Cardiac fibroblasts secrete exosome microRNA to suppress cardiomyocyte pyroptosis in myocardial ischemia/reperfusion injury.

Molecular mechanisms underlying myocardial ischemia/reperfusion (MI/R) injury and effective strategies to treat MI/R injury are both in shortage. Although pyroptosis of cardiomyocytes and the protective role of cardiac fibroblasts (CFs) have been well recognized as targets to reduce MI/R injury and sudden cardiac death (SCD), the connection has not yet been established. Here, we showed that CFs protected cardiomyocytes against MI/R-induced injury through suppression of pyroptosis. A novel molecular mechanism underpinning this effect was further identified. Under hypoxia/reoxygenation condition, CFs were found to secrete exosomes, which contain increased level of microRNA-133a (miR-133a). These exosomes then delivered miR-133a into cardiomyocytes to target ELAVL1 and repressed cardiomyocyte pyroptosis. Based on this finding, we successfully developed a new strategy that used exosomes derived from CFs with overexpressed miR-133a to enhance the therapeutic outcomes for the MI/R injury. Overall, our results provide a novel molecular basis for understanding and treating MI/R injury, and our study also provides novel insight for the postmortem diagnosis of MI/R injury induced SCD by using exosome biomarker in forensic.

Neuraminidase 1 is a driver of experimental cardiac hypertrophy.

AIMS: Despite considerable therapeutic advances, there is still a dearth of evidence on the molecular determinants of cardiac hypertrophy that culminate in heart failure. Neuraminidases are a family of enzymes that catalyze the cleavage of terminal sialic acids from glycoproteins or glycolipids. This study sought to characterize the role of neuraminidases in pathological cardiac hypertrophy and identify pharmacological inhibitors targeting mammalian neuraminidases. METHODS AND RESULTS: Neuraminidase 1 (NEU1) was highly expressed in hypertrophic hearts of mice and rats, and this elevation was confirmed in patients with hypertrophic cardiomyopathy (n = 7) compared with healthy controls (n = 7). The increased NEU1 was mainly localized in cardiomyocytes by co-localization with cardiac troponin T. Cardiomyocyte-specific NEU1 deficiency alleviated hypertrophic phenotypes in response to transverse aortic constriction or isoproterenol hydrochloride infusion, while NEU1 overexpression exacerbated the development of cardiac hypertrophy. Mechanistically, co-immunoprecipitation coupled with mass spectrometry, chromatin immunoprecipitation, and luciferase assays demonstrated that NEU1 translocated into the nucleus and interacted with GATA4, leading to Foetal gene (Nppa and Nppb) expression. Virtual screening and experimental validation identified a novel compound C-09 from millions of compounds that showed favourable binding affinity to human NEU1 (KD = 0.38 µM) and effectively prevented the development of cardiac remodelling in cellular and animal models. Interestingly, anti-influenza drugs zanamivir and oseltamivir effectively inhibited mammalian NEU1 and showed new indications of cardio-protection. CONCLUSIONS: This work identifies NEU1 as a critical driver of cardiac hypertrophy and inhibition of NEU1 opens up an entirely new field of treatment for cardiovascular diseases.

Comparison of one-month versus twelve-month dual antiplatelet therapy after implantation of drug-eluting stents guided by either intravascular ultrasound or angiography in patients with acute coronary syndrome: rationale and design of prospective, multicenter, randomized, controlled IVUS-ACS and ULTIMATE-DAPT trial.

