the clinical treatment of angina pectoris and confers benefits to patients with acute coronary syndrome who have received percutaneous coronary intervention. However, the precise mechanisms underlying SJP intervention in MIRI remain unclear., Purpose: This study aimed to demonstrate, both in vivo and in vitro, that SJP could alleviate autophagy in MIRI by regulating miR-193a-3p to target and upregulate the demethylase ALKBH5., Methods: An in vitro hypoxia/reoxygenation model was established using H9c2 cells, while an in vivo MIRI model was established using Wistar rats. A lentivirus harboring the precursor sequence of miR-193a-3p was employed for its overexpression. Adeno-associated viruses were used to silence both miR-193a-3p and ALKBH5 expressions. Cardiac function, infarct size, and tissue structure in rats were assessed using echocardiography, triphenyl tetrazolium chloride (TTC) staining, and HE staining, respectively. Terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) was employed to detect the levels of apoptosis in rat cardiac tissue. m 6 A methylation levels were assessed using colorimetry. GFP-RFP-LC3B was used to monitor autophagic flux and transmission electron microscopy was used to evaluate the development of autophagosomes. Western Blot and qRT-PCR were respectively employed to assess the levels of autophagy-related proteins and miR-193a-3p., Results: SJP alleviated autophagy, preserved cardiac function, and minimized myocardial damage in the hearts of MIRI rats. SJP attenuated autophagy in H/R H9C2 cells. Elevated levels of miR-193a-3p were observed in the cardiac tissues of MIRI rats and H/R H9C2 cells, whereas SJP downregulated miR-193a-3p levels in these models. ALKBH5, a target gene of miR-193, is negatively regulated by miR-193a-3p. Upon overexpression of miR-193a-3p or silencing of ALKBH5, m 6 A methylation decreased, and the autophagy-attenuating effects of SJP and its components, senkyunolide A and l-borneol, were lost in H/R H9C2 cells, whereas in MIRI rats, these effects were not abolished but merely weakened. Further investigation indicated that the METTL3 inhibitor STM2475, combined with the silencing of miR-193a-3p, similarly attenuated autophagy in the hearts of MIRI rats. This suggests that a reduction in m 6 A methylation is involved in autophagy alleviation., Conclusion: We demonstrated that SJP mitigates autophagy in MIRI by downregulating miR-193a-3p, enhancing ALKBH5 expression, and reducing m 6 A methylation, a mechanism potentially attributed to its constituents, senkyunolide A and l-borneol., Competing Interests: Declaration of competing interest The authors declare that the research was conducted without any commercial or financial relationships that could be perceived as potential conflicts of interest., (Copyright © 2024 The Author(s). Published by Elsevier GmbH.. All rights reserved.)

Objectives: This study aimed to evaluate the level of adherence to medication among patients with ischaemic heart disease (IHD) in Oman and assess the related factors., Methods: This cross-sectional questionnaire-based study among patients with IHD attending the outpatient clinic at Sultan Qaboos University Hospital, Muscat, Oman, was performed between January and December 2021., Results: A total of 105 patients (mean age = 49.9 ± 11.1 years, 78.1% male) were recruited. Most of the patients (80%) reported taking the medications by themselves; 77 (73.3%) patients said that over the preceding 2 weeks, they had missed at least 3 doses of their medication. The reasons for missing the medications included forgetting (100%), having to take too many tablets (57%), feeling that the tablets are not effective (48%) and having to take the tablets too often each day (23%). The factors responsible for patients failing to take medications could not be identified., Conclusion: Medication adherence was low among patients with IHD in Oman, with high pill burden being the most common reason for non-adherence. Physicians must bear this in mind when reviewing patients., Competing Interests: CONFLICTS OF INTEREST: The authors declare no conflicts of interest., (© Copyright 2024, Sultan Qaboos University Medical Journal, All Rights Reserved.)

