Ticagrelor alone versus ticagrelor plus aspirin from month 1 to month 12 after percutaneous coronary intervention in patients with acute coronary syndromes (ULTIMATE-DAPT): a randomised, placebo-controlled, double-blind clinical trial.

BACKGROUND: Following percutaneous coronary intervention with stent placement to treat acute coronary syndromes, international clinical guidelines generally recommend dual antiplatelet therapy with aspirin plus a P2Y12 receptor inhibitor for 12 months to prevent myocardial infarction and stent thrombosis. However, data on single antiplatelet therapy with a potent P2Y12 inhibitor earlier than 12 months after percutaneous coronary intervention for patients with an acute coronary syndrome are scarce. The aim of this trial was to assess whether the use of ticagrelor alone, compared with ticagrelor plus aspirin, could reduce the incidence of clinically relevant bleeding events without an accompanying increase in major adverse cardiovascular or cerebrovascular events (MACCE). METHODS: In this randomised, placebo-controlled, double-blind clinical trial, patients aged 18 years or older with an acute coronary syndrome who completed the IVUS-ACS study and who had no major ischaemic or bleeding events after 1-month treatment with dual antiplatelet therapy were randomly assigned to receive oral ticagrelor (90 mg twice daily) plus oral aspirin (100 mg once daily) or oral ticagrelor (90 mg twice daily) plus a matching oral placebo, beginning 1 month and ending at 12 months after percutaneous coronary intervention (11 months in total). Recruitment took place at 58 centres in China, Italy, Pakistan, and the UK. Patients were required to remain event-free for 1 month on dual antiplatelet therapy following percutaneous coronary intervention with contemporary drug-eluting stents. Randomisation was done using a web-based system, stratified by acute coronary syndrome type, diabetes, IVUS-ACS randomisation, and site, using dynamic minimisation. The primary superiority endpoint was clinically relevant bleeding (Bleeding Academic Research Consortium [known as BARC] types 2, 3, or 5). The primary non-inferiority endpoint was MACCE (defined as the composite of cardiac death, myocardial infarction, ischaemic stroke, definite stent thrombosis, or clinically driven target vessel revascularisation), with an expected event rate of 6·2% in the ticagrelor plus aspirin group and an absolute non-inferiority margin of 2·5 percentage points between 1 month and 12 months after percutaneous coronary intervention. The two co-primary endpoints were tested sequentially; the primary superiority endpoint had to be met for hypothesis testing of the MACCE outcome to proceed. All principal analyses were assessed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT03971500, and is completed. FINDINGS: Between Sept 21, 2019, and Oct 27, 2022, 3400 (97·0%) of the 3505 participants in the IVUS-ACS study were randomly assigned (1700 patients to ticagrelor plus aspirin and 1700 patients to ticagrelor plus placebo). 12-month follow-up was completed by 3399 (>99·9%) patients. Between month 1 and month 12 after percutaneous coronary intervention, clinically relevant bleeding occurred in 35 patients (2·1%) in the ticagrelor plus placebo group and in 78 patients (4·6%) in the ticagrelor plus aspirin group (hazard ratio [HR] 0·45 [95% CI 0·30 to 0·66]; p<0·0001). MACCE occurred in 61 patients (3·6%) in the ticagrelor plus placebo group and in 63 patients (3·7%) in the ticagrelor plus aspirin group (absolute difference -0·1% [95% CI -1·4% to 1·2%]; HR 0·98 [95% CI 0·69 to 1·39]; pnon-inferiority<0·0001, psuperiority=0·89). INTERPRETATION: In patients with an acute coronary syndrome who had percutaneous coronary intervention with contemporary drug-eluting stents and remained event-free for 1 month on dual antiplatelet therapy, treatment with ticagrelor alone between month 1 and month 12 after the intervention resulted in a lower rate of clinically relevant bleeding and a similar rate of MACCE compared with ticagrelor plus aspirin. Along with the results from previous studies, these findings show that most patients in this population can benefit from superior clinical outcomes with aspirin discontinuation and maintenance on ticagrelor monotherapy after 1 month of dual antiplatelet therapy. FUNDING: The Chinese Society of Cardiology, the National Natural Scientific Foundation of China, and the Jiangsu Provincial & Nanjing Municipal Clinical Trial Project. TRANSLATION: For the Mandarin translation of the abstract see Supplementary Materials section.

Proprotein convertase subtilisin/kexin 9 inhibitor downregulates microRNA-130a-3p expression in hepatocytes to alleviates atherosclerosis progression.

Proprotein convertase subtilisin/kexin 9 (PCSK9) inhibitors have been shown to regulate lipid metabolism and reduce the risk of cardiovascular events. This study explores the effect and potential mechanism of PCSK9 inhibitors on lipid metabolism and coronary atherosclerosis. HepG2 cells were incubated with PCSK9 inhibitor. ApoE-/- mice were fed with a high fat to construct an atherosclerosis model, and then treated with PCSK9 inhibitor (8 mg/kg for 8 w). PCSK9 inhibitor downregulated microRNA (miRNA)-130a-3p expression in a dose-dependent manner. And, miR-130a-3p could bind directly to the 3' untranslated region (3'-UTR) region of LDLR to down-regulate LDLR expression in HepG2 cells, as confirmed by the luciferase reporter gene assay. In addition, miR-130a-3p overexpression significantly attenuated the promoting effect of PCSK9 inhibitor on LDLR and DiI-LDL uptake in HepG2 cells. More importantly, in vivo experiments confirmed that PCSK9 inhibitor could significantly inhibit miR-130a-3p levels and promote LDLR expression in liver tissues, thus regulating serum lipid profile and alleviating the progression of coronary atherosclerosis. PCSK9 inhibitor could moderately improve coronary atherosclerosis by regulating miR-130a-3p/LDLR axis, providing an exploitable strategy for the treatment of coronary atherosclerosis.