BACKGROUND: Current guidelines recommend administering dual antiplatelet therapy (DAPT) for 12 months to patients with acute coronary syndromes (ACS) and without contraindications after drug-eluting stent (DES) implantation. A recent study reported that 3 months of DAPT followed by ticagrelor monotherapy is effective and safe in ACS patients undergoing DES implantation compared with the standard duration of DAPT. However, it is unclear whether antiplatelet monotherapy with ticagrelor alone versus ticagrelor plus aspirin reduces the incidence of clinically relevant bleeding without increasing the risk of major adverse cardiovascular and cerebrovascular events (MACCEs) in ACS patients undergoing percutaneous coronary intervention (PCI) with DES implantation guided by either intravascular ultrasound (IVUS) or angiography who have completed a 1-month course of DAPT with aspirin plus ticagrelor. METHODS: The IVUS-ACS and ULTIMATE-DAPT is a prospective, multicenter, randomized, controlled trial designed to determine (1) whether IVUS-guided versus angiography-guided DES implantation in patients with ACS reduces the risk of target vessel failure (TVF) at 12 months and (2) whether ticagrelor alone versus ticagrelor plus aspirin reduces the risk of clinically relevant bleeding without increasing the risk of MACCE 1-12 months after the index PCI in ACS patients undergoing DES implantation guided by either IVUS or angiography. This study will enroll 3486 ACS patients eligible for DES implantation, as confirmed by angiographic studies. The patients who meet the inclusion criteria and none of the exclusion criteria will be randomly assigned in a 1:1 fashion to the IVUS- or angiography-guided group (first randomization). All enrolled patients will complete a 1-month course of DAPT with aspirin plus ticagrelor after the index PCI. Patients with no MACCEs or major bleeding (≥Bleeding Academic Research Consortium (BARC) 3b) within 30 days will be randomized in a 1:1 fashion to either the ticagrelor plus matching placebo (SAPT)group or ticagrelor plus aspirin (DAPT)group for an additional 11 months (second randomization). The primary endpoint of the IVUS-ACS trial is TVF at 12 months, including cardiac death, target vessel myocardial infarction (TVMI), or clinically driven target vessel revascularization (CD-TVR). The primary superiority endpoint of the ULTIMATE-DAPT trial is clinically relevant bleeding, defined as BARC Types 2, 3, or 5 bleeding, and the primary non-inferiority endpoint of the ULTIMATE-DAPT trial is MACCE, defined as cardiac death, myocardial infarction, ischemic stroke, CD-TVR, or definite stent thrombosis occurring 1-12 months in the second randomized population. CONCLUSION: The IVUS-ACS and ULTIMATE-DAPT trial is designed to test the efficacy and safety of 2 different antiplatelet strategies in ACS patients undergoing PCI with DES implantation guided by either IVUS or angiography. This study will provide novel insights into the optimal DAPT duration in ACS patients undergoing PCI and provide evidence on the clinical benefits of IVUS-guided PCI in ACS patients.

Transcatheter closure for postinfarction ventricular septal defect: A meta-analysis of the current evidence.

OBJECTIVE: Postinfarction ventricular septal defect (PIVSD) is a severe complication of acute myocardial infarction (AMI). Transcatheter closure (TCC) is an alternative option to surgical repair. This study was undertaken to examine the published literature to provide objective evidence for TCC using a meta-analysis. METHODS: We searched for significant medical and publisher databases. Two reviewers checked the quality of the studies and extracted data. Eligible studies included single-arm studies and comparative studies. Weighted means, pooled event rates, efficacy outcomes and odds ratios (ORs) for immediate shunt reduction (ISR), presence of cardiogenic shock (CS), New York Heart Association (NYHA) class IV, time from AMI to ventricular septal defect (VSD), and time to VSD closure was estimated. RESULTS: A total of 27 single-arm articles (462 patients) were included. The pooled event rate was 89.7% (95% confidence interval [CI]: 0.772-1.021) for successful device implantation, 80.9% (95% CI: 0.645-0.972) for ISR, 31.5% (95% CI: 0.149-0.482) for 30-day mortality, and 25.3% (95% CI: 0.072-0.434) for 30-day mortality of primary closure at the acute phase. CS (OR = 3.607, 95% CI: 2.301-5.653), NYHA class IV (OR = 6.491, 95% CI: 1.444-29.188) and time to VSD closure were risk predictors for TCC. There was no correlation between defect size (OR = 2.592, 95% CI: 0.380-17.661) and mortality. CONCLUSION: TCC should be a relatively safe and minimally invasive method for PIVSD, with an excellent successful device implantation rate and acceptable low 30-day mortality. The procedure appears promising, but its safety and efficacy could only be demonstrated by randomized controlled trials. Therefore, the mortality of data comparing surgery to TCC compels the need for future comparative trials.

IRF-1 mediates the suppressive effects of mTOR inhibition on arterial endothelium.

