Punicalagin attenuates isoproterenol-induced myocardial infarction through nuclear factor erythroid 2-related factor 2/silent information regulator transcript-1-mediated inhibition of inflammation and cardiac stress markers in experimental animal models.

Myocardial infarction (MI) is a significant global health issue and the leading cause of death. Myocardial infarction (MI) is characterized by events such as damage to heart cells and stress generated by inflammation. Punicalagin (PCN), a naturally occurring bioactive compound found in pomegranates, exhibits a diverse array of pharmacological effects against many disorders. This study aimed to assess the preventive impact of PCN, with its potential anti-inflammatory and antioxidant properties, on myocardial injury caused by isoproterenol (ISO) in rats and elucidate the possible underlying mechanisms. Experimental rats were randomly categorized into four groups: control group (fed a regular diet for 15 days), PCN group (orally administered PCN at 50 mg/kg body weight (b.w.) for 15 days), ISO group (subcutaneously administered ISO (85 mg/kg b.w.) on days 14 and 15 to induce MI), and PCN+ISO group (orally preadministered PCN (50 mg/kg b.w.) for 15 days and administered ISO (85 mg/kg b.w.) on days 14 and 15). The rat cardiac tissue was then investigated for cardiac marker, oxidative stress marker, and inflammatory marker expression levels. PCN prevented ISO-induced myocardial injury, suppressing the levels of creatine kinase-myocardial band, C-reactive protein, homocysteine, cardiac troponin T, and cardiac troponin I in the rats. Moreover, PCN treatment reversed (P<0.01) the ISO-induced increase in blood pressure, attenuated lipid peroxidation markers, and depleted both enzymatic and nonenzymatic markers in the rats. Additionally, PCN inhibited (P<0.01) ISO-induced overexpression of oxidative stress markers (p-38, p-c-Jun N-terminal kinase, and p-extracellular signal-regulated kinase 1), inflammatory markers (nuclear factor-kappa B, tumor necrosis factor-alpha, and interleukin-6), and matrix metalloproteinases and decreased the levels (P<0.01) of apoptosis proteins in the rats. Nuclear factor erythroid 2-related factor 2/silent information regulator transcript-1 (Nrf2/Sirt1) is a major cellular defense protein that regulates and scavenges oxidative toxic substances through apoptosis. Therefore, overexpression of Nrf2/Sirt1 to inhibit inflammation and oxidative stress is considered a novel target for preventing MI. PCN also significantly enhanced the expression of Nrf2/Sirt1 in ISO-induced rats. Histopathological analyses of cardiac tissue revealed that PCN treatment exhibited a protective effect on the heart tissue, mitigating damage. These findings show that by activating the Nrf2/Sirt1 pathway, PCN regulates oxidative stress, inflammation, and apoptosis, hence providing protection against ISO-induced myocardial ischemia.

In patients with type 2 diabetes and recent MI, colchicine reduced a composite CV outcome at 23 mo.

SOURCE CITATION: Roubille F, Bouabdallaoui N, Kouz S, et al. Low-dose colchicine in patients with type 2 diabetes and recent myocardial infarction in the COLchicine Cardiovascular Outcomes Trial (COLCOT). Diabetes Care. 2024;47:467-470. 38181203.

N-acetylcysteine Protects Against Myocardial Ischemia-Reperfusion Injury Through Anti-ferroptosis in Type 1 Diabetic Mice.

The hearts of subjects with diabetes are vulnerable to ischemia-reperfusion injury (IRI). In contrast, experimentally rodent hearts have been shown to be more resistant to IRI at the very early stages of diabetes induction than the heart of the non-diabetic control mice, and the mechanism is largely unclear. Ferroptosis has recently been shown to play an important role in myocardial IRI including that in diabetes, while the specific mechanisms are still unclear. Non-diabetic control (NC) and streptozotocin-induced diabetic (DM) mice were treated with the antioxidant N-acetylcysteine (NAC) in drinking water for 4 week starting at 1 week after diabetes induction. Mice were subjected to myocardial IRI induced by occluding the coronary artery for 30 min followed by 2 h of reperfusion, subsequently at 1, 2, and 5 week of diabetes induction. The post-ischemic myocardial infarct size in the DM mice was smaller than that in NC mice at 1 week of diabetes but greater than that in the NC mice at 2 and 5 week of diabetes, which were associated with a significant increase of ferroptosis at 2 and 5 week but a significant reduction of ferroptosis at 1 week of diabetes. NAC significantly attenuated post-ischemic ferroptosis as well as oxidative stress and reduced infarct size at 2 and 5 week of diabetes. Application of erastin, a ferroptosis inducer, reversed the cardioprotective effects of NAC. It is concluded that increased oxidative stress and ferroptosis are the major factors attributable to the increased vulnerability to myocardial IRI in diabetes and that attenuation of ferroptosis represents a major mechanism whereby NAC confers cardioprotection against myocardial IRI in diabetes.