[miR-509-3p promotes oxidized low-density lipoprotein-induced apoptosis in mouse aortic endothelial cells].

OBJECTIVE: To investigate the effect of microRNA-509-3p (miR-509-3p) on the apoptosis of atherosclerotic vascular endothelial cells. METHODS: Mouse aortic endothelial cells (MAECs) were divided into normal control group, oxidized low-density lipoprotein (ox-LDL) group, miR-509-3p overexpression group, miR-509-3p overexpression control group, miR-509-3p inhibitor + ox-LDL group, and miR-509-3p inhibitor control + ox-LDL group. MAEC were induced with 100 mg/L ox-LDL for 24 hours, and then transfected with miR-509-3p overexpression/inhibitor and corresponding control for 48 hours. The miR-509-3p expression in MAECs exposed to ox-LDL was detected using real-time fluorescence quantitative polymerase chain reaction (RT-qPCR). Flow cytometry was used to detect the level of apoptosis, and cell counting kit (CCK-8) was used to detect the proliferation activity of MAECs. The direct gene targets of miR-509-3p were predicted using bioinformatics analyses and confirmed using a dual luciferase reporter assay. The expression of Bcl-2 mRNA and protein was detected by RT-qPCR and Western blotting, respectively. RESULTS: Compared with the normal control group, miR-509-3p was significantly upregulated in ox-LDL-stimulated MAECs (1.68±0.85 vs. 1.00±0.30, t = 2.398, P < 0.05). After transfection of MAECs with miR-509-3p overexpression, the luciferase activity of the BCL2 3'UTR WT reporter gene was significantly lower than that of miR-509-3p overexpression control group (0.83±0.06 vs. 1.00±0.07, t = 4.531, P = 0.001). The luciferase activity of the BCL2 3'-UTR mutant (MUT) reporter gene was not significantly different from that of miR-509-3p overexpression control group (0.94±0.05 vs. 1.00±0.08, t = 1.414, P = 0.188). Compared with the normal control group and miR-509-3p mimics control group, the cell proliferation activity was decreased [(0.60±0.06)% vs. (1.00±0.09)%, (0.89±0.04)%, both P < 0.01], the percentage of apoptotic cells were increased [(23.46±2.02)% vs. (7.66±1.52)%, (10.40±0.78)%, both P < 0.05], and the mRNA and protein expression of Bcl-2 were significantly downregulated (Bcl-2 mRNA: 0.52±0.13 vs. 1.00±0.36, 1.10±0.19, Bcl-2 protein: 0.42±0.07 vs. 1.00±0.11, 0.93±0.10, both P < 0.01) in miR-509-3p overexpression group. Compared with the ox-LDL group, inhibition of miR-509-3p expression could increase the proliferation activity of MAECs induced by ox-LDL [(0.64±0.35)% vs. (0.34±0.20%)%, P < 0.05], and reduce the apoptosis rate [(13.59±2.22)% vs. (29.84±5.19)%, P < 0.01], and up-regulated the expression of Bcl-2 mRNA and protein in MAECs induced by ox-LDL (Bcl-2 mRNA relative expression: 0.82±0.09 vs. 0.52±0.10, Bcl-2 protein relative expression: 0.83±0.17 vs. 0.40±0.07, both P < 0.05). CONCLUSIONS: Bcl-2 was one of the target genes of miR-509-3p. miR-509-3p can reduce the proliferation activity of endothelial cells, reduce the expression of Bcl-2, and promote cell apoptosis, thereby promoting the occurrence and development of atherosclerosis. Inhibition of miR-509-3p expression may be a potential therapeutic target for atherosclerosis.

GLUT1 Mediates the Metabolic Reprogramming and Inflammation of CCR2$

BACKGROUND: Macrophages expressing CC chemokine receptor 2 (CCR2) possess characteristics and performance akin to M1 polarized macrophages, which promote inflammation. Advanced heart failure (HF) patients with higher abundance of CCR2+ macrophages are more likely to experience adverse remodeling. The precise mechanism of CCR2+ macrophages in how they affect the progression of dilated cardiomyopathy remains unknown. METHODS: Cardiac biopsy samples from dilated cardiomyopathy patients (DCM) were used for immunohistochemistry and immunofluorescence staining. PCR is employed to identify the IL-1ß, IL-6, TNF-α, TGF-ß, MMP2, MMP9, PKM1, PKM1, GLUT1, GLUT2, GLUT3, GLUT4, PDK1, PFKFB3, PFK1 and HK2 mRNA expression of CCR2+ monocytes/macrophages from the peripheral blood of DCM patients. Seahorse was used to evaluate the oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) of CCR2+ monocytes/macrophages. 2-DG was used to simulate a lack of glucose. Lentivirus containing GLUT1 inhibitory sequence was used to knockdown GLUT1 gene expression of CCR2+ monocytes/macrophages. Western Blot and immunofluorescence staining was used to evaluate the expression of NLRP3. RESULTS: Immunostaining results of cardiac biopsy tissue from dilated cardiomyopathy (DCM) patients demonstrated that the progression to HF was associated with an increase in the number of CCR2+ macrophages. PCR results demonstrated that CCR2 monocytes and macrophages derived from the blood of DCM patients expressed elevated levels of inflammatory factors and up regulation of glycolysis related genes. In addition, OCR and glucose uptake experiments confirmed that increased glucose uptake of these cells was associated with greater inflammation and correlated with a worsening of cardiac function. limiting the glucose supply to CCR2+ monocytes and macrophages, or suppressing the activity of glucose transporter 1 (GLUT1) could reduce inflammation levels. CONCLUSIONS: These results suggest that CCR2+ monocytes and macrophages rely on metabolic reprogramming to trigger inflammatory response and contribute to myocardial injury and the progression of DCM.