AIMS: Mammalian target of rapamycin (mTOR) inhibitors used in drug-eluting stents (DES) to control restenosis have been found to delay endothelialization and increase incidence of late-stent thrombosis through mechanisms not completely understood. We revealed that mTOR inhibition (mTORi) upregulated the expression of cell growth suppressor IRF-1 in primary human arterial endothelial cells (HAEC). This study aimed to examine how mTOR-regulated IRF-1 expression contributes to the suppressive effect of mTORi on arterial endothelial proliferation. METHODS AND RESULTS: Western blotting, quantitative PCR, and a dual-luciferase reporter assay indicated that mTOR inhibitors rapamycin and torin 1 upregulated IRF-1 expression and increased its transcriptional activity. IRF-1 in turn contributed to the suppressive effect of mTORi by mediating HAEC apoptosis and cell cycle arrest in part through upregulation of caspase 1 and downregulation of cyclin D3, as revealed by CCK-8 assay, Annexin V binding assay, measurement of activated caspase 3, BrdU incorporation assay, and matrigel tube formation assay. In a mouse model of femoral artery wire injury, administration of rapamycin inhibited EC recovery, an effect alleviated by EC deficiency of IRF-1. Chromatin immunoprecipitation assay with HAEC and rescue expression of wild type or dominant-negative IRF-1 in EC isolated from Irf1-/- mice confirmed transcriptional regulation of IRF-1 on the expression of CASP1 and CCND3. Furthermore, mTORi activated multiple PKC members, among which PKCζ was responsible for the growth-inhibitory effect on HAEC. Activated PKCζ increased IRF1 transcription through JAK/STAT-1 and NF-κB signaling. Finally, overexpression of wild type or mutant raptor incapable of binding mTOR indicated that mTOR-free raptor contributed to PKCζ activation in mTOR-inhibited HAEC. CONCLUSIONS: The study reveals an IRF-1-mediated mechanism that contributes to the suppressive effects of mTORi on HAEC proliferation. Further study may facilitate the development of effective strategies to reduce the side effects of DES used in coronary interventions.

Swietenine extracted from Swietenia relieves myocardial hypertrophy induced by isoprenaline in mice.

As a traditional plant medicine in tropical areas, Swietenia macrophylla seeds are usually applied for some chronic diseases, including hypertension, diabetes, and so on. Few studies have been carried out to identify the effective elements in seed extract and their indications. In this study, we first investigated the functions of the swietenine, an extract from S. macrophylla seeds, using a model of myocardial hypertrophy induced by isoprenaline (ISO). At cellular level, H9c2 cell hypertrophy was also established through the treatment with ISO. The cardiac pathological remodeling was evaluated by echocardiography and histological analysis. Western blot and RT-qPCR were used to detect the expression of possible hypertrophy-promoting genes. Here, our results indicated that swietenine remarkably attenuated ISO-induced myocardial hypertrophy in vivo and in vitro. Moreover, Akt phosphorylation, ANP and BNP mRNA expression were efficiently decreased. Based on these findings, we concluded that swietenine might be a promising anti-hypertrophic agent against cardiac hypertrophy.

An interaction between BRG1 and histone modifying enzymes mediates lipopolysaccharide-induced proinflammatory cytokines in vascular endothelial cells.

Vascular inflammation is the culprit for a host of human diseases. The underlying mechanism, however, is not definitively elucidated. In the present study, we investigated the interplay between different epigenetic factors during lipopolysaccharide (LPS) induced synthesis of proinflammatory cytokines in cultured vascular endothelial cells. We report that in response to LPS treatment, NF-κB was deplored to its target promoters along with the chromatin remodeling protein BRG1. Paralleling these changes trimethylated H3K9 became erased from while trimethylated H3K4 started to accumulate on the NF-κB target promoters. Further analysis revealed that LPS stimulation resulted in sequential recruitment of the H3K9 tri-demethylase JMJD2A and the H3K4 trimethyltransferase SET1A to the NF-κB target promoters. JMJD2A mediated-H3K9 demethylation served as a prerequisite for SET1A to bind to the NF-κB target promoters. Both JMJD2A and SET1A were essential for LPS-induced transactivation of proinflammatory cytokines by sustaining the binding of NF-κB. Of key importance, BRG1 coordinated the sequential recruit of and the interplay between JMJD2A and SET1A. In conclusion, our data unveil a novel epigenetic mechanism that contributes to LPS-induced vascular inflammation.

Chicoric acid ameliorates sepsis-induced cardiomyopathy via regulating macrophage metabolism reprogramming.