Symptomatic women with angina are more likely to have ischemia with no obstructive coronary arteries (INOCA) compared to men. In both men and women, the finding of INOCA is not benign and is associated with adverse cardiovascular events, including myocardial infarction, heart failure and angina hospitalizations. Women with INOCA have more angina and a lower quality of life compared to men, but they are often falsely reassured because of a lack of obstructive coronary artery disease (CAD) and a perception of low risk. Coronary microvascular dysfunction (CMD) is a key pathophysiologic contributor to INOCA, and non-invasive imaging methods are used to detect impaired microvascular flow. Coronary vasospasm is another mechanism of INOCA, and can co-exist with CMD, but usually requires invasive coronary function testing (CFT) with provocation testing for a definitive diagnosis. In addition to traditional heart disease risk factors, inflammatory, hormonal and psychological risk factors that impact microvascular tone are implicated in INOCA. Treatment of risk factors and use of anti-atherosclerotic and anti-anginal medications offer benefit. Increasing awareness and early referral to specialized centers that focus on INOCA management can improve patient-oriented outcomes. However, large, randomized treatment trials to investigate the impact on major adverse cardiovascular events (MACE) are needed. In this focused review, we discuss the prevalence, pathophysiology, presentation, diagnosis and treatment of INOCA.

Hawthorn leaf has shown therapeutic effects in the patients with myocardial ischemia. Our study combines network pharmacology, molecular docking techniques, and in vitro experiment with the aim of revealing the mechanism of hawthorn leaves in the treatment of myocardial ischemia. The active ingredients and corresponding targets of hawthorn leaf through Traditional Chinese Medicine System Pharmacology and Swiss Target Prediction databases. Targets related to myocardial ischemia were retrieved by Gene Card, Online Mendelian Inheritance in Man, Disgenet, and Therapeutic Targets Database databases. Cytoscape software was used to construct an ingredient-target-organ network and enrichment analysis of common targets was analyzed. Molecular docking verification of the core compound and target interactions was performed using MOE software. In vitro cell experiment was performed to verify the findings from bioinformatics analysis. Six active components and 107 potential therapeutic targets were screened. The protein-protein interaction network analysis indicated that 10 targets, including AKT1 and EGFR, were hub genes. Quercetin, kaempferol and isorhamnetin were taken as core active components. Through pathway enrichment analysis, nearly 455 Gene Ontology entries and 77 Kyoto Encyclopedia of Genes and Genomes pathways were obtained, mainly including PI3K/Akt, estrogen and other signaling pathways. Molecular docking prediction showed that three main active ingredients were firmly combined with the core targets. Cellular experiments showed that quercetin alleviated oxidative damage in cells and regulated the expression of PI3K, P-AKT/AKT and Bax/Bcl-2 proteins. This study identified the potential targets of Hawthorn leaf against myocardial ischemia using network pharmacology and in vitro verification, which provided a new understanding of the pharmacological mechanisms of Hawthorn leaf in treatment of myocardial ischemia., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Coronary microvascular dysfunction (CMD) is a common cause of ischemia but no obstructive coronary artery disease that results in an inability of the coronary microvasculature to meet myocardial oxygen demand. CMD is challenging to diagnose and manage due to a lack of mechanistic research and targeted therapy. Recent evidence suggests we can improved patient outcomes by stratifying antianginal therapies according to the diagnosis revealed by invasive assessment of the coronary microcirculation. This review article appraises the evidence for management of CMD, which includes treatment of cardiovascular risk, antianginal therapy and therapy for atherosclerosis., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Inflammation and disruption of cardiac metabolism are prevalent in the setting of myocardial ischemia. Canagliflozin, a sodium-glucose costransporter-2 inhibitor, has beneficial effects on the heart, though the precise mechanisms are unknown. This study investigated the effects of canagliflozin therapy on metabolic pathways and inflammation in ischemic myocardial