The efficacy and safety of quantitative flow ratio-guided complete revascularization in patients with ST-segment elevation myocardial infarction and multivessel disease: A pilot randomized controlled trial.

BACKGROUND: In patients with ST-segment elevation myocardial infarction (STEMI) and multivessel disease (MVD), the treatment strategy for non-infarct-related artery (non-IRA) remains controversial. Quantitative flow ratio (QFR) is a new angiography-based physiological assessment index. However, there is little evidence on the practical clinical application of QFR. METHODS: Two hundred and twenty-nine patients with STEMI and MVD were recruited for this study. Patients were randomly assigned to either receive QFR-guided complete revascularization (QFR-G-CR) of non-IRA or receive no further invasive treatment. The primary (1°) endpoint analyzed included death due to all causes, non-fatal myocardial infarction (MI), and ischemia-induced revascularization at 12 months post-surgery. Secondary (2°) endpoints included cardiovascular death, unstable angina, stent thrombosis, New York Heart Association (NYHA) class IV heart failure, and stroke at 1 year post surgery. Massive bleeding and contrast-associated acute kidney injury (CAKI) were used as safety endpoints. RESULTS: Around the 12 month follow up, the 1o outcome was recorded in 11/115 patients (9.6%) in the QFR-G-CR population, relative to 23/114 patients (20.1%) in the IRA-only PCI population (hazard ratio [HR]: 0.45; 95% confidence interval [CI]: 0.22-0.92; p = 0.025). Unstable angina in 6 (5.2%) and 16 (14.0%) patients (HR: 0.36; 95% CI: 0.14-0.92; p = 0.026), respectively. No marked alterations were found in the massive bleeding and CAKI categories. CONCLUSIONS: In conclusion, STEMI and MVD patients can benefit from QFR-G-CR of non-IRA lesions in the initial stages of acute MI. This can help reduce incidences of major adverse cardiovascular events and unstable angina, relative to IRA treatment only. Chinese Clinical Trial Registration number: ChiCTR2100044120.

Culprit vessel vs. immediate multivessel vs. out-of-hospital staged intervention for patients with non-ST-segment elevation myocardial infarction and multivessel disease.

Background and aims: The optimal interventional strategy remains undetermined in hemodynamically stable patients with NSTEMI and MVD. This study aimed to examine clinical prognosis among culprit vessel, immediate multivessel, and staged percutaneous coronary intervention (PCI) in patients with NSTEMI and MVD. Methods: This retrospective, observational, single-center study included 943 hemodynamically stable patients with NSTEMI and MVD who had undergone successful drug-eluting stent (DES) implantation from January 2014 to December 2019. Patients were categorized into culprit lesion-only PCI (CL-PCI), immediate multivessel PCI (MV-PCI), and out-of-hospital staged MV-PCI according to PCI strategy. The primary outcome was the composite of major adverse cardiac events (MACEs), including all-cause death, myocardial infarction (MI), or unplanned repeat revascularization. The secondary outcomes were all-cause death, cardiac death, MI, and unplanned repeat revascularization. Results: Over a median follow-up of 59 months, immediate MV-PCI was associated with a lower risk of all-cause death than CL-PCI (HR: 0.591, 95%CI: 0.364-0.960, P = 0.034). Out-of-hospital staged MV-PCI was associated with a reduced risk of MACE (HR: 0.448, 95%CI: 0.314-0.638, P < 0.001) and all-cause death (HR: 0.326, 95%CI: 0.183-0.584, P < 0.001) compared with CL-PCI. The above results were accordant after multivariate COX analysis and propensity score matching. MACE (HR: 0.560, 95%CI: 0.385-0.813, P = 0.002) and repeat revascularization (HR: 0.627, 95%CI: 0.400-0.982, P = 0.041) were significantly less likely to occur with out-of-hospital MV-PCI rather than immediate MV-PCI. However, the incidences of primary and secondary outcomes were comparable between immediate and staged PCI after confounder adjustment using multivariate regression and propensity score matching analysis. For subgroup analyses stratified by synergy between PCI with taxus and cardiac surgery score, staged MV-PCI was found to lower the risk of MACE compared with immediate MV-PCI in patients with more complex coronary disease. Conclusion: Hemodynamically stable patients with NSTEMI and MVD benefited from the strategy of MV-PCI. Patients with complex coronary anatomy treated with out-of-hospital staged MV-PCI rather than immediate MV-PCI had lower risks of MACE. These need to be confirmed in the future randomized study.

The abnormal level and prognostic potency of multiple inflammatory cytokines in PCI-treated STEMI patients.

OBJECTIVE: Inflammatory cytokines modulate atherogenesis and plaque rupture to involve in ST-segment elevation myocardial infarction (STEMI) progression. The present study determined eight inflammatory cytokine levels in 212 percutaneous coronary intervention (PCI)-treated STEMI patients, aiming to comprehensively investigate their potency in estimating major adverse cardiac event (MACE) risk. METHODS: Serum tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, IL-6, IL-8, IL-10, IL-17A, vascular cell adhesion molecule-1 (VCAM-1), and intercellular adhesion molecule-1 (ICAM-1) of 212 PCI-treated STEMI patients and 30 angina pectoris patients were determined using enzyme-linked immunosorbent assay. RESULTS: TNF-α (52.5 (43.9-62.6) pg/ml versus 46.4 (39.0-59.1) pg/ml, p = 0.031), IL-8 (61.6 (49.6-81.7) pg/ml versus 46.7 (32.5-63.1) pg/ml, p = 0.001), IL-17A (57.4 (45.7-77.3) pg/ml versus 43.2 (34.2-64.6) pg/ml, p = 0.001), and VCAM-1 (593.6 (503.4-811.4) ng/ml versus 493.8 (390.3-653.7) ng/ml, p = 0.004) levels were elevated in STEMI patients compared to angina pectoris patients, while IL-1ß (p = 0.069), IL-6 (p = 0.110), IL-10 (p = 0.052), and ICAM-1 (p = 0.069) were of no difference. Moreover, both IL-17A high (vs. low) (p = 0.026) and VCAM-1 high (vs. low) (p = 0.012) were linked with increased cumulative MACE rate. The multivariable Cox's analysis exhibited that IL-17A high (vs. low) (p = 0.034) and VCAM-1 high (vs. low) (p = 0.014) were independently associated with increased cumulative MACE risk. Additionally, age, diabetes mellitus, C-reactive protein, multivessel disease, stent length, and stent type were also independent factors for cumulative MACE risk. CONCLUSION: IL-17A and VCAM-1 high level independently correlate with elevated MACE risk in STEMI patients, implying its potency in identifying patients with poor prognoses.

