Revisiting an old relationship: the causal associations of the ApoB/ApoA1 ratio with cardiometabolic diseases and relative risk factors-a mendelian randomization analysis.

BACKGROUND: It has been confirmed that the ApoB/ApoA1 ratio is closely associated with the incidence of cardiometabolic diseases (CMD). However, due to uncontrolled confounding factors in observational studies, the causal relationship of this association remains unclear. METHODS: In this study, we extracted the ApoB/ApoA1 ratio and data on CMD and its associated risk factors from the largest European Genome-Wide Association Study. The purpose was to conduct Mendelian Randomization (MR) analysis. The causal relationship between the ApoB/ApoA1 ratio and CMD was evaluated using both univariable and multivariable MR analyses. Furthermore, bidirectional MR analysis was performed to estimate the causal relationship between the ApoB/ApoA1 ratio and risk factors for CMD. The final verification confirmed whether the ApoB/ApoA1 ratio exhibits a mediating effect in CMD and related risk factors. RESULTS: In terms of CMD, a noteworthy correlation was observed between the increase in the ApoB/ApoA1 ratio and various CMD, including ischemic heart disease, major adverse cardiovascular events, aortic aneurysm, cerebral ischemic disease and so on (all PFDR<0.05). Meanwhile, the ApoB/ApoA1 ratio was significantly associated with CMD risk factors, such as hemoglobin A1c, fasting insulin levels, waist-to-hip ratio, sedentary behavior, and various others, demonstrating a notable causal relationship (all PFDR<0.05). Additionally, the ApoB/ApoA1 ratio played a mediating role in CMD and relative risk factors. CONCLUSIONS: This MR study provides evidence supporting the significant causal relationship between the ApoB/ApoA1 ratio and CMD and its risk factors. Moreover, it demonstrates the mediating effect of the ApoB/ApoA1 ratio in CMD and its risk factors. These findings suggest that the ApoB/ApoA1 ratio may serve as a potential indicator for identifying the risk of developing CMD in participants.

CTRP13 Mitigates Endothelial Cell Ferroptosis via the AMPK/KLF4 Pathway: Implications for Atherosclerosis Protection.

BACKGROUND C1q/tumor necrosis factor-related protein 13 (CTRP13) preserves endothelial function and possesses anti-oxidation activity. However, its effects on ferroptosis of human umbilical vein endothelial cells (HUVECs) remain unclear. We investigated the effects of CTRP13 on HUVEC ferroptosis induced by oxidized low-density lipoprotein (ox-LDL) and explored the underlying mechanisms of CTRP13 against ferroptosis via the AMPK/KLF4 pathway. MATERIAL AND METHODS Cell Counting Kit-8 assay was used to evaluate cell viability. Lactate dehydrogenase activity and malondialdehyde content analysis were performed to evaluate the cell membrane integrity and lipid peroxidation. Mito-Tracker, JC-1, and 2',7'-dichlorofluorescein di-acetate were used to evaluate the biological activity of mitochondria, mitochondrial membrane potential, and reactive oxygen species (ROS) in endothelial cells. The ferroptosis indicator expressions, recombinant solute carrier family 7, member 11, glutathione peroxidase 4 (GPX4), and acyl-CoA synthetase long-chain family member 4 were examined using real-time reverse transcription-polymerase chain reaction and Western blot. Immunofluorescence staining detected GPX4 location in endothelial cells. RESULTS The results demonstrate that CTRP13 (450 ng/mL) prevented HUVEC ferroptosis by inhibiting ROS overproduction and mitochondrial dysfunction, and CTRP13 accelerated antioxidant enzyme expression levels, such as heme oxygenase 1, superoxide dismutase 1, and superoxide dismutase 2, compared with the ox-LDL (100 µg/mL) group for 48 h. Additionally, CTRP13 treatment increased p-AMPK/AMPK expression by 47.65% (P<0.05) while decreasing Krüppel-like factor 4 expression by 37.43% (P<0.05) in ox-LDL-induced HUVECs and elucidated the protective effect on endothelial dysfunction from ferroptosis. CONCLUSIONS These findings provide new insights for understanding the effects and mechanism of CTRP13 on preventing endothelial cell ferroptosis.