tissue using a swine model of chronic myocardial ischemia., Methods: Sixteen Yorkshire swine underwent placement of an ameroid constrictor to the left circumflex artery to induce chronic ischemia. Two weeks later, pigs received either no drug (n = 8) or 300 mg canagliflozin (n = 8) daily. Five weeks later, pigs underwent terminal harvest and tissue collection., Results: Canagliflozin treatment was associated with a trend toward decreased expression of fatty acid oxidation inhibitor acetyl-CoA carboxylase and decreased phosphorylated/inactivated acetyl-CoA carboxylase, a promotor of fatty acid oxidation, compared with control ischemic myocardium (P = .08, P = .03). There was also a significant modulation in insulin resistance markers p-IRS1, p-PKCα, and phosphoinositide 3-kinase in ischemic myocardium of the canagliflozin group compared with the control group (all P < .05). Canagliflozin treatment was associated with a significant increase in inflammatory markers interleukin 6, interleukin 17, interferon-gamma, and inducible nitric oxide synthase (all P < .05). There was a trend toward decreased expression of the anti-inflammatory cytokines interleukin 10 (P = .16) and interleukin 4 (P = .31) with canagliflozin treatment., Conclusion: The beneficial effects of canagliflozin therapy appear to be associated with inhibition of fatty acid oxidation and enhancement of insulin signaling in ischemic myocardium. Interestingly, canagliflozin appears to increase the levels of several inflammatory markers, but further studies are required to better understand how canagliflozin modulates inflammatory signaling pathways., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Ethnopharmacological Relevance: The peeled roots, stems, and twigs of Syringa pinnatifolia Hemsl., known as Shan-Chen-Xiang (SCX) in Chinese, has the traditional effects such as anti-Khii, clearing heat and relieving pain. It has been clinically applied for the treatment of heart failure and mental abnormalities, and gradually replaced agarwood in Mongolian medicine., Aim of Study: The present study aims to evaluate whether the key subfraction C (C), a half composition in mass of total ethanol extract (T) of SCX, exerts an equivalent effect against acute myocardial ischemia (AMI) compared to fraction I (I), and what was the potential pharmacologically active constituents of SCX., Materials and Methods: Cardiac function, serum marker enzymes, and myocardial tissue pathology of infarcted mice with ligation of the anterior descending (LAD) branch of the left coronary artery were used to evaluate the anti-AMI effect of C and its equivalent potency to that of I. LCMS-IT-TOF was used to identify the main constituents in C and C - . The new and known compounds were isolated from C by a combination of mass spectrometry and bioactivity-guided fractionation methods, and structures were elucidated by extensive spectroscopic and chemical methods, including calculated 13 C NMR data, calculated electronic circular dichroism, and single-crystal X-ray crystallography. The protective effect of isolates against oxidative injury induced by H 2 O 2 in H9c2 cells was evaluated according to a previously reported protocol., Results: The results of cardiac function, serum marker enzymes and myocardial tissue pathology observations (fosinopril as a positive drug) suggested that C (40 mg/kg, orally administered once a day for 7 days) possessed the anti-AMI effect and was equivalent to that of I, while C - did not show the positive effect. Then, 32 lignans were isolated from C, including the majors (8R,8'R,9S)-4,4'-dihydroxy-3,3',9-trimethoxy-9,9'-epoxylignan (24) and (8R,8'R,9R)-4,4'-dihydroxy-3,3',9-trimethoxy-9,9'-epoxylignan (25), which were confirmed by HPLC and LC-MS characterization. Among them, 15 ones were previously undescribed, including a pair of enantiomers (6a/6b), and 11 ones (1, 2, 6a/6b, 8, 10, 12, 16, 17, 24, and 25) exhibited protective effect against oxidative injury to H9c2 cells at different concentrations (ranged from 0.156 to 80 μM)., Conclusion: C (40 mg/kg) exerts cardioprotective effect in mice, which was equivalent to that of I and T. Lignans, including both representative compounds (24, 25) and other undescribed molecules with low content, significantly contribute to the anti-AMI effect of SCX. However, the anti-AMI property assessment of SCX should not exclude the contribution from the representative sesquiterpenoid ZER. Hence, the exploration of the final potential substances in SCX requires further investigation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)