Correlation of triglyceride-glucose index and dyslipidaemia with premature coronary heart diseases and multivessel disease: a cross-sectional study in Tianjin, China.

OBJECTIVES: Over the past decade, the incidence and global burden of coronary heart disease (CHD) have increased in the young population. We aimed to identify patient characteristics and risk factors for premature CHD, including single-vessel disease (SVD) and multivessel disease (MVD). DESIGN: Retrospective, cross-sectional study. SETTING: Demographic and clinical data of patients with CHD were collected from the patient medical records of a tertiary hospital in Tianjin, China, between 2014 and 2017. PARTICIPANTS: A total of 2846 patients were enrolled in the study. PRIMARY AND SECONDARY OUTCOME MEASURES: Premature CHD, which is the primary outcome, was defined as men<45 years and women<55 years. MVD, which is the secondary outcome, was defined as at least two vessels with ≥50% stenosis. Logistic regression models were applied to analyse the characteristics and risk factors of premature CHD and MVD. RESULTS: Most of the characteristics between patients with premature and mature CHD were not statistically significant. A significantly higher dyslipidaemia prevalence was found in female patients with premature CHD (OR=1.412, 95% CI: 1.029 to 1.936). In the crude model, instead of premature SVD, premature (OR=2.065, 95% CI: 1.426 to 2.991) or mature (OR=1.837, 95% CI: 1.104 to 3.056) MVD was more common in female patients with the highest triglyceride-glucose (TyG) index quartile than those with the lowest TyG index quartile. In male patients, the same trend was observed for mature MVD (OR=2.272, 95% CI: 1.312 to 3.937). The significance of the TyG index was not revealed in multivariate analyses; however, hypertension, diabetes, obesity, smoking, old myocardial infarction and lipoprotein (a) showed a positive association with MVD. CONCLUSIONS: Dyslipidaemia should be considered as an effective factor for the prediction and prevention of premature CHD in women. The TyG index can be a simple auxiliary indicator that can be used in population-based cardiovascular disease screening for the early identification of vascular disease severity.

Phthalate promotes atherosclerosis through interacting with long-non coding RNA and induces macrophage foam cell formation and vascular smooth muscle damage.

BACKGROUND: Phthalates are commonly used in variety of plastic products. Previously it has been revealed that di (2-ethylhexyl) phthalate (DEHP), as the most common member of the class of phthalates, may disturb cholesterol homeostasis and deregulate the inflammatory response, and leading to accelerate the atherosclerosis process. In this regard, the aim of the current study is to explore the underlying mechanism of DEHP-induced atherosclerosis through the increasing of foam cell formation and Vascular Smooth Muscle Cells (VSMCs) damage via the interaction of long-non coding RNA (GAS5) and miR-145-5p. METHODS: ApoE-/- mice were used to evaluate the in vivo study. RAW264.7 and VSMCs were used to evaluate the effect of DEHP on formation of foam cell, cell proliferation, and cell damage in vitro. Animals were treated with DEHP (5% w/w of food) orally and cells were treated with medium containing of 100 µM DEHP; qRT-PCR, Western blotting, flowcytometry, IHC, oil red O, BODIPY, and autophagic vacuoles assay were used to evaluate the effect of DEHP on formation of atherosclerosis. RESULTS: DEHP significantly accelerated the formation of atherosclerosis in mice and alter the lipid profile in mice. In addition, after treating VSMCs with DEHP, GAS5 was significantly up-regulated and miR-145-5p was down-regulated. In VSMCs treated with DEHP, we observed that GAS5 could be used as the competing endogenous RNA (ceRNA) of miR-145-5p to regulate the proliferation and apoptosis of VSMCs; and the expression of GAS5 was correlated with the expression of miR-145-5p. DEHP increased the ox-LDL uptake by macrophage and increasing the formation of foam cells. Besides, GAS5 knocking down reversed the effect of DEHP on foam cell formation and ox-LDL uptake. CONCLUSION: DEHP could accelerate the atherosclerosis process through increasing VSMCs damage and formation of macrophage foam cell by increasing lipid uptake though down regulating lncRNA GAS5 and altering in regulation of miR-145-5p.

The Effect of Osteoprotectin (OPG)/Receptor Activator of Nuclear Factor-κB Ligand (RANKL)/Receptor Activator of Nuclear Factor-κB (RANK) Gene Methylation on Aortic Valve Calcified.