The protective effect of Macrostemonoside T from Allium macrostemon Bunge against Isoproterenol-Induced myocardial injury via the PI3K/Akt/mTOR signaling pathway.

Myocardial injury (MI) signifies a pathological aspect of cardiovascular diseases (CVDs) such as coronary artery disease, diabetic cardiomyopathy, and myocarditis. Macrostemonoside T (MST) has been isolated from Allium macrostemon Bunge (AMB), a key traditional Chinese medicine (TCM) used for treating chest stuffiness and pains. Although MST has demonstrated considerable antioxidant activity in vitro, its protective effect against MI remains unexplored. To investigate MST's effects in both in vivo and in vitro models of isoproterenol (ISO)-induced MI and elucidate its underlying molecular mechanisms. This study established an ISO-induced MI model in rats and assessed H9c2 cytotoxicity to examine MST's impact on MI. Various assays, including histopathological staining, TUNEL staining, immunohistochemical staining, DCFH-DA staining, JC-1 staining, ELISA technique, and Western blot (WB), were utilized to explore the potential molecular mechanisms of MI protection. In vivo experiments demonstrated that ISO caused myocardial fiber disorders, elevated cardiac enzyme levels, and apoptosis. However, pretreatment with MST significantly mitigated these detrimental changes. In vitro experiments revealed that MST boosted antioxidant enzyme levels and suppressed malondialdehyde (MDA) production in H9c2 cells. Concurrently, MST inhibited ISO-induced reactive oxygen species (ROS) production and mitigated the decline in mitochondrial membrane potential, thereby reducing the apoptosis rate. Moreover, pretreatment with MST elevated the expression levels of p-PI3K, p-Akt, and p-mTOR, indicating activation of the PI3K/Akt/mTOR signaling pathway and consequent protection against MI. MST attenuated ISO-induced MI in rats by impeding apoptosis through activation of the PI3K/Akt/mTOR signaling pathway. This study presents potential avenues for the development of precursor drugs for CVDs.

Impact of preventive substrate catheter ablation on implantable cardioverter-defibrillator interventions in patients with ischaemic cardiomyopathy and infarct-related coronary chronic total occlusion.

AIMS: Primary prevention patients with ischaemic cardiomyopathy and chronic total occlusion of an infarct-related coronary artery (CTO) are at a particularly high risk of implantable cardioverter-defibrillator (ICD) therapy occurrence. The trial was designed to evaluate the efficacy of preventive CTO-related substrate ablation strategy in ischaemic cardiomyopathy patients undergoing primary prevention ICD implantation. METHODS AND RESULTS: The PREVENTIVE VT study was a prospective, multicentre, randomized trial including ischaemic patients with ejection fraction ≤40%, no documented ventricular arrhythmias (VAs), and evidence of scar related to the coronary CTO. Patients were randomly assigned 1:1 to a preventive substrate ablation before ICD implantation or standard therapy with ICD implantation only. The primary outcome was a composite of appropriate ICD therapy or unplanned hospitalization for VAs. Secondary outcomes included the primary outcome's components, the incidence of appropriate ICD therapies, cardiac hospitalization, electrical storm, and cardiovascular (CV) mortality. Sixty patients were included in the study. During the mean follow-up of 44.7 ± 20.7 months, the primary outcome occurred in 5 (16.7%) patients undergoing preventive substrate ablation and in 13 (43.3%) patients receiving only ICD [hazard ratio (HR): 0.33; 95% confidence interval (CI): 0.12-0.94; P = 0.037]. Patients in the preventive ablation group also had fewer appropriate ICD therapies (P = 0.039) and the electrical storms (Log-rank: P = 0.01). While preventive ablation also reduced cardiac hospitalizations (P = 0.006), it had no significant impact on CV mortality (P = 0.151). CONCLUSION: Preventive ablation of the coronary CTO-related substrate in patients undergoing primary ICD implantation is associated with the reduced risk of appropriate ICD therapy or unplanned hospitalization due to VAs.