BACKGROUND: Sepsis-related cardiac dysfunction is believed to be a primary cause of high morbidity and mortality. Metabolic reprogramming is closely linked to NLRP3 inflammasome activation and dysregulated glycolysis in activated macrophages, leading to inflammatory responses in septic cardiomyopathy. Succinate dehydrogenase (SDH) and succinate play critical roles in the progression of metabolic reprogramming in macrophages. Inhibition of SDH may be postulated as an effective strategy to attenuate macrophage activation and sepsis-induced cardiac injury. PURPOSE: This investigation was designed to examine the role of potential compounds that target SDH in septic cardiomyopathy and the underlying mechanisms involved. METHODS/RESULTS: From a small molecule pool containing about 179 phenolic compounds, we found that chicoric acid (CA) had the strongest ability to inhibit SDH activity in macrophages. Lipopolysaccharide (LPS) exposure stimulated SDH activity, succinate accumulation and superoxide anion production, promoted mitochondrial dysfunction, and induced the expression of hypoxia-inducible factor-1α (HIF-1α) in macrophages, while CA ameliorated these changes. CA pretreatment reduced glycolysis by elevating the NAD+/NADH ratio in activated macrophages. In addition, CA promoted the dissociation of K(lysine) acetyltransferase 2A (KAT2A) from α-tubulin, and thus reducing α-tubulin acetylation, a critical event in the assembly and activation of NLRP3 inflammasome. Overexpression of KAT2A neutralized the effects of CA, indicating that CA inactivated NLRP3 inflammasome in a specific manner that depended on KAT2A inhibition. Importantly, CA protected the heart against endotoxin insult and improved sepsis-induced cardiac mitochondrial structure and function disruption. Collectively, CA downregulated HIF-1α expression via SDH inactivation and glycolysis downregulation in macrophages, leading to NLRP3 inflammasome inactivation and the improvement of sepsis-induced myocardial injury. CONCLUSION: These results highlight the therapeutic role of CA in the resolution of sepsis-induced cardiac inflammation.

Cichoric acid ameliorates sepsis-induced acute kidney injury by inhibiting M1 macrophage polarization.

Cichoric acid (CA), a widely utilized polyphenolic compound in medicine, has garnered significant attention due to its potential health benefits. Sepsis-induced acute kidney disease (AKI) is related with an elevated risk of end-stage kidney disease (ESKD). However, it remains unclear whether CA provides protection against septic AKI. The aim of this study is to investigated the protective effect and possible mechanisms of CA against LPS-induced septic AKI. Sepsis-induced AKI was induced in mice through intraperitoneal injection of lipopolysaccharide (LPS), and RAW264.7 macrophages were incubated with LPS. LPS exposure significantly increased the levels of M1 macrophage biomarkers while reducing the levels of M2 macrophage indicators. This was accompanied by the release of inflammatory factors, superoxide anion production, mitochondrial dysfunction, activation of succinate dehydrogenase (SDH), and subsequent succinate formation. Conversely, pretreatment with CA mitigated these abnormalities. CA attenuated hypoxia-inducible factor-1α (HIF-1α)-induced glycolysis by lifting the NAD+/NADH ratio in macrophages. Additionally, CA disrupted the K (lysine) acetyltransferase 2A (KAT2A)/α-tubulin complex, thereby reducing α-tubulin acetylation and subsequently inactivating the NLRP3 inflammasome. Importantly, administration of CA ameliorated LPS-induced renal pathological damage, apoptosis, inflammation, oxidative stress, and disturbances in mitochondrial function in mice. Overall, CA restrained HIF-1α-mediated glycolysis via inactivation of SDH, leading to NLRP3 inflammasome inactivation and the amelioration of sepsis-induced AKI.

Association of the polymorphisms of the cholesteryl ester transfer protein gene with coronary artery disease: a meta-analysis.

Aims: This meta-analysis aimed to assess the association of the polymorphisms of cholesterol ester transfer protein (CETP) rs708272 (G>A), rs5882 (G>A), rs1800775 (C>A), rs4783961 (G>A), rs247616 (C>T), rs5883 (C>T), rs1800776 (C>A), and rs1532624 (C>A) with coronary artery disease (CAD) and the related underlying mechanisms. Methods: A comprehensive search was performed using five databases such as PubMed, EMBASE, Web of Science, Cochrane Library and Scopus to obtain the appropriate articles. The quality of the included studies was assessed by the Newcastle-Ottawa Scale. The statistical analysis of the data was performed using STATA 17.0 software. The association between CETP gene polymorphisms and risk of CAD was estimated using the pooled odds ratio (OR) and 95% confidence interval (95% CI). The association of CETP gene polymorphisms with lipids and with CETP levels was assessed using the pooled standardized mean difference and corresponding 95% CI. P < 0.05 was considered statistically significant. Results: A total of 70 case-control studies with 30,619 cases and 31,836 controls from 46 articles were included. The results showed the CETP rs708272 polymorphism was significantly associated with a reduced risk of CAD under the allele model (OR = 0.846, P < 0.001), the dominant model (OR = 0.838, P < 0.001) and the recessive model (OR = 0.758, P < 0.001). AA genotype and GA genotype corresponded to higher high-density lipoprotein cholesterol (HDL-C) concentrations in the blood compared with GG genotype across the studied groups (all P < 0.05). The CETP rs5882 and rs1800775 polymorphisms were not significantly associated with CAD under the allele model (P = 0.802, P = 0.392), the dominant model (P = 0.556, P = 0.183) and the recessive model (P = 0.429, P = 0.551). Similarly, the other mentioned gene polymorphisms were not significantly associated with CAD under the three genetic models. Conclusions: The CETP rs708272 polymorphism shows a significant association with CAD, and the carriers of the allele A are associated with a lower risk of CAD and higher HDL-C concentrations in the blood compared to the non-carriers. The CETP rs5882, rs1800775, rs4783961, rs247616, rs5883, rs1800776, and rs1532624 are not significantly associated with CAD. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42023432865, identifier: CRD42023432865.