A landscape of Long non-coding RNAs reveals the leading transcriptome alterations in murine aorta during aging.

Considerable studies have given convincing evidence of a forefront position for vascular aging in preventing cardiovascular disease. Various functions of Long non-coding RNAs (lncRNAs) are becoming increasingly distinct in aging-related diseases. This study aims at a better insight into the expression profile and mechanisms of lncRNAs in vascular senescence. High-throughput sequencing was used to detect the differential expression (DE) of lncRNAs and mRNAs in the aorta of 96 W and 8 W-old mice, while 1423 lncRNAs and 80 mRNAs were differentially expressed. By performing GO and KEGG enrichment analysis, we found that DE lncRNAs were mainly involved in purine metabolism and cGMP-PKG signaling pathways. In addition, a co-expression functional network of DE lncRNAs and DE mRNAs was constructed, and ENSMUST00000218874 could interact with 41 DE mRNAs, suggesting that it may play an essential role in vascular senescence. This study reveals DE lncRNAs in naturally aging vascular, which may provide new ideas and targets for aging-related cardiovascular diseases.

H-type Hypertension Status and Influencing Factors of the Elderly People Over 80 Years Old Based on Random Forest Model.

Hypertension is a common chronic disease in elderly people over 80 years old. Clinically, H-type hypertension occurs when hypertension coexists with hyperhomocysteinemia level of ≥ 10 umol/L. Effective identification of risk factors for H-type hypertension in the elderly can greatly improve patient prognosis.Consecutively, 494 patients with hypertension admitted to the Fourth Affiliated Hospital of Harbin Medical University from January 2019 to December 2021 were selected as the study population. They were divided into H-type hypertension (n = 197) and non-H-type hypertension groups (n = 297). Patient data were collected, including basic information, history, and clinical data. The random forest model and LASSO analysis were used to screen the influencing factors for H-type hypertension. Multiple stepwise regression analysis was used to analyze the selected variables.A total of 197 elderly people over 80 years old suffered from H-type hypertension, with an incidence rate of 39.88%. The random forest model and LASSO analysis results showed that the top 8 independent variables in importance ranking were ejection fraction (EF), fibrinogen, glycated hemoglobin (HbA1c), B-type natriuretic peptide, creatinine, fasting blood glucose, uric acid, and serum triiodothyronine levels. The results of multivariate analysis showed that EF was the protective factor, while fibrinogen, HbA1c, and creatinine were the risk factors for H-type hypertension in elderly people over 80 years old (P < 0.05).Healthcare professionals can indirectly assess the prevalence of H-type hypertension by focusing on EF, fibrinogen, creatinine, and HbA1c in elderly hypertensive patients. This provided proactive intervention and medical services to improve prognosis outcomes.

Peripheral atherosclerosis in acute coronary syndrome patients with plaque rupture vs plaque erosion: A prospective coronary optical coherence tomography and peripheral ultrasound study.

BACKGROUND: Plaque rupture (PR) and plaque erosion (PE) are 2 distinct, different, and most common culprit lesion morphologies responsible for acute coronary syndrome (ACS). However, the prevalence, distribution, and characteristics of peripheral atherosclerosis in ACS patients with PR vs PE has never been studied. The aim of this study was to assess peripheral atherosclerosis burden and vulnerability evaluated by vascular ultrasound in ACS patients with coronary PR vs PE identified by optical coherence tomography (OCT). METHODS: Between October 2018 and December 2019, 297 ACS patients who underwent preintervention OCT examination of the culprit coronary artery were enrolled. Peripheral ultrasound examinations of carotid, femoral, and popliteal arteries were performed before discharge. RESULTS: Overall, 265 of 297 (89.2%) patients had at least one atherosclerotic plaque in a peripheral arterial bed. Compared with coronary PE, patients with coronary PR had a higher prevalence of peripheral atherosclerotic plaques (93.4% vs 79.1%, P < .001), regardless of location: carotid, femoral, or popliteal arteries. The number of peripheral plaques per patient was significantly larger in the coronary PR group than coronary PE (4 [2-7] vs 2 [1-5], P < .001). Additionally, there was a greater prevalence of peripheral vulnerable characteristics including plaque surface irregularity, heterogeneous plaque, and calcification in patients with coronary PR vs PE. CONCLUSIONS: Peripheral atherosclerosis exists commonly in patients presenting with ACS. Patients with coronary PR had greater peripheral atherosclerosis burden and more peripheral vulnerability compared to those with coronary PE, suggesting that comprehensive evaluation of peripheral atherosclerosis and multidisciplinary cooperative management maybe necessary, especially in patients with PR. TRIAL REGISTRATION: clinicaltrials.gov (NCT03971864).