Protective effect of esculentoside A against myocardial infarction via targeting C-X-C motif chemokine receptor 2.

Myocardial infarction (MI) is the primary cause of cardiac mortality. Esculentoside A (EsA), a triterpenoid saponin, has anti-inflammatory and antioxidant activities. However, its effect on MI remains unknown. In this study, the protective effect and mechanisms of EsA against MI were investigated. EsA significantly alleviated hypoxia-induced HL-1 cell injury, including increasing cell viability, inhibiting reactive oxygen species (ROS) production, mitochondrial membrane potential (MMP) and lactate dehydrogenase (LDH) leakage. In mouse MI model by left coronary artery (LAD) ligating, EsA obviously restored serum levels of creatine kinase isoenzymes (CK-MB), cardiac troponin I (cTnI), superoxide dismutase (SOD) and malondialdehyde (MDA). In addition, the cardioprotective effect of EsA was further confirmed by infarct size, electrocardiogram and echocardiography. Mechanistically, the targeted binding relationship between EsA and C-X-C motif chemokine receptor 2 (CXCR2) was predicted by molecular docking and dynamics, and validated by small molecule pull-down and surface plasmon resonance tests. EsA inhibited CXCR2 level both in vitro and in vivo, correspondingly alleviated oxidative stress by suppressing NOX1 and NOX2 and relieved inflammation through inhibiting p65 and p-p65. It demonstrated that EsA could play a cardioprotective role by targeting CXCR2. However, the effect of EsA against MI was abolished in combination with CXCR2 overexpression both in vitro and in vivo. This study revealed that EsA showed excellent cardioprotective activities by targeting CXCR2 to alleviate oxidative stress and inflammation in MI. EsA may function as a novel CXCR2 inhibitor and a potent candidate for the prevention and intervention of MI in the future.

Secondary Prevention in Patients With Stroke Versus Myocardial Infarction: Analysis of 2 National Cohorts.

BACKGROUND: The implementation of preventive therapies among patients with stroke remains inadequately explored, especially when compared with patients with myocardial infarction (MI), despite sharing similar vascular risk profiles. We tested the hypothesis that participants with a history of stroke have a worse cardiovascular prevention profile in comparison to participants with MI. METHODS AND RESULTS: In cross-sectional analyses within the UK Biobank and All of Us Research Program, involving 14 760 (9193 strokes, 5567 MIs) and 7315 (2948 strokes, 4367 MIs) participants, respectively, we evaluated cardiovascular prevention profiles assessing low-density lipoprotein (<100 mg/dL), blood pressure (systolic, <140 mm Hg; and diastolic, <90 mm Hg), statin and antiplatelet use, and a cardiovascular prevention score that required meeting at least 3 of these criteria. The results revealed that, within the UK Biobank, patients with stroke had significantly lower odds of meeting all the preventive criteria compared with patients with MI: low-density lipoprotein control (odds ratio [OR], 0.73 [95% CI, 0.68-0.78]; P<0.001), blood pressure control (OR, 0.63 [95% CI, 0.59-0.68]; P<0.001), statin use (OR, 0.45 [95% CI, 0.42-0.48]; P<0.001), antiplatelet therapy use (OR, 0.30 [95% CI, 0.27-0.32]; P<0.001), and cardiovascular prevention score (OR, 0.42 [95% CI, 0.39-0.45]; P<0.001). Similar patterns were observed in the All of Us Research Program, with significant differences across all comparisons (P<0.05), and further analysis suggested that the odds of having a good cardiovascular prevention score were influenced by race and ethnicity as well as neighborhood deprivation levels (interaction P<0.05 in both cases). CONCLUSIONS: In 2 independent national cohorts, patients with stroke showed poorer cardiovascular prevention profiles and lower adherence to guideline-directed therapies compared with patients with MI. These findings underscore the need to explore the reasons behind the underuse of secondary prevention in vulnerable stroke survivors.