To evaluate the effect of the methylation of osteoprotectin (OPG)/receptor activator of nuclear factor-κB ligand (RANKL)/receptor activator of nuclear factor-κB (RANK) pathway on aortic valve calcification, the aortic valve tissue was collected from 38 aortic stenosis (AS) patients who underwent valve replacement. OPG and RANKL gene methylation, RT-PCR, and ELISA were performed. Hematoxylin-eosin staining (HE), alizarin red-S staining, and immunohistochemically staining of OPG, RANKL, and CD68 were simultaneously performed. The patients were divided into noncalcified group (n = 21) and calcified group (n = 17). The methylation rate of OPG gene in noncalcified group was higher than that in calcified group (P = 0.027). The methylation degree of RANKL gene was generally lower, but the noncalcified group was still higher than that in the calcified group (P = 0.025). RT-PCR analysis showed that the mRNA expression of OPG and RANKL was higher in calcified group than in noncalcified group (P = 0.007 and P = 0.036, respectively), and the mRNA expression was negatively correlated with the gene methylation rate. The protein expression of OPG and RANKL was detected by immunohistochemistry and ELISA, showing significantly increased in calcified group (P = 0.004 and P = 0.042, respectively). Soluble RANKL (sRANKL) in CD68-positive group was significantly different from that in negative group (0.1243 ± 0.0321 vs 0.0984 ± 0.0218 pg/mL, P = 0.007). There was no significant difference in OPG value between positive group (1.9411 ± 0.4554 ng/mL) and negative group (1.8422 ± 0.5218 ng/mL, P = 0.587). In conclusion, the degree of methylation of OPG and RANKL genes may play an important role in regulating valve calcification in AS patients.

Risk factors for cardiac rupture after acute ST-segment elevation myocardial infarction during the percutaneous coronary intervention era: a retrospective case-control study.

Background: In percutaneous coronary intervention (PCI) era, more clinically valuable risk factors are still needed to determine the occurrence of cardiac rupture (CR). Therefore, we aimed to provide evidence for the early identification of CR in ST-segment elevation myocardial infarction (STEMI). Methods: A total of 22,016 consecutive patients with STEMI admitted to Cangzhou Central Hospital and Tianjin Chest Hospital from January 2013 to July 2021 were retrospectively included, among which 195 patients with CR were included as CR group. From the rest 21,820 STEMI patients without CR, 390 patients at a ratio of 1:2 were included as the control group. A total of 66 patients accepted PCI in the CR group, and 132 patients who accepted PCI in the control group at a ratio of 1:2 were included. The status of first medical contact, laboratory examinations, and PCI characteristics were recorded. Multivariate logistic regression analysis was used to investigate the risk factors related to CR. Results: There was a higher proportion of patients with myocardial infarction (MI) in the high lateral wall in the CR group (23.6% vs. 8.2%, P<0.001). The proportion of single lesions was lower in the CR group (24.2% vs. 45.5%, P=0.004). Female (OR =2.318, 95% CI: 1.431-3.754, P=0.001), age (OR =1.066, 95% CI: 1.041-1.093, P<0.001), smoking (OR =1.750, 95% CI: 1.086-2.820, P=0.022), total chest pain time (OR =1.017, 95% CI: 1.000-1.035, P=0.049), recurrent acute chest pain (OR =2.750, 95% CI: 1.535-4.927, P=0.001), acute myocardial infarction (AMI) in the high lateral wall indicated by ECG (OR =5.527, 95% CI: 2.798-10.918, P<0.001), acute heart failure (OR =3.585, 95% CI: 2.074-6.195, P<0.001), and NT-proBNP level (OR =1.000, 95% CI: 1.000-1.000, P=0.023) were risk factors for CR in all patients. In patients who accepted PCI, single lesion (OR =0.421, 95% CI: 0.204-0.867, P=0.019), preoperative thrombolysis in myocardial infarction (TIMI) grade (OR =0.358, 95% CI: 0.169-0.760, P=0.007), and postoperative TIMI grade (OR =0.222, 95% CI: 0.090-0.546, P=0.001) were risk factors for CR. Conclusions: Non-single lesions and preoperative and postoperative TIMI grades were risk factors for CR in patients who accepted PCI. In addition to previously reported indicators, we found that AMI in the high lateral wall maybe helpful in early and accurate identification and prevention of possible CR.

A comparison of drug-eluting stent and coronary artery bypass grafting in mildly to moderately ischemic heart failure.

AIMS: The best revascularization strategy for patients with ischaemic heart failure (IHF) remains unclear. Current evidence and guidelines mainly focus on patients with severe ischaemic heart failure (ejection fraction [EF] < 35%). There are limited data comparing clinical outcomes of coronary artery bypass grafting (CABG) with implantation of drug-eluting stents (DESs) in patients with mild to moderate ischaemic heart failure (EF 35-50%). It is therefore unknown whether percutaneous coronary intervention (PCI) with DES implantation can provide comparable outcomes to CABG in these patients. METHODS AND RESULTS: From January 2016 to December 2017, we enrolled patients with mildly to moderately reduced EF (35-50%) who had undergone PCI with DESs or CABG. Patients with a history of CABG, presented with acute ST-elevation myocardial infarction (MI) or acute heart failure, and patients who had undergone CABG concomitant valvular or aortic surgery were excluded. Propensity score-matching analysis was performed between the two groups. Kaplan-Meier analysis and multivariate Cox proportional hazard regression were applied to assess all-cause mortality and individual end points. A total of 2050 patients (1330 PCIs and 720 CABGs) were included, and median follow-up was 45 months (interquartile range 40 to 54). There were significant differences in all-cause death between the two groups: 77 patients in the PCI group and 27 in the CABG group (DES vs. CABG: 5.8% vs. 3.8%, P = 0.045). After propensity score matching for the entire population, 601 matched pairs were obtained. The long-term cumulative rate of all-cause death was significantly different between the two groups (DES vs. CABG: 5.8% vs. 2.7%, P = 0.006). No differences were found in the rates of cardiac death (DES vs. CABG: 4.8% vs. 3.0%, P = 0.096), recurrent MI (DES vs. CABG: 4.0% vs. 2.8%, P = 0.234), and stroke (DES vs. CABG: 6.8% vs. 5.2%, P = 0.163). The rate of repeat coronary revascularization was significantly higher in the PCI group than in the CABG group (12.1% vs. 6.0%, P = 0.000). CONCLUSIONS: Considering the higher long-term survival rate and lower repeat-revascularization rate, CABG may be superior to DES implantation in patients with mildly to moderately reduced EF (35-50%) and significant CAD.