Metabolite-assisted models improve risk prediction of coronary heart disease in patients with diabetes.

Background: Patients with diabetes have a two-to four-fold increased incidence of cardiovascular diseases compared with non-diabetics. Currently, there is no recognized model to predict the occurrence and progression of CVDs in diabetics. Objective: This work aimed to develop a metabolic biomarker-assisted model, a combination of metabolic markers with clinical variables, for risk prediction of CVDs in diabetics. Methods: A total of 475 patients with diabetes were studied. Each patient underwent coronary angiography. Plasma samples were analyzed by liquid chromatography-quadrupole time-of-flight mass spectrometry. Ordinal logistic regression and random forest were used to screen metabolites. Receiver operating characteristic (ROC) curve, nomogram, and decision curve analysis (DCA) were employed to evaluate their prediction performances. Results: Ordinal logistic regression screened out 34 differential metabolites (adjusted-false discovery rate p < 0.05) from 2059 ion features by comparisons of diabetics with and without CVDs. Random forest identified methylglutarylcarnitine and lysoPC (18:0) as the metabolic markers (mean decrease gini >1.0) for non-significant CVDs (nos-CVDs) versus normal coronary artery (NCA), 1,3-Octadiene and 3-Octanone for acute coronary syndrome (ACS) versus nos-CVDs, and lysoPC (18:0) for acute coronary syndrome versus normal coronary artery. For risk prediction, the metabolic marker-assisted models provided areas under the curve of 0.962-0.979 by ROC (0.576-0.779 for the base models), and c-indices of 0.8477-0.9537 by nomogram analysis (0.1514-0.5196 for the base models). Decision curve analysis (DCA) showed that the models produced greater benefits throughout a wide range of risk probabilities compared with the base model. Conclusion: Metabolic biomarker-assisted model remarkably improved risk prediction of cardiovascular disease in diabetics (>90%).

Comparison of prognosis between coronary computed tomography angiography versus invasive coronary angiography for stable coronary artery disease: a systematic review and meta-analysis.

Background: The impact of using invasive coronary angiography (ICA) or coronary computed tomography angiography (CCTA) as an initial examination on the incidence of major adverse cardiovascular events (MACEs) in patients with stable coronary artery disease and the occurrence of major operation-related complications is uncertain. Objective: This study aimed to explore the effects of ICA vs. CCTA on MACEs, all-cause death, and major operation-related complications. Methods: A systematic search of electronic databases (PubMed and Embase) was conducted for randomized controlled trials and observational studies comparing MACEs between ICA and CCTA from January 2012 to May 2022. The primary outcome measure was analyzed using a random-effects model as a pooled odds ratio (OR). The main observations were MACEs, all-cause death, and major operation-related complications. Results: A total of six studies, comprising 26,548 patients, met the inclusion criteria (ICA n = 8,472; CCTA n = 18,076). There were statistically significant differences between ICA and CCTA for MACE [OR 1.37; 95% confidence interval (CI), 1.06-1.77; p = 0.02], all-cause death (OR 1.56; 95% CI, 1.38-1.78; p < 0.00001), and major operation-related complications (OR 2.10; 95% CI, 1.23-3.61; p = 0.007) among patients with stable coronary artery disease. Subgroup analysis demonstrated statistically significant results in the impact of ICA or CCTA on MACEs according to the length of follow-up. Compared to CCTA, ICA was related to a higher incidence of MACEs in the subgroup with a short follow-up (≤3 years) (OR 1.74; 95% CI, 1.54-1.96; p < 0.00001). Conclusions: Among patients with stable coronary artery disease, an initial examination with ICA was significantly associated with the risk of MACEs, all-cause death, and major procedure-related complications compared to CCTA in this meta-analysis.