A novel protective role of lipoxin in inhibiting diabetic vascular calcification via YAP signalling: Health prevention and regulation.

Vascular calcification is highly prevalent in diabetes patients, with detrimental consequences and no effective prevention and treatment strategies are currently available. Though the protective effect of lipoxin (LX) against vascular diseases has been demonstrated, its effect on diabetic vascular calcification remains unknown. AGEs dose-dependently induced calcification and the expression of osteogenesis-related markers, coupled with the activation of yes-associated protein (YAP). Mechanistically, YAP activation enhanced the AGE-induced osteogenic phenotype and calcification, but inhibition of YAP signalling alleviated this response. Further, an in vivo diabetic mouse model was established using a combination of a high-fat diet and multiple formulations of low-dose streptozotocin. Consistent with the in vitro results, diabetes promoted YAP expression and its subcellular localization in the nucleus in the arterial tunica media. The results demonstrate that LX attenuates the trans-differentiation and calcification of VSMCs in diabetes mellitus via YAP signalling, suggesting LX to be a potent therapeutic for preventing diabetic vascular calcification.

Vaspin alleviates the lncRNA LEF1-AS1-induced osteogenic differentiation of vascular smooth muscle cells via the Hippo/YAP signaling pathway.

Vascular calcification (VC) is closely related to higher cardiovascular mortality and morbidity, and vascular smooth muscle cell (VSMC) switching to osteogenic-like cells is crucial for VC. LncRNA LEF1-AS1 promotes atherosclerosis and dental pulp stem cells calcification, while its role in VC remains unknown. Visceral adipose tissue-derived serine protease inhibitor (vaspin) is an adipokine regulating bone metabolism. However, the relationship between vaspin and VC is still unclear. We aimed to explore the role of LEF1-AS1 on VSMC osteogenic transition, whether vaspin inhibited LEF1-AS1-mediated osteogenic differentiation of VSMCs, and the responsible mechanism. In this study, quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting analysis indicated that LEF1-AS1 overexpression significantly upregulated osteogenic marker Runt-related transcription factor-2 (RUNX2) level and downregulated VSMC contractile marker α-smooth muscle actin (α-SMA) level. Alizarin red staining, alkaline phosphatase (ALP) staining, ALP activity assay, and calcium content assay also suggested that LEF1-AS1 overexpression promoted calcium deposition in VSMCs. However, vaspin treatment abolished this phenomenon. Mechanistically, LEF1-AS1 markedly decreased phosphorylated YAP level, while vaspin reversed LEF1-AS1-induced phosphorylated YAP decline. Our results revealed that LEF1-AS1 accelerated the osteogenic differentiation of VSMCs by regulating the Hippo/YAP pathway, while vaspin eliminated the LEF1-AS1-meditated VSMCs osteogenic phenotype switch.

Irisin inhibits PCSK9 expression through activating AMPK-SREBP2 pathway.