Do platelets protect the heart against ischemia/reperfusion injury or exacerbate cardiac ischemia/reperfusion injury? The role of PDGF, VEGF, and PAF.

BACKGROUND: Acute myocardial infarction (AMI) is one of the main causes of death. It is quite obvious that there is an urgent need to develop new approaches for treatment of AMI. OBJECTIVE: This review analyzes data on the role of platelets in the regulation of cardiac tolerance to ischemia/reperfusion (I/R). METHODS: It was performed a search of topical articles using PubMed databases. FINDINGS: Platelets activated by a cholesterol-enriched diet, thrombin, and myocardial ischemia exacerbate I/R injury of the heart. The P2Y12 receptor antagonists, remote ischemic postconditioning and conditioning alter the properties of platelets. Platelets acquire the ability to increase cardiac tolerance to I/R. Platelet-derived growth factors (PDGFs) increase tolerance of cardiomyocytes and endothelial cells to I/R. PDGF receptors (PDGFRs) were found in cardiomyocytes and endothelial cells. PDGFs decrease infarct size and partially abrogate adverse postinfarction remodeling. Protein kinase C, phosphoinositide 3-kinase, and Akt involved in the cytoprotective effect of PDGFs. Vascular endothelial growth factor increased cardiac tolerance to I/R and alleviated adverse postinfarction remodeling. The platelet-activating factor (PAF) receptor inhibitors increase cardiac tolerance to I/R in vivo. PAF enhances cardiac tolerance to I/R in vitro. It is possible that PAF receptor inhibitors could protect the heart by blocking PAF receptor localized outside the heart. PAF protects the heart through activation of PAF receptor localized in cardiomyocytes or endothelial cells. Reactive oxygen species and kinases are involved in the cardioprotective effect of PAF. CONCLUSION: Platelets play an important role in the regulation of cardiac tolerance to I/R.

Stachydrine hydrochloride protects the ischemic heart by ameliorating endoplasmic reticulum stress through a SERCA2a dependent way and maintaining intracellular Ca2+ homeostasis.

This study aimed to explore the effects and mechanism of action of stachydrine hydrochloride (Sta) against myocardial infarction (MI) through sarcoplasmic/endoplasmic reticulum stress-related injury. The targets of Sta against MI were screened using network pharmacology. C57BL/6 J mice after MI were treated with saline, Sta (6 or 12 mg kg-1) for 2 weeks, and adult mouse and neonatal rat cardiomyocytes (AMCMs and NRCMs) were incubated with Sta (10-4-10-6 M) under normoxia or hypoxia for 2 or 12 h, respectively. Echocardiography, Evans blue, and 2,3,5-triphenyltetrazolium chloride (TTC) staining were used for morphological and functional analyses. Endoplasmic reticulum stress (ERS), unfolded protein reaction (UPR), apoptosis signals, cardiomyocyte contraction, and Ca2+ flux were detected using transmission electron microscopy (TEM), western blotting, immunofluorescence, and sarcomere and Fluo-4 tracing. The ingredient-disease-pathway-target network revealed targets of Sta against MI were related to apoptosis, Ca2+ homeostasis and ERS. Both dosages of Sta improved heart function, decreased infarction size, and potentially increased the survival rate. Sta directly alleviated ERS and UPR and elicited less apoptosis in the border myocardium and hypoxic NRCMs. Furthermore, Sta upregulated sarcoplasmic reticulum Ca2+-ATPase 2a (SERCA2a) in both ischaemic hearts and hypoxic NRCMs, accompanied by restored sarcomere shortening, resting intracellular Ca2+, and Ca2+ reuptake time constants (Tau) in Sta-treated hypoxic ARCMs. However, 2,5-di-t-butyl-1,4-benzohydroquinone (BHQ) (25 µM), a specific SERCA inhibitor, totally abolished the beneficial effect of Sta in hypoxic cardiomyocytes. Sta protects the heart from MI by upregulating SERCA2a to maintain intracellular Ca2+ homeostasis, thus alleviating ERS-induced apoptosis.

Intraprocedural continuous saline infusion lines significantly reduce the incidence of acute kidney injury during endovascular procedures for stroke and myocardial infarction: evidence from a systematic review and meta-regression.

