NEDD4L-mediated RASGRP2 suppresses high-glucose and oxLDL-induced vascular endothelial cell dysfunctions by activating Rap1 and R-Ras.

BACKGROUND: Ras guanyl-releasing protein 2 (RASGRP2) is an important regulator mediating endothelial cell function. However, whether RASGRP2 mediates diabetes mellitus (DM)-related atherosclerosis (AS) progression by regulating endothelial cell functions is unknown. METHODS: Human cardiac microvascular endothelial cells (HCMECs) were treated with high-glucose (HG) and oxidized low-density lipoprotein (oxLDL). The expression of RASGRP2 and neural precursor cell expressed developmentally downregulated 4-like (NEDD4L) was examined by quantitative real-time PCR and western blot (WB). Cell viability, apoptosis, migration, angiogenesis were detected by CCK8 assay, flow cytometry, transwell assay and tube formation assay. ROS production and cell permeability were tested to assess cell function. Rap1 and R-Ras protein levels were examined using WB. The interaction between RASGRP2 and NEDD4L was confirmed by Co-IP assay and ubiquitination assay. Exosomes were isolated from adipose-derived MSC (ADMSC)-transfected RASGRP2 overexpression vector, and then co-cultured with HG + oxLDL-induced HCMECs. RESULTS: RASGRP2 was lowly expressed in HG + oxLDL-induced HCMECs. RASGRP2 overexpression inhibited HG + oxLDL-induced HCMECs permeability, apoptosis and ROS production, while accelerated cell viability, migration and angiogenesis. NEDD4L could interact with RASGRP2 by ubiquitination, thus inhibiting RASGRP2 protein stability to degrade its expression. Functional experiments showed that NEDD4L knockdown suppressed HG + oxLDL-induced HCMECs dysfunction, while these effects were reversed by RASGRP2 downregulation. ADMSC-Exo overexpressed RASGRP2 could promote cell viability, migration and angiogenesis, while suppress permeability, apoptosis and ROS production in HG + oxLDL-induced HCMECs. CONCLUSION: Our data showed that targeting NEDD4L/RASGRP2 axis or inducing RASGRP2-modified ADMSC-Exo might be the efficient strategy for alleviating DM-related AS.

Explainable machine learning models for predicting 30-day readmission in pediatric pulmonary hypertension: A multicenter, retrospective study.

Background: Short-term readmission for pediatric pulmonary hypertension (PH) is associated with a substantial social and personal burden. However, tools to predict individualized readmission risk are lacking. This study aimed to develop machine learning models to predict 30-day unplanned readmission in children with PH. Methods: This study collected data on pediatric inpatients with PH from the Chongqing Medical University Medical Data Platform from January 2012 to January 2019. Key clinical variables were selected by the least absolute shrinkage and the selection operator. Prediction models were selected from 15 machine learning algorithms with excellent performance, which was evaluated by area under the operating characteristic curve (AUC). The outcome of the predictive model was interpreted by SHapley Additive exPlanations (SHAP). Results: A total of 5,913 pediatric patients with PH were included in the final cohort. The CatBoost model was selected as the predictive model with the greatest AUC for 0.81 (95% CI: 0.77-0.86), high accuracy for 0.74 (95% CI: 0.72-0.76), sensitivity 0.78 (95% CI: 0.69-0.87), and specificity 0.74 (95% CI: 0.72-0.76). Age, length of stay (LOS), congenital heart surgery, and nonmedical order discharge showed the greatest impact on 30-day readmission in pediatric PH, according to SHAP results. Conclusions: This study developed a CatBoost model to predict the risk of unplanned 30-day readmission in pediatric patients with PH, which showed more significant performance compared with traditional logistic regression. We found that age, LOS, congenital heart surgery, and nonmedical order discharge were important factors for 30-day readmission in pediatric PH.

A web-based prediction model for overall survival of elderly patients with early renal cell carcinoma: a population-based study.

BACKGROUND: The number of elderly patients with early renal cell carcinoma (RCC) is on the rise. However, there is still a lack of accurate prediction models for the prognosis of early RCC in elderly patients. It is necessary to establish a new nomogram to predict the prognosis of elderly patients with early RCC. METHODS: The data of patients aged above 65 years old with TNM stage I and II RCC were downloaded from the SEER database between 2010 and 2018. The patients from 2010 to 2017 were randomly assigned to the training cohort (n = 7233) and validation cohort (n = 3024). Patient data in 2018(n = 1360) was used for external validation. We used univariable and multivariable Cox regression model to evaluate independent prognostic factors and constructed a nomogram to predict the 1-, 3-, and 5-year overall survival (OS) rates of patients with early-stage RCC. Multiple parameters were used to validate the nomogram, including the consistency index (C-index), the calibration plots, the area under the receiver operator characteristics (ROC) curve, and the decision curve analysis (DCA). RESULTS: The study included a total of 11,617 elderly patients with early RCC. univariable and multivariable Cox regression analysis based on predictive variables such as age, sex, histologic type, Fuhrman grade, T stage, surgery type, tumors number, tumor size, and marriage were included to establish a nomogram. The C-index of the training cohort and validation cohort were 0.748 (95% CI: 0.760-0.736) and 0.744 (95% CI: 0.762-0.726), respectively. In the external validation cohort, C-index was 0.893 (95% CI: 0.928-0.858). The calibration plots basically coincides with the diagonal, indicating that the observed OS was almost equal to the predicted OS. It was shown in DCA that the nomogram has more important clinical significance than the traditional TNM stage. CONCLUSION: A novel nomogram was developed to assess the prognosis of an elderly patient with early RCC and to predict prognosis and formulate treatment and follow-up strategies.