AIMS: Previous studies found that irisin attenuated the vascular wall inflammation caused by Oxidized low-density lipoprotein (ox-LDL), and recent experiments have shown that proprotein convertase subtilisin/kexin type 9 (PCSK9) can act on various cells in the vascular wall to induce inflammatory responses. But, the relationship between irisin and PCSK9 has not been reported. The aim of this study was to investigate the effect of irisin on PSCK9 in endothelial cells and hepatocytes under the induction of ox-LDL. METHODS: Experiments were performed using human umbilical vein endothelial cells and Hep G2, and cells were treated with irisin and (or) ox-LDL for evaluating expression of PCSK9 and downstream inflammatory proteins, while the expression levels of AMP-dependent protein kinase (AMPK) and sterol-regulatory element binding protein 2 (SREBP2) were also examined. Then Compound C was used to inhibit AMPK activation and SiAMPK for silencing of AMPK mRNA, and the above assays were also performed to deeply validate the role of the AMPK-SREBP2 pathway. RESULTS: Irisin treatment significantly downregulated the expression of PCSK9 and inflammation-related proteins induced by ox-LDL, also restored the content of p-AMPK and reduced the SREBP2 content. After the use of Compound C or SiAMPK, the content of p-AMPK was obviously decreased, and the positive effect of irisin was greatly weakened. CONCLUSIONS: This study demonstrates that irisin suppresses PCSK9 expression through the AMPK-SREBP2 pathway and ameliorates ox-LDL-induced endothelial cells inflammation.

Relationship between non-culprit lesion plaque characteristics changes and in-stent neoatherosclerosis formation: 1-year follow-up optical coherence tomography study.

The relationship between the in-stent neoatherosclerosis (ISNA) formation and the plaque's characteristic changes in the non-culprit lesion is unclear. We aim to investigate the plaque characteristics changes at non-culprit lesions between patients with ISNA and without ISNA formation at 1-year follow-up. We retrospectively enrolled patients who had DES implantation in de novo lesion and underwent immediately after stenting and 1-year follow-up optical coherence tomography (OCT) examination. OCT-defined ISNA was defined as the presence of lipid-laden neointima or calcification within the culprit stent with a longitudinal extension of ≥1 mm. Non-culprit lesions were divided into two groups: ISNA group (with ISNA) and non-ISNA group (without ISNA). Plaque characteristics of non-culprit lesions were evaluated at baseline and 1-year follow-up. In total, 89 patients with 89 non-culprit lesions (ISNA: n = 37; non-ISNA: n = 52) were included in the analyses. The lesions in the ISNA group show a smaller minimum lumen area compared to the non-ISNA group at 1-year follow-up (2.57 ± 1.08 mm2 versus 3.20 ± 1.62 mm2, p = 0.044). The lesions of the ISNA group show a significant decrease in minimum lumen area changes percent (-7.25% versus 6.46%, p = 0.039). And there are more lesions with minimum lumen area (64.9% versus 38.5%, p = 0.014) and minimum lumen diameter (64.9% versus 40.4%, p = 0.023) decrease in the ISNA group. Furthermore, the lesions in ISNA group have more plaques with lipid core length increase (25.0% versus 10.0%, p = 0.040), more plaques with FCT decrease (50.0% versus 74.0%, p = 0.027) and less TCFA change to non-TCFA (33.3% versus 87.5%, p = 0.010). The plaque characteristic changes in non-culprit lesions are closely related to ISNA formation. The ISNA formation may accompany by a tardier plaque stabilization process in non-culprit lesions.

Is the effect of atorvastatin 60 mg on stabilization of lipid-rich plaque equivalent to that of rosuvastatin 10 mg? A serial optical coherence tomography combined with intravascular ultrasound imaging.

OBJECTIVES: This study aimed to compare the effect of atorvastatin 60 (AT60) mg to that of rosuvastatin 10 (RT10) mg on the morphological changes in lipid-rich plaques (LRPs) and plaque volume, using serial optical coherence tomography (OCT) and intravascular ultrasound imaging (IVUS). BACKGROUND: Intensive lipid lowering therapy by statin provides more clinical benefit compared to that of moderate lipid lowering therapy. METHODS: Fifty patients who underwent OCT and IVUS at baseline, 6, and 12 months were grouped by statin therapy into the AT60 mg (n = 27) and RT10 mg (n = 23) groups. The relationships between absolute and percentage changes in biomarkers and fibrous cap thickness (FCT) during follow-up were investigated using a simple regression analysis. RESULTS: At 6 months, the mean low-density lipoprotein cholesterol level reduced from 113.5 to 65.5 mg/dl (AT60 mg group) and 100.2 to 72.2 mg/dl (RT10 mg groups). A continuous increase in FCT from baseline to 12 months was observed in both groups (p < .001, p < .001, respectively). Mean lipid arc significantly decreased in both AT60 mg (189.0 ± 55.9°, 170.9 ± 60.2°, 155.6 ± 50.6°, p < .001) and RT10 mg (160.0 ± 45.6°, 151.2 ± 48.5°, 141.1 ± 52.9°, p = .010) groups. Plaque burden did not change significantly in both groups. CONCLUSIONS: Lipid-lowering therapy effect with AT60 mg was equivalent to that of RT10 mg in terms of change in plaque morphology. AT60 mg showed more intensive low-density lipid cholesterol level reduction compared to RT10 mg while RT10 mg was effective in increasing the high-density lipid cholesterol level. Both statin therapies could effectively stabilize LRPs.