Myocardin-related transcription factor A, regulated by serum response factor, contributes to diabetic cardiomyopathy in mice.

AIMS: Diabetic cardiomyopathy is a significant contributor to the global pandemic of heart failure. In the present study we investigated the involvement of myocardin-related transcription factor A (MRTF-A), a transcriptional regulator, in this process. MATERIALS AND METHODS: Diabetic cardiomyopathy was induced in mice by feeding with a high-fat diet (HFD) or streptozotocin (STZ) injection. KEY FINDINGS: We report that MRTF-A was up-regulated in the hearts of mice with diabetic cardiomyopathy. MRTF-A expression was also up-regulated by treatment with palmitate in cultured cardiomyocytes in vitro. Mechanistically, serum response factor (SRF) bound to the MRTF-A gene promoter and activated MRTF-A transcription in response to pro-diabetic stimuli. Knockdown of SRF abrogated MRTF-A induction in cardiomyocytes treated with palmitate. When cardiomyocytes conditional MRTF-A knockout mice (MRTF-A CKO) and wild type (WT) mice were placed on an HFD to induce diabetic cardiomyopathy, it was found that the CKO mice and the WT mice displayed comparable metabolic parameters including body weight, blood insulin concentration, blood cholesterol concentration, and glucose tolerance. However, both systolic and diastolic cardiac function were exacerbated by MRTF-A deletion in the heart. SIGNIFICANCE: These data suggest that MRTF-A up-regulation might serve as an important compensatory mechanism to safeguard the deterioration of cardiac function during diabetic cardiomyopathy.

The Role of Gynostemma pentaphyllum in Regulating Hyperlipidemia.

Developing effective and safe lipid-lowering drugs is highly urgent. This study aims to investigate the effectiveness and underlying mechanisms of Gynostemma pentaphyllum (GP) in the treatment of hyperlipidemia. First, a meta-analysis was performed to determine the lipid-lowering effects of GP. Thereafter, hyperlipidemia was induced in mice using a high-fat diet (HFD) and was subsequently treated with Gynostemma pentaphyllum extract (GPE) by daily gavage for 12 weeks. The body weight, tissue weight, blood lipid level, and liver lipid level were determined. Additionally, mouse serum samples were subjected to metabolomic profiling and feces were collected at different time points for metagenomic analysis via 16S rDNA sequencing. A total of 15 out of 1520 studies were retrieved from six databases. The pooled results of the meta-analysis showed that GP effectively reduced triglyceride levels and increased high-density lipoprotein cholesterol (both [Formula: see text]). Animal experiments revealed that GPE administration significantly reduced body weight, ameliorated high blood lipid levels, limited lipid deposition, and improved insulin resistance. Furthermore, GPE treatment markedly changed the intestinal microbiota structure and constitution of tryptophan metabolites. In conclusion, our results confirm the lipid-lowering effect of GP, which may be partly attributable to regulation of the intestinal microbiota and tryptophan metabolism.

Comprehensive evaluation of time-varied outcomes for invasive and conservative strategies in patients with NSTE-ACS: a meta-analysis of randomized controlled trials.