Remodelling of gut microbiota by Berberine attenuates trimethylamine N-oxide-induced platelet hyperreaction and thrombus formation.

Berberine is an extract derived from Chinese herbs with pleiotropic cardiovascular protective effects. However, the underlying mechanism remains unclear because of its poor bioavailability. Herin, we aimed to investigate whether berberine affects choline diet-induced arterial thrombosis and explore the potential mechanism. Ultrasound and optical coherence tomography were used to assess the potential risk of artery thrombosis in vivo. The plasma concentrations of trimethylamine N-oxide (TMAO) and trimethylamine (TMA) were quantified with mass spectrometry. Enzyme-linked immunosorbent assay (ELISA) and quantitative real-time polymerase chain reaction (qPCR) were utilized to detect the levels of microbial TMA-lyase choline utilization C (CutC) in faeces. Gut microbiota analysis was performed with 16S rRNA gene sequencing. For in vitro studies, platelet aggregometry, intracellular Ca2+ measurement, ATP release assay, flow cytometry and Western blot were applied to identify the effects of TMAO on platelets. Berberine treatment significantly decreased the CutC levels in the caecal contents, reduced choline diet-induced TMA and TMAO production, and subsequently, reduced the arterial thrombosis potential risk. Berberine administration remodelled the structure of gut microbiota in rats and increased the levels of the genus Lactobacillus. Finally, TMAO enhanced platelet reactivity to collagen by promoting the phosphorylation levels of extracellular signal-regulated kinase 1/2 (ERK1/2) and Jun N-terminal kinase (JNK) in platelets. These results demonstrate that berberine attenuates the risk of choline diet-induced arterial thrombosis by changing the gut microbial composition and reducing TMAO generation.

Establishment of a Novel Mouse Model for Atherosclerotic Vulnerable Plaque.

Background and Aims: Acute coronary syndrome (ACS) is a group of clinical syndromes characterized by rupture or erosion of atherosclerotic unstable plaques. Effective intervention for vulnerable plaques (VP) is of great significance to reduce adverse cardiovascular events. Methods: Fbn1C1039G+/- mice were crossbred with LDLR-/- mice to obtain a novel model for atherosclerotic VP. After the mice were fed with a high-fat diet (HFD) for 12 or 24 weeks, pathological staining and immunohistochemistry analyses were employed to evaluate atherosclerotic lesions. Results: Compared to control mice, Fbn1C1039G+/-LDLR-/- mice developed more severe atherosclerotic lesions, and the positive area of oil red O staining in the aortic sinus was significantly increased after 12 weeks (21.7 ± 2.0 vs. 6.3 ± 2.1) and 24 weeks (32.6 ± 2.5 vs. 18.7 ± 2.6) on a HFD. Additional vulnerable plaque characteristics, including significantly larger necrotic cores (280 ± 19 vs. 105 ± 7), thinner fiber caps (14.0 ± 2.8 vs. 32.6 ± 2.7), apparent elastin fiber fragmentation and vessel dilation (3,010 ± 67 vs. 1,465 ± 49), a 2-fold increase in macrophage number (8.5 ± 1.0 vs. 5.0 ± 0.6), obviously decreased smooth muscle cell number (0.6 ± 0.1 vs. 2.1 ± 0.2) and an ~25% decrease in total collagen content (33.6 ± 0.3 vs. 44.9 ± 9.1) were observed in Fbn1C1039G+/-LDLR-/- mice compared with control mice after 24 weeks. Furthermore, spontaneous plaque rupture, neovascularization, and intraplaque hemorrhage were detected in the model mouse plaque regions but not in those of the control mice. Conclusions: Plaques in Fbn1C1039G+/-LDLR-/- mice fed a HFD show many features of human advanced atherosclerotic unstable plaques. These results suggest that the Fbn1C1039G+/-LDLR-/- mouse is a novel model for investigating the pathological and physiological mechanisms of advanced atherosclerotic unstable plaques.

Correction to: Roles of microRNA-34a targeting SIRT1 in mesenchymal stem cells.

An amendment to this paper has been published and can be accessed via the original article.

Intraplaque neovascularization attenuated statin benefit on atherosclerotic plaque in CAD patients: A follow-up study with combined imaging modalities.

BACKGROUND AND AIMS: Plaque progression increases the risk of a cardiovascular event. This study aims to determine whether intraplaque neovascularization (NV) associates with a greater risk of plaque progression. METHODS: Baseline and 12-month follow-up IVUS was used in combination with baseline OCT to assess 164 non-culprit plaques in 118 CAD patients. A generalized estimating equation approach with exchangeable correlation structure was used to correct for the dependency of repeated measurements. RESULTS: Patients were divided into two groups according to NV (52 patients with 62 NV plaques, 66 patients with 102 non-NV plaques). Non-culprit plaques in the NV group exhibited a more frequent occurrence of TCFA (p = 0.004), macrophage (p = 0.005), cholesterol crystal (p = 0.012), calcification (p = 0.030), thinner fibrous cap thickness (FCT) [(86.8 ±â€¯55.1) vs. (127.4 ±â€¯70.1) µm, p = 0.015], larger lipid arc [(219.5 ±â€¯66.9) vs. (179.8 ±â€¯61.4), p = 0.002] compared to the non-NV group. A large change in percent atheroma volume (PAV), plaque plus media cross-sectional area (P&M CSA), plaque volume, and plaque burden was observed from baseline to follow-up in the NV group. Changes in P&M CSA, plaque volume, and plaque burden showed