Predictors of Coronary Plaque Erosion in Current and Non-Current Smokers With ST-Segment Elevation Myocardial Infarction　- An Optical Coherence Tomography Study.

BACKGROUND: Smoking is an important risk factor of plaque erosion. This study aimed to investigate the predictors of plaque erosion in current and non-current smokers presenting with ST-segment elevation myocardial infarction (STEMI).Methods and Results:A total of 1,320 STEMI patients with culprit plaque rupture or plaque erosion detected by pre-intervention optical coherence tomography were divided into a current smoking group (n=715) and non-current smoking group (n=605). Plaque erosion accounted for 30.8% (220/715) of culprit lesions in the current smokers and 21.2% (128/605) in the non-current smokers. Multivariable analysis showed age <50 years, single-vessel disease and the absence of dyslipidemia were independently associated with plaque erosion rather than plaque rupture, regardless of smoking status. In current smokers, diabetes mellitus (odds ratio [OR]: 0.29; 95% confidence interval [CI]: 0.10-0.83; P=0.021) was negatively associated with plaque erosion as compared with plaque rupture. In non-current smokers, minimal lumen area (MLA, OR: 1.37; 95% CI: 1.16-1.62; P<0.001) and nearby bifurcation (OR: 3.20; 95% CI: 1.98-5.16; P<0.001) were positively related to plaque erosion, but not plaque rupture. CONCLUSIONS: In patients with STEMI, the presence of diabetes mellitus significantly increased the risk of rupture-based STEMI but may not have reduced the risk of plaque erosion-based STEMI in current smokers. Nearby bifurcation and larger MLA were associated with plaque erosion in non-current smokers.

Methotrexate Therapy Promotes Cell Coverage and Stability in in-Stent Neointima.

PURPOSE: Anti-proliferative drugs released from drug-eluting stents delay cell coverage and vascular healing, which increases the risk of late stent thrombosis. We assessed the potential effects of systemic methotrexate (MTX) on cell coverage, vascular healing and inflammation activation in vivo and in vitro. METHODS: We applied MTX in the right common carotid artery in a rabbit stenting model to determine the impact on cell coverage and inflammation activation using a serial optical coherence tomography (OCT) analysis and elucidated the molecular mechanism of MTX in human umbilical vein endothelial cells (HUVECs). RESULTS: Low-dose MTX promoted the development of cell coverage and vascular healing, which was associated with fewer uncovered struts (%) and cross-sections with any uncovered struts (%) at 4 weeks of stenting. The MTX group also exhibited lower rates of heterogeneity, microvessels and per-strut low-signal-intensity layers, indicating neointimal instability at 12 weeks of stenting. In vitro, low-dose MTX strongly inhibited HUVEC apoptosis, promoted proliferation and inhibited inflammatory activation by targeting the phosphoinositide 3-kinase (PI3K)/AKT signalling pathway. CONCLUSION: Low-dose MTX may be a key means of promoting early cell coverage via the inhibition of the inflammatory response and stability of neointima by targeting inflammatory pathways after stent implantation.

Proteomics Profiling Reveals Insulin-Like Growth Factor 1, Collagen Type VI α-2 Chain, and Fermitin Family Homolog 3 as Potential Biomarkers of Plaque Erosion in ST-Segment Elevated Myocardial Infarction.