Background: Results from randomized controlled trials (RCTs) and meta-analyses comparing invasive and conservative strategies in patients with non-ST-elevation acute coronary syndrome (NSTE-ACS) are highly debatable. We systematically evaluate the efficacy of invasive and conservative strategies in NSTE-ACS based on time-varied outcomes. Methods: The RCTs for the invasive versus conservative strategies were identified by searching PubMed, Cochrane Central Register of Controlled Trials, Embase, and ClinicalTrials.gov. Trial data for studies with a minimum follow-up time of 30 days were included. We categorized the follow-up time into six varied periods, namely, ≤6 months, 1 year, 2 years, 3 years, 5 years, and ≥10 years. The time-varied outcomes were major adverse cardiovascular event (MACE), death, myocardial infarction (MI), rehospitalization, cardiovascular death, bleeding, in-hospital death, and in-hospital bleeding. Risk ratios (RRs) and 95% confidence intervals (Cis) were calculated. The random effects model was used. Results: This meta-analysis included 30 articles of 17 RCTs involving 12,331 participants. We found that the invasive strategy did not provide appreciable benefits for NSTE-ACS in terms of MACE, death, and cardiovascular death at all time points compared with the conservative strategy. Although the risk of MI was reduced within 6 months (RR 0.80, 95% CI 0.68-0.94) for the invasive strategy, no significant differences were observed in other periods. The invasive strategy reduced the rehospitalization rate within 6 months (RR 0.69, 95% CI 0.52-0.90), 1 year (RR 0.73, 95% CI 0.63-0.86), and 2 years (RR 0.77, 95% CI 0.60-1.00). Of note, an increased risk of bleeding (RR 1.80, 95% CI 1.28-2.54) and in-hospital bleeding (RR 2.17, 95% CI 1.52-3.10) was observed for the invasive strategy within 6 months. In subgroups stratified by high-risk features, the invasive strategy decreased MACE for patients aged ≥65 years within 6 months (RR 0.68, 95% CI 0.58-0.78) and 1 year (RR 0.75, 95% CI 0.62-0.91) and showed benefits for men within 6 months (RR 0.71, 95% CI 0.55-0.92). In other subgroups stratified according to diabetes, ST-segment deviation, and troponin levels, no significant differences were observed between the two strategies. Conclusions: An invasive strategy is superior to a conservative strategy in reducing early events for MI and rehospitalizations, but the invasive strategy did not improve the prognosis in long-term outcomes for patients with NSTE-ACS. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021289579, identifier PROSPERO 2021 CRD42021289579.

Effects of coenzyme Q10 supplementation on statin-induced myopathy: a meta-analysis of randomized controlled trials.

BACKGROUND: Statins can trigger a series of muscle-related adverse events, commonly referred to collectively as statin-induced myopathy. Although coenzyme Q10 (CoQ10) is widely used as a supplement in statin therapy, there is little clinical evidence for this practice. AIM: This study aims to assess the effect of adding CoQ10 on statin-induced myopathy. METHODS: Searching the PubMed, EMBASE, and the Cochrane Library databases to identify randomized controlled trials investigating the effect of adding CoQ10 on creatine kinase (CK) activity and degree of muscle pain as two indicators of statin-induced myopathy. Two reviewers will independently extract data from the included articles. RESULTS: Study screening included a randomized controlled trial of oral CoQ10 versus placebo in patients with statin-induced myopathy. We had a total of 8 studies in which 472 patients were treated with statins: 6 studies with 281 participants assessed the impact of adding CoQ10 on CK activity, and 4 studies with 220 participants were included to evaluate the impacts of CoQ10 addition on muscle pain. Compared with the controls, CK activity increased after adding CoQ10, but the change was not significant (mean difference, 3.29 U/L; 95% CI, - 29.58 to 36.17 U/L; P = 0.84). Similarly, the meta-analysis did not benefit CoQ10 over placebo in improving muscle pain (standardized mean difference, - 0.59; 95% CI, - 1.54 to 0.36; P = 0.22). CONCLUSION: The outcomes of this meta-analysis of existing randomized controlled trials showed that supplementation with CoQ10 did not have any significant benefit in improving statin-induced myopathy.

Di-n-butyl phthalate regulates vascular smooth muscle cells phenotypic switching by MiR-139-5p-MYOCD pathways.

Di-n-butyl phthalate (DBP) is ubiquitous in environment and has been detected in almost all human bodies. Few data could be found about the effects of DBP on cardiovascular system, though its reproductive toxicities have been studied extensively. This study aimed to explore effects of DBP on phenotypic switching of vascular smooth muscle cells (VSMCs), an essential step during the formation of atherosclerosis (AS). A7r5 cells were employed and exposed to various levels of DBP (10-9, 10-8, 10-7, 10-6, and 10-5 M) or DMSO as control. CCK-8 assay was used to detect the effects of DBP on cell viability. Expressions of mRNA/miRNAs and proteins were measured by qRT-PCR and western blotting, respectively. Bioinformatic analysis and dual-luciferase reporter assay were used to analyze the combination between miR-139-5p and Myocardin (MYOCD). Results revealed that DBP at 10-7 M prompted phenotypic switching from contractile to synthetic of VSMCs by inhibiting contractile VSMCs marker genes via suppressing the expression of MYOCD. Moreover, miR-139c-5p directly targeted MYOCD 3'UTR and modulated MYOCD expression. Besides, DBP inhibited the expression of MYOCD and VSMCs marker genes by upregulating miR-139-5p. Collectively, these data suggested that DBP could promote the phenotypic switching from contractile to synthetic of VSMCs in A7r5 cells through miR-139-5p-MYOCD.

Epigenetic repression of THBD transcription by BRG1 contributes to deep vein thrombosis.