Syringaresinol attenuates sepsis-induced cardiac dysfunction by inhibiting inflammation and pyroptosis in mice.

The mortality of sepsis-induced cardiac dysfunction (SICD) is very high due to the complex pathophysiological mechanism. Syringaresinol (SYR) is a natural abstract which possesses anti-inflammatory property. The present study aims was to identify the protective impact of SYR on sepsis-induced cardiac dysfunction and investigate the specific mechanisms. We found that SYR improved the cardiac function and alleviated myocardial injury in mice that subjected to cecal ligation and puncture, in addition, SIRT1 expression was significantly elevated after SYR treatment compared to sepsis group both in vivo and in vitro, along with suppression of NLRP3 activation and proinflammatory cytokines release. However, SIRT1 inhibitor EX427 abolished the impact of SYR on LPS-induced pyroptosis in cardiomyocytes. Furthermore, molecular docking analysis predicted that there is high affinity between SYR and estrogen receptor (ER), ER inhibitor ICI182780, the specific ERß inhibitor PHTP and the specific ERαinhibitor AZD9496 were used to examine the role of ER in the protective effect of SYR against SICD, and the results suggested that ER activation was essential for the cardioprotective function of SYR. In conclusion, SYR ameliorates SICD via the ER/SIRT1/NLRP3/GSDMD pathway.

Flow reserve fraction: the optimal choice in lesion assessing and interventional guiding for patient with unstable angina pectoris and intermediate lesion wrapped with myocardial bridge: a case report.

BACKGROUND: It is difficult to choose correctly interventional strategy for coronary intermediate lesions combined with myocardial bridge. Endovascular imaging is advocated to guide treatment, but flow reserve fraction (FFR) is not recommended to guide the interventional treatment of myocardial bridge disease because of the inaccurate judgment misled by myocardial bridge. CASE PRESENTATION: In this study, we reported a case of a 56-year-old male patient with unstable angina pectoris (UAP). From his coronary angiography, we found diffuse stenosis near the midsection of the left anterior descending (LAD) branch and the presence of a severe myocardial bridge in the lesion area. We were sure that the LAD was culprit vessel and this lesion was culprit lesion. Both FFR and intravenous ultrasound (IVUS) were performed and the conclusions of them are different. Although stent implantation is not usually recommended in the myocardial bridge area. However, after careful examination, a stent was finally implanted under the precise guidance of FFR. And the patient recovered well up-to now. CONCLUSIONS: This case illustrates that FFR functional test was complimentary to intravascular imaging test for the coronary intermediate lesion, especially the lesion wrapped with myocardial bridges, both in assessing the lesion and in guiding treatment.

Loss of TRIM21 alleviates cardiotoxicity by suppressing ferroptosis induced by the chemotherapeutic agent doxorubicin.

BACKGROUND: Doxorubicin, an anthracycline chemotherapeutic agent, is widely used in the treatment of many cancers. However, doxorubicin posts a great risk of adverse cardiovascular events, which are thought to be caused by oxidative stress. We recently reported that the ubiquitin E3 ligase TRIM21 interacts and ubiquitylates p62 and negatively regulates the p62-Keap1-Nrf2 antioxidant pathway. Therefore, we sought to determine the role TRIM21 in cardiotoxicity induced by oxidative damage. METHODS: Using TRIM21 knockout mice, we examined the effects of TRIM21 on cardiotoxicity induced by two oxidative damage models: the doxorubicin treatment model and the Left Anterior Descending (LAD) model. We also explored the underlying mechanism by RNA-sequencing of the heart tissues, and by treating the mouse embryonic fibroblasts (MEFs), immortalized rat cardiomyocyte line H9c2, and immortalized human cardiomyocyte line AC16 with doxorubicin. FINDINGS: TRIM21 knockout mice are protected from heart failure and fatality in both the doxorubicin and LAD models. Hearts of doxorubicin-treated wild-type mice exhibit deformed mitochondria and elevated level of lipid peroxidation reminiscent of ferroptosis, which is alleviated in TRIM21 knockout hearts. Mechanistically, TRIM21-deficient heart tissues and cultured MEFs and H9c2 cells display enhanced p62 sequestration of Keap1 and are protected from doxorubicin-induced ferroptosis. Reconstitution of wild-type but not the E3 ligase-dead and the p62 binding-deficient TRIM21 mutants impedes the protection from doxorubicin-induced cell death. INTERPRETATION: Our study demonstrates that TRIM21 ablation protects doxorubicin-induced cardiotoxicity and illustrates a new function of TRIM21 in ferroptosis, and suggests TRIM21 as a therapeutic target for reducing chemotherapy-related cardiotoxicity. FUNDING: NIH (CA129536; DK108989): data collection, analysis. Shanghai Pujiang Program (19PJ1401900): data collection. National Natural Science Foundation (31971161): data collection. Department of Veteran Affairs (BX004083): data collection. Tianjin Science and Technology Plan Project (17ZXMFSY00020): data collection.

Homocysteine promotes cardiac fibrosis by regulating the Akt/FoxO3 pathway.