BACKGROUND: Plaque erosion (PE) has been considered a secondary pathogenesis of ST-segment elevated myocardial infarction (STEMI) following plaque rupture (PR). Previous studies demonstrated that they had different demographic and histology characteristics and need different treatment strategy. But there are few non-invasive plasma biomarkers for distinguishing them. The present study aimed to identify non-invasive predictive biomarkers for PE and PR in patients with STEMI.Methods and Results:A total 108 patients were recruited and grouped into a PE group (n=36), a PR group (n=36), and an unstable angina pectoris (UAP) (n=36) group for analysis. A 9-plex tandem mass tag (TMT)-based proteomics was used to compare plasma protein profiles of PE, PR, and UAP. In total, 36 significant differential proteins (DPs) were identified among groups, 10 of which were screened out using bio-information analysis and validated with enzyme-linked immunosorbent assay (ELISA). The relationship of angiography and optical coherence tomography (OCT) imaging data and the 10 target DPs was analyzed statistically. Logistic regression showed elevated collagen type VI α-2 chain (COL6A2) and insulin-like growth factor 1 (IGF1), and decreased fermitin family homolog 3 (FERMT3), were positively associated with PE. Multivariate analysis indicated IGF1, FERMT3, and COL6A2 had independent predictive ability for PE. IGF1 was inversely correlated with lumen stenosis and the lipid arc of the plaque. CONCLUSIONS: IGF1, COL6A2, and FERMT3 are potential predictive biomarkers of PE in STEMI patients. And IGF1 was negatively correlated with the developing of culprit plaque.

Poor cardiovascular health status among Chinese women.

BACKGROUND: Systematic investigation and analysis of cardiovascular health status (CVHS) of Chinese women is rare. This study aimed to assess CVHS and atherosclerotic cardiovascular disease (ASCVD) burden in the Chinese women physicians (CWP) and community-based non-physician cohort (NPC). METHODS: In this prospective, multicenter, observational study, CVHS using the American Heart Association (AHA) defined 7 metrics (such as smoking and fasting glucose) and ASCVD risk factors including hypertension, hyperlipidemia and type-2 diabetes were evaluated in CWP compared with NPC. RESULTS: Of 5832 CWP with a mean age of 44 ± 7 years, only 1.2% achieved the ideal CVHS and 90.1% showed at least 1 of the 7 AHA CVHS metrics at a poor level. Total CVHS score was significantly decreased and ASCVD risk burden was increased in postmenopausal subjects in CWP although ideal CVHS was not significantly influenced by menopause. Compared to 2596 NPC, fewer CWP had ≥ 2 risk factors (8% vs. 27%, P < 0.001); CWP scored significantly higher on healthy factors, a composite of total cholesterol, blood pressure, fasting glucose (P < 0.001), but, poorly on healthy behaviors (P < 0.001), specifically in the physical activity component; CWP also showed significantly higher levels of awareness and rates of treatment for hypertension and hyperlipidemia, but, not for type-2 diabetes. CONCLUSION: Chinese women's cardiovascular health is far from ideal and risk intervention is sub-optimal. Women physicians had lower ASCVD burden, scored higher in healthy factors, but, took part in less physical activity than the non-physician cohort. These results call for population-specific early and improved risk intervention.

Atheroprotective effects of methotrexate via the inhibition of YAP/TAZ under disturbed flow.

BACKGROUND: Atherosclerosis preferentially develops in regions of disturbed flow (DF). Emerging evidence indicates that yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ), which are both effectors of the Hippo pathway, sense different blood flow patterns and regulate atherosclerotic lesions. We previously found that methotrexate (MTX) reduces in-stent neoatherosclerosis, decreases the plaque burden, and has an effect on local fluid shear stress. Here, we investigated the atheroprotective effect of MTX under DF and the mechanisms underlying these properties. METHODS: Human umbilical vein endothelial cells (HUVECs) were subjected to biomechanical stretch using a parallel-plate flow system and treated with or without MTX at therapeutically relevant concentrations. Additionally, an extravascular device was used to induce DF in the left common carotid artery of C57BL/6 mice, followed by treatment with MTX or 0.9% saline. The artery was then assessed histopathologically after 4 weeks on a Western diet. RESULTS: We observed that MTX significantly inhibited DF-induced endothelial YAP/TAZ activation. Furthermore, it markedly decreased pro-inflammatory factor secretion and monocyte adhesion in HUVECs but had no effect on apoptosis. Mechanistically, AMPKa1 depletion attenuated these effects of MTX. Accordingly, MTX decreased DF-induced plaque formation, which was accompanied by YAP/TAZ downregulation in vivo. CONCLUSIONS: Taken together, we conclude that MTX exerts protective effects via the AMP-dependent kinase (AMPK)-YAP/TAZ pathway. These results provide a basis for the prevention and treatment of atherosclerosis via the inhibition of YAP/TAZ.