BACKGROUND: Deep vein thrombosis (DVT) with its major complication, pulmonary embolism, is a global health problem. Endothelial dysfunction is involved in the pathogenesis of DVT. We have previously demonstrated that endothelial specific deletion of Brahma-related gene 1 (BRG1) ameliorates atherosclerosis and aneurysm in animal models. Whether endothelial BRG1 contributes to DVT development remains undetermined. METHODS: DVT was induced in mice by ligation of inferior vena cava. Deletion of BRG1 in endothelial cells was achieved by crossing the Cdh5-ERT-Cre mice with the Brg1loxp/loxp mice. RESULTS: Here we report that compared to the wild type mice, BRG1 conditional knockout (CKO) mice displayed substantially decreased DVT susceptibility characterized by decreased weight and size of thrombus and reduced immune infiltration. In endothelial cells, thrombomodulin (THBD) expression was significantly decreased by TNF-α stimulation, while BRG1 knockdown or inhibition recovered THBD expression. Further analysis revealed that BRG1 deficiency decreased the CpG methylation levels of the THBD promoter induced by TNF-α. Mechanistically, BRG1 directly upregulated DNMT1 expression after TNF-α treatment in endothelial cells. More importantly, administration of a small-molecule BRG1 inhibitor PFI-3 displayed potent preventive and therapeutic potentials in the DVT model. CONCLUSIONS: Our findings implicate BRG1 as an important regulator of DVT pathogenesis likely through epigenetic regulation of THBD expression in endothelial cells and provide translational proof-of-concept for targeting BRG1 in DVT intervention.

Subclavian steal syndrome associated with Sjogren's syndrome: A case report.

BACKGROUND: Subclavian steal syndrome (SSS) caused by Sjogren's syndrome is rare, especially for elderly patients with risk factors for atherosclerosis. The current report presents the uncommon etiology and treatment of SSS, aiming to improve doctor's clinical experience. CASE SUMMARY: A 69-year-old man was diagnosed with hypertension and acute cerebral infarction presenting with left upper limb weakness and pain even gradually aggravating to left limb hemiplegia 30 years ago. He was managed with antihypertensive and antithrombotic therapy; however, his condition was recurrent, and he never had any further examination. It was found that the difference of the bilateral upper arm systolic pressure was over 20 mmHg, and Doppler examination showed that the blood flow of the left vertebral artery was reversed, suggesting SSS. Further tests revealed a benign lymphoepithelial lesion in salivary gland tissue, confirming the Sjogren's syndrome. CONCLUSION: The patient was found to have hypertension when he was 33 years old, and the blood pressure of both sides was asymmetric, which was ignored. The patient's symptoms of dizziness and upper limb weakness were misdiagnosed as general cerebral infarction. It is necessary to test the aorta computed tomography angiography to prove secondary hypertension factors such as Sjogren's syndrome.

Antihypertensive Drug Use and the Risk of Depression: A Systematic Review and Network Meta-analysis.

Background: Although numerous cohort studies have reported an association between antihypertensives use and depression, the exact effect of antihypertensives on depression remains unclear. Objective: To clarify the association between antihypertensives use and risk of depression. Methods: We retrieved relevant literature using PubMed database until August 30, 2021. Four main classes of antihypertensives, thus, angiotensin antagonists, beta blockers, calcium channel blockers and diuretics were studied. The incidence of depression was pooled based on a single drug category. Network meta-analyses were conducted to comprehensively assess the effects of the four classes of antihypertensives on the risk of depression. Results: A total of nine out of 9,557 studies involving 414,873 subjects were retrieved. The pooled results showed a positive association between the use of calcium channel blockers and symptoms of depression [odds ratio (OR): 1.09, 95% confidence interval (CI):1.06-1.13], while use of the angiotensin antagonists, beta blockers and diuretics was not associated with risk of depression. Subgroup analysis suggested a significant relationship between beta blockers usage and risk of depression in cohort studies (OR:1.21, 95% CI: 1.16-1.26). The results of network meta-analysis indicated that all other three classes of drugs increased the risk of depression: angiotensin antagonists (OR: 1.30, 95% CI: 1.04-1.63), beta blockers (OR: 1.53, 95% CI: 1.22-1.91), and calcium channel blockers (OR: 1.40, 95% CI: 1.12-1.75), compared with diuretics. Conclusion: In conclusion, our results indicate that the use of angiotensin antagonists, beta blockers and calcium channel blockers are potential risk factors of depression.