BACKGROUND: Contrast media used in mechanical therapies for stroke and myocardial infarction represent a significant cause of acute kidney injury (AKI) in acute medical scenarios. Although the continuous saline infusion line (CSIL) is a standard procedure to prevent thrombus formation within the catheter during neurovascular interventions of mechanical thrombectomy (MT), it is not utilized in percutaneous coronary interventions (PCI). METHODS: A systematic review of the incidence of AKI after MT for stroke treatment was performed. These data were compared with those reported in the literature regarding the incidence of AKI after PCI for acute myocardial infarction. A random-effect model meta-regression was performed to explore the effects of CSIL on AKI incidence, using clinical details as covariates. RESULTS: A total of 18 and 33 studies on MT and PCI were included, respectively, with 69,464 patients (30,138 [43.4%] for MT and 39,326 [56.6%] for PCI). The mean age was 63.6 years±5.8 with male 66.6%±12.8. Chronic kidney disease ranged 2.0-50.3%. Diabetes prevalence spanned 11.1% to 53.0%. Smoking status had a prevalence of 7.5-72.0%. Incidence of AKI proved highly variable (I2=98%, Cochrane's Q 2985), and appeared significantly lower in the MT subgroup than in the PCI subgroups (respectively 8.3% [95% confidence interval: 4.7-11.9%] vs. 14.7 [12.6-16.8%], P<0.05). Meta-regression showed that CSIL was significantly associated with a decreased incidence of AKI (OR=0.93 [1.001-1.16]; P=0.03). CONCLUSIONS: Implementation of CSIL during endovascular procedures in acute settings was associated with a significant decrease in the risk of AKI, and its safety should be routinely considered in such interventions.

"Expression of concern": publication bias for positive preclinical cardioprotection studies.

The present analysis reports on the robustness of preclinical cardioprotection studies with infarct size as endpoint which were published in Basic Research in Cardiology, Cardiovascular Research, and Circulation Research between January 2013 and December 2023. Only 26 out of 269 papers with technically robust analysis of infarct size by triphenyltetrazolium chloride staining, magnetic resonance imaging or single photon emission tomography applied a prospective power analysis. A retrospective power calculation revealed that only 75% of the reported data sets with statistically significant positive results from all these studies had a statistical power of ≥ 0.9, and an additional 9% had a statistical power ≥ 0.8. The remaining 16% of all significant positive data sets did not even reach the 0.8 threshold. Only 13% of all analyzed data sets were neutral. We conclude that neutral studies are underreported and there is indeed a significant lack of robustness in many of the published preclinical cardioprotection studies which may contribute to the difficulties of translating cardioprotection to patient benefit.

Protective effects of ginsenoside F2 on isoproterenol-induced myocardial infarction by activating the Nrf2/HO-1 and PI3K/Akt signaling pathways.

BACKGROUND: Ginsenoside F2 (GF2) serves as the principal intestinal metabolite resulting from the oral intake of Panax ginseng and Panax quinquefolius, exhibiting antioxidative, hypolipidemic, antitumor, and anti-inflammatory properties. Nevertheless, its effect on myocardial infarction (MI) is still unknown. PURPOSE: The purpose of this study is to investigate the protective effect and the underlying mechanisms of GF2 against isoproterenol (ISO)-induced MI. METHODS: ISO-induced H9c2 cardiomyocytes and MI rat models were utilized as in vitro and in vivo models to evaluate the impact of anti-MI of GF2. The underlying mechanisms were investigated using a variety of methodologies, including electrocardiography, Western blot analysis, histopathological examination, immunofluorescence, immunohistochemistry, and ELISA techniques. RESULTS: In vivo experiments, our results indicated that GF2 significantly ameliorated ISO-induced electrocardiographic (ECG) abnormalities, myocardial fiber necrosis, rupture, fibrosis of myocardial tissues, and suppressed cardiac enzyme activities. Meanwhile, GF2 notably raised the activity of antioxidant enzymes like CAT, GSH, and SOD. Furthermore, it downregulated Keap1 expression level while upregulating NQO1, Nrf2, and HO-1 expression levels. Additionally, GF2 suppressed the expression of the cleaved caspase-3 and pro-apoptotic protein Bax while promoting the expression of anti-apoptotic proteins Bcl-2, p-PI3K, and p-Akt. TUNEL fluorescence results also demonstrated that GF2 effectively inhibited cardiomyocyte apoptosis. Furthermore, consistent with the results of animal experiments, GF2 considerably attenuated ROS generation, changed apoptosis and mitochondrial function, and reduced oxidative stress in ISO-induced H9c2 cardiomyocytes through activating Nrf2/HO-1 and PI3K/Akt signaling pathways. CONCLUSION: Taken together, GF2 ameliorated MI by preventing cardiocyte apoptosis, oxidative stress, and mitochondrial dysfunction via modulating the Nrf2/HO-1 and PI3K/Akt signaling pathways, showing potential as a treatment strategy for treating MI.