Interleukin-35 promotes early endothelialization after stent implantation by regulating macrophage activation.

Background: Early strut coverage after sirolimus-eluting stent (SES) implantation is associated with the activation of inflammation, but the underlying mechanisms are not completely understood. The present study aimed to identify the relationship between the anti-inflammatory cytokine interleukin (IL) 35 (IL-35) and early strut coverage in vivo and in vitroMethods: We utilized a retrospective study design to measure IL-35 levels in 68 stents from 68 patients with coronary artery disease and recorded serial optical coherence tomography (OCT) images (0 and 3 months) to assess stent endothelialization. The mechanism underlying the regulatory effects of IL-35 on macrophages and human umbilical vein endothelial cells (HUVECs) was also investigated. SESs were surgically implanted into the right common carotid arteries of 200 male New Zealand White rabbits receiving intravenous injections of IL-35 or a placebo.Results: At the 3-month OCT evaluation, complete endothelium coverage was correlated with IL-35 levels. IL-35 induced the activation of an anti-inflammatory M2-like macrophage phenotype by targeting the signal transducer and activators of transcription (STAT)1/4 signalling pathway, and IL-35-treated macrophages induced endothelial proliferation and alleviated endothelial dysfunction. IL-35-treated New Zealand White rabbits with implanted SESs showed lower percentages of cross-sections with an uncovered strut, elevated mean neointimal hyperplasia (NIH) thickness, and inhibited inflammatory responses.Conclusions: We investigated the effect of IL-35 expression on early stent endothelialization in vivo and in vitro and identified a crucial role for IL-35 in inducing the activation of an anti-inflammatory M2-like macrophage phenotype. The present study highlights a new therapeutic strategy for early stent endothelialization.

In vivo predictors of plaque erosion in patients with ST-segment elevation myocardial infarction: a clinical, angiographical, and intravascular optical coherence tomography study.

Aims: Plaque erosion is a significant substrate of acute coronary thrombosis. This study sought to determine in vivo predictors of plaque erosion in patients with ST-segment elevation myocardial infarction (STEMI). Methods and results: A prospective series of 822 STEMI patients underwent pre-intervention optical coherence tomography. Using established diagnostic criteria, 209 had plaque erosion (25.4%) and 564 had plaque rupture (68.6%). Plaque erosion was more frequent in women <50 years when compared with those ≥50 years of age (P = 0.009). There was a similar, but less striking, trend in men (P = 0.011). Patients with plaque erosion were more frequently current smokers but had fewer other coronary risk factors (dyslipidaemia, hypertension, chronic kidney disease, and diabetes mellitus) than those with plaque rupture. There was a preponderance of plaque erosion in the left anterior descending artery (LAD; 61.2%), whereas plaque rupture was more equally distributed in both the LAD (47.0%) and right coronary artery (43.3%). Despite the similar spatial distribution of erosions and ruptures over the lengths of the coronary arteries, plaque erosion occurred more frequently near a bifurcation (P < 0.001). In the multivariable analysis, age <50 years, current smoking, absence of other coronary risk factors, lack of multi-vessel disease, reduced lesion severity, larger vessel size, and nearby bifurcation were significantly associated with plaque erosion. Nearby bifurcation and current smoking were especially notable in men, while age <50 years was most predictive in women. Conclusions: Plaque erosion was a predictable clinical entity distinct from plaque rupture in STEMI patients, and gender-specific role of risk factors in plaque erosion should be considered.

A Novel Rabbit Model for In-Stent Neoatherosclerosis.