BACKGROUND: Evaluated plasma homocysteine (Hcy) is an independent risk factor for cardiac fibrosis which is a common feature of cardiovascular disease, although the mechanisms are still unclear. This study aims to explore the mechanism of Hcy-induced cardiac fibrosis. METHODS: The mRNA and protein levels of Forkhead box O3 (FoxO3) and differentiation markers were detected in primary cardiac fibroblasts (CFs) after 300 µM Hcy treatment. Scratch and transwell migration assay were used to determine the effect of Hcy on proliferation and migration in CFs. The protein levels involved in the fibrotic processes in mice fed with high methionine diet (HMD) for 4 or 8 weeks were investigated by western blot. CFs were infected with FoxO3 recombinant adenovirus to explore the potential role of FoxO3 in Hcy-induced cardiac dysfunction. RESULTS: Hcy treatment significantly promoted the differentiation, proliferation and migration of CFs, while FoxO3 activity were decreased in CFs. In HMD hearts, the protein levels of TIMP1, Fibronectin and α-SMA were increased after 4 or 8 weeks, but the FoxO3 activity was decreased. Moreover, the HMD hearts had a higher level of Bcl2 but lower of Bax and LC3II protein. In addition, FoxO3 overexpression attenuates Hcy-induced dysfunction in CFs. CONCLUSIONS: Hcy promotes myofibroblast activation and resistance to autophagy and apoptosis in CFs, and eventually results in cardiac fibrosis by regulating the Akt/FoxO3 pathway. Thus, FoxO3 is a promising therapeutic target to prevent cardiac remodeling.

Effects of miR-124-3p regulation of the p38MAPK signaling pathway via MEKK3 on apoptosis and proliferation of macrophages in mice with coronary atherosclerosis.

BACKGROUND: Atherosclerosis (AS) is the main cause of myocardial infarction and stroke. Macrophage apoptosis in the early stages can attenuate lesions, while in the late stage it is associated with AS plaque rupture. OBJECTIVES: To explore the effects of miR-124-3p regulation of the p38MAPK signaling pathway via the MEKK3 gene on the apoptosis and proliferation of macrophages in mice with coronary AS. MATERIAL AND METHODS: Fifty male apolipoprotein E (ApoE) -/- mice were equally assigned to a normal group and a coronary AS group. In the AS group, the mice were given a high-fat diet to establish a coronary AS model. The macrophages of the mice were isolated for culture and divided into 7 groups: normal, negative control (NC), control, miR-124-3p mimic, miR-124-3p inhibitor, si-MEKK3, and miR-124-3p inhibitor+si-MEKK3. RESULTS: Compared with the normal group, the AS group had lower expression levels of miR-124-3p and higher expression levels of MEKK3 and p-p38MAPK in the coronary artery tissue and peritoneal macrophages (all p < 0.050). We found that miR-124-3p could negatively regulate MEKK3 expression. Compared with the control group, the miR-124-3p mimic group and si-MEKK3 group had greater cell apoptosis rates and Bax levels, weaker cell proliferation and invasion abilities, slower cell cycle progression, and lower PCNA and Bcl-2 levels (all p < 0.050). This trend was also displayed in the miR-124-3p inhibitor+si-MEKK3 group when compared with the miR-124-3p inhibitor group, and in the si-MEKK3 group when compared with the miR-124-3p inhibitor+si-MEKK3 group (all p < 0.050). CONCLUSIONS: miR-124-3p overexpression can downregulate MEKK3 expression and inhibit the expression of the p38MAPK signaling pathway, thereby inhibiting macrophage proliferation and promoting macrophage apoptosis in mice with coronary AS.

NEAT1 knockdown suppresses endothelial cell proliferation and induces apoptosis by regulating miR­638/AKT/mTOR signaling in atherosclerosis.

Long non­coding RNAs (lncRNAs) have been validated to mediate the development of atherosclerosis (AS). In the present study, the molecular mechanisms and functions of lncRNA nuclear paraspeckle assembly transcript 1 (NEAT1) in the advancement of human aortic endothelial cells (HAECs) were investigated. The levels of lncRNA­NEAT1 and miR­638 expression in clinical samples and cells were explored via quantitative reverse transcription polymerase chain reaction. Colony formation and CCK­8 assays were performed to determine the proliferative capacity of cells, and the apoptotic capacity of cells was analyzed on the basis of apoptotic cell proportion and caspase­3 activity. Then, the proportion of cells and correlations among phosphoglycerate kinase 1 (PGK1), NEAT1, and miR­638 were determined through RNA immunoprecipitation and luciferase assays and bioinformatics analysis. Moreover, the expression levels of Ki­67, proliferating cell nuclear antigen, PGK1, Bax, Bcl­2, (p)­mTOR, (p)­AKT, and ß­catenin were analyzed via western blot analysis. In the serum of patients with AS and HAECs induced by oxidized low­density lipoprotein (ox­LDL), the expression level of miR­638 was decreased, whereas that of NEAT1 was increased. After ox­LDL therapy, NEAT1 knockdown suppressed HAEC proliferation and stimulated HAEC apoptosis, which could be reversed by the miR­638 inhibitor. NEAT1 inhibited miR­638 expression through direct mutual action. The following mechanical investigations revealed that PGK1 was a miR­638 target, whose expression was increased by NEAT1, a competing endogenous RNA of miR­638. Additionally, the miR­638 inhibitor contributed to proliferation and suppressed apoptosis through the activation of the AKT/mTOR signaling pathway in ox­LDL­induced HAECs. NEAT1 adjusted the AKT/mTOR signaling pathway via miR­638 in ox­LDL­induced HAECs to accelerate their proliferation and impede their apoptosis. This result revealed that NEAT1 may be valuable in the treatment of AS.

Preventive Effects of Nicorandil Against Contrast-Induced Nephropathy in Patients With Moderate Renal Insufficiency Undergoing Percutaneous Coronary Intervention.