Upregulation of CIRP by its agonist prevents the development of heart failure in myocardial infarction rats.

BACKGROUND: Downregulated expression of cold-inducible RNA binding protein (CIRP), a stress-response protein, has been demonstrated in the hearts of patients with heart failure (HF). However, whether CIRP plays a critical role in the pathogenesis of HF remains unknown. Zr17-2 is a recently identified CIRP agonist, which can enhance the expression of CIRP in hearts. Herein, we evaluated the effects of zr17-2 on the development of HF in a rat model of myocardial infarction (MI). METHODS: Male SD rats were pretreated with CIRP agonist zr17-2 or vehicle saline for 6 consecutive days, followed by MI induction. 1-week post-MI, cardiac function, and structural and molecular changes were determined by echocardiography and molecular biology methods. RESULTS: Excitingly, we found that pretreatment with zr17-2 significantly attenuated MI-induced cardiac dysfunction and dilation, coupled with reduced infarction size and cardiac remodeling. In addition, increased inflammatory response in the peri-infarcted heart including macrophage infiltration and the expression of inflammatory genes were all significantly decreased by zr17-2 pretreatment, suggesting an anti-inflammatory effect of zr17-2. Moreover, zr17-2 pretreatment also upregulated the antioxidant genes (e.g. NQO-1, Nrf2, and HO-1) level in the hearts. In isolated cultured cardiomyocytes, pretreatment with zr17-2 markedly attenuated cell injury and apoptosis induced by oxidative injury, along with elevation of Nrf2-related antioxidant genes and CIRP. However, silencing CIRP abolished zr17-2's antioxidant effects against oxidative injury, confirming that zr17-2's role is dependent on CIRP. CONCLUSION: Collectively, our study suggests CIRP plays a crucial role in the development of HF and a beneficial effect of CIRP agonist in preventing MI-induced HF, possibly via anti-inflammatory and anti-oxidant pathways.

Comparing screening based on the NHS Health Check and Polypill Prevention Programmes in the primary prevention of heart attacks and strokes.

OBJECTIVE: To compare the NHS Health Check Programme with the Polypill Prevention Programme in the primary prevention of heart attacks and strokes. DESIGN: Use of published data and methodology to produce flow charts of the two programmes to determine screening performance and heart attacks and strokes prevented. SETTING: The UK population. INTERVENTION: The NHS Health Check Programme using a QRISK score on people aged 40-74 to select those eligible for a statin is compared with the Polypill Prevention Programme in people aged 50 or more to select people for a combination of a statin and three low-dose blood pressure lowering agents. In both programmes, people had no history of heart attack or stroke. MAIN OUTCOME MEASURES: In 1000 people, the number of heart attacks and strokes prevented in the two programmes. RESULTS: In the hypothetical perfect situation with 100% uptake and adherence to the screening protocol, in every 1000 persons, the NHS Health Check would prevent 287 cases of a heart attack or stroke in individuals who would gain on average about 4 years of life without a heart attack or stroke amounting to 1148 years in total, the precise gain depending on the extent of treatment for those with raised blood pressure, and 136 would be prescribed statins with no benefit. The corresponding figures for the Polypill Prevention Programme are 316 individuals who would, on average, gain 8 years of life without a heart attack or stroke, amounting to 2528 years in total, and 260 prescribed the polypill with no benefit. Based on published estimates of uptake and adherence in the NHS Health Check Programme, in practice only 24 cases per 1000 are currently benefitting instead of 287, amounting to 96 years gained without a heart attack or stroke. CONCLUSIONS: The Polypill Prevention Programme is by design simpler with the potential of preventing many more heart attacks and strokes than the NHS Health Check Programme.