In-stent neoatherosclerosis is an important problem after percutaneous coronary intervention. To explore the mechanisms and treatment of in-stent neoatherosclerosis, an animal model is needed. To avoid the disadvantages of current animal models, such as excessive use of X-rays and a high mortality rate, we attempted to develop an improved animal model. We explored a method that uses a short time interval to establish a rabbit model of in-stent neoatherosclerosis with a high survival rate and to evaluate its indicators. Sixty rabbits were divided into three equal groups: group A, the traditional method; group B, the standard intervention method; and group C, the improved method. In group C, we made two small incisions in each rabbit's neck, separated the common carotid, punctured it, and implanted a stent. The incision was then sutured. Four weeks later, we used optical coherence tomography (OCT) to scan all rabbits for neoatherosclerosis. We found no significant differences in OCT data between our new animal model and the traditional and interventional groups (P > 0.05). The technological success rate was higher in the new animal model (P < 0.001). We developed a new method to establish an animal model of neoatherosclerosis, which had similar results to the traditional and interventional methods.

C1q/TNF-Related Protein 9 Inhibits THP-1 Macrophage Foam Cell Formation by Enhancing Autophagy.

During the pathogenesis of early atherosclerosis, lipid-loaded macrophages are involved in plaque development and progression. As a novel adipokine, C1q/tumor necrosis factor-related protein-9 (CTRP9) has beneficial effects in cardiovascular disease. However, previous reports have not studied whether the formation of macrophage foam cell induced by oxidized low-density lipoprotein (ox-LDL) is affected by CTRP9. According to our study, in ox-LDL-induced THP-1 macrophages, CTRP9 could reduce the quantity of lipid droplets, lower the level of cholesteryl ester (CE), promote cholesterol efflux, as well as increase the expression level of the cholesterol transport receptors ATP-binding membrane cassette transporter A1 (ABCA1) and G1 (ABCG1). In addition, the protein of LC3 II is elevated and that of p62 is decreased in CTRP9-treated foam cells by enhancing autophagy. However, using 3-methyladenine (3-MA) abolished the role of CTRP9 by inhibiting autophagy. Mechanistically, the autophagy-promoting effects of CTRP9 on foam cells was reversed by an AMPK inhibitor, Compound C, which inhibited the signaling pathway of adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR). These results show that CTRP9 protects against atherosclerosis by promoting cholesterol efflux to reduce the formation of foam cell in virtue of inducing autophagy in an AMPK/mTOR signaling pathway-dependent manner.

Effective anti-thrombotic therapy without stenting: intravascular optical coherence tomography-based management in plaque erosion (the EROSION study).

AIMS: Plaque erosion, compared with plaque rupture, has distinctly different underlying pathology and therefore may merit tailored therapy. In this study, we aimed to assess whether patients with acute coronary syndrome (ACS) caused by plaque erosion might be stabilized by anti-thrombotic therapy without stent implantation. METHODS AND RESULTS: This was a single-centre, uncontrolled, prospective, proof-of concept study. Patients with ACS including ST-segment elevation myocardial infarction were prospectively enrolled. If needed, aspiration thrombectomy was performed. Patients diagnosed with plaque erosion by optical coherence tomography (OCT) and residual diameter stenosis <70% on coronary angiogram were treated with anti-thrombotic therapy without stenting. OCT was repeated at 1 month and thrombus volume was measured. The primary endpoint was >50% reduction of thrombus volume at 1 month compared with baseline. The secondary endpoint was a composite of cardiac death, recurrent ischaemia requiring revascularization, stroke, and major bleeding. Among 405 ACS patients with analysable OCT images, plaque erosion was identified in 103 (25.4%) patients. Sixty patients enrolled and 55 patients completed the 1-month follow-up. Forty-seven patients (47/60, 78.3%; 95% confidence interval: 65.8-87.9%) met the primary endpoint, and 22 patients had no visible thrombus at 1 month. Thrombus volume decreased from 3.7 (1.3, 10.9) mm3 to 0.2 (0.0, 2.0) mm3. Minimal flow area increased from 1.7 (1.4, 2.4) mm2 to 2.1 (1.5, 3.8) mm2. One patient died of gastrointestinal bleeding, and another patient required repeat percutaneous coronary intervention. The rest of the patients remained asymptomatic. CONCLUSION: For patients with ACS caused by plaque erosion, conservative treatment with anti-thrombotic therapy without stenting may be an option.