We investigated the preventive effect of nicorandil on contrast-induced nephropathy (CIN) in patients with moderate renal insufficiency undergoing percutaneous coronary intervention (PCI). A total of 250 patients with a creatinine clearance (crCl) ≤60 mL/min undergoing PCI were randomly assigned to either a nicorandil group (nicorandil 10 mg 3 times/d and hydration; n = 125) or a control group (hydration only; n = 125). The first end point was the incidence of CIN defined as an increase in serum creatinine (Scr) levels by ≥0.5 mg/dL or ≥25% within 72 hours after exposure to the contrast medium. The secondary end points were (1) changes in Scr, blood urea nitrogen, and crCl and (2) the incidence of major adverse events during hospitalization. The incidence of CIN was 1.6% (2/125) in the nicorandil group and 9.6% (12/125) in the control group (P = .011). There was no obvious difference in the incidence of major adverse events during hospitalization between the nicorandil and the control group (4.0% vs 4.8%, P = 1.000). Multivariate logistic regression analysis showed that nicorandil was a protective factor for CIN (odds ratios = 0.126, 95% confidence interval: -19.996 to -0.932, P = .012). Prophylactic administration of nicorandil may prevent against CIN in patients with moderate renal insufficiency undergoing PCI.

[Relationship between serum levels of osteoproteins, inflammatory cytokines and coronary heart disease and disease severity].

OBJECTIVE: To explore the relationship between serum levels of osteoprotein (OPG), soluble nuclear factor-κB receptor activator ligand (sRANKL), inflammatory factors and coronary heart disease (CHD) and its severity. METHODS: The patients who underwent coronary angiography (CAG) due to chest pain admitted to department of cardiology of Tianjin Chest Hospital from April 2017 to December 2018 were enrolled, and they were divided into CHD group and non-CHD group according to the CAG results. The gender, age, history of hypertension, smoking history, diabetes, the levels of cholesterol (TC), high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C), apolipoprotein AI (apoAI), apolipoprotein B (apoB), lipoprotein (a) [Lp (a)], MB isoenzyme of creatine kinase (CK-MB) and other clinical data of patients were collected. The serum levels of OPG, sRANKL, matrix metalloproteinase-9 (MMP-9), monocyte chemotactic protein-1 (MCP-1), insulin-like growth factor-1 (IGF-1) and interleukin-6 (IL-6) were determined by enzyme-linked immunosorbent assay (ELISA). According to the results of CAG, the patients with CHD were divided into single-, double-, triple-branch coronary artery lesion groups, and the relationship between the levels of serum OPG, sRANKL, inflammatory factors and the degree of coronary artery lesions was observed. Multivariate Logistic regression was used to analyze the risk factors of CHD, and receiver operating characteristic (ROC) curve was plotted to analyze the predictive value of main risk factors for CHD. RESULTS: A total of 472 patients were enrolled in the final analysis during the study period, including 264 patients in the CHD group, 208 patients in the non-CHD group, 79 patients in the CHD group with single-branch disease, 75 patients with double-branch disease, and 110 patients with three-branch disease. (1) Compared with the non-CHD group, the CHD group had more older male patients, as well as higher proportion of hypertension and diabetes, the levels of serum Lp (a) and CK-MB were significantly increased, and the levels of serum HDL-C and apoAI were significantly lowered. There was no statistically significant difference in serum TC, LDL-C, or apoB between the two groups. The levels of serum OPG, MMP-9, MCP-1, IGF-1 and IL-6 in the CHD group were significantly higher than those in the non-CHD group [OPG (µg/L): 1.79±0.50 vs. 1.50±0.30, MMP-9 (µg/L): 57.91 (33.50, 130.46) vs. 38.33 (29.43, 109.78), MCP-1 (µg/L): 298.30 (207.96, 537.16) vs. 252.73 (165.22, 476.01), IGF-1 (µg/L): 734.03±486.11 vs. 217.75±126.45, IL-6 (ng/L): 64.76±40.25 vs. 48.60±15.80, all P < 0.05], and the levels of serum sRANKL was significantly lower than that in the non-CHD group (ng/L: 344.31±122.14 vs. 378.74±109.27, P < 0.05). (2) The serum OPG level showed a slight upward tendency with the increase in the number of coronary artery lesions, and the sRANKL level showed a slight downward tendency [OPG (µg/L) in the single-, double-, triple-branch coronary artery lesion groups was 1.74±0.49, 1.76±0.50, 1.85±0.52, and sRANKL (ng/L) was 354.96±116.64, 340.05±124.24, 339.57±125.03, respectively) without statistically significant differences (all P > 0.05). The levels of IGF-1 and IL-6 were increased with the number of coronary artery lesions [IGF-1 (µg/L) in the single-, double- and triple-branch coronary artery lesions groups was 372.13±258.42, 676.06±350.29, 1 033.47±468.06, and IL-6 (ng/L) was 48.87±16.72, 65.36±18.84, 75.76±22.72, respectively], and the differences among different lesion groups were statistically significant (all P < 0.01). Correlation analysis showed that IGF-1 level was significantly positively correlated with the number of coronary artery lesions (r = 0.612, P < 0.01), while IL-6 was not correlated with the number of coronary artery lesions (r = 0.185, P > 0.05). (3) Multivariate Logistic regression analysis showed that elevated serum OPG and IGF-1 levels were risk factors for CHD [OPG: odds ratio (OR) = 1.995, 95% confidence interval (95%CI) = 1.936-2.067, P = 0.012; IGF-1: OR = 1.009, 95%CI = 1.004-1.015, P = 0.001]. (4) ROC curve analysis showed that the area under ROC curve (AUC) of OPG and IGF-1 was 0.716 and 0.867, respectively. When the cut-off value of OPG was 1.13 µg/L, the sensitivity was 81.7%, the specificity was 58.1%; when the cut-off value of sRANKL was 401.20 µg/L, the sensitivity was 69.7%, the specificity was 95.7%. CONCLUSIONS: CHD was associated with increased in OPG, related inflammatory cytokines including MMP-9, MCP-1, IGF-1 and IL-6, and decreased in sRANKL. The level of IGF-1 was positively correlated with the severity of CHD. The serum levels of OPG and IGF-1 were risk factors for CHD, which had good predictive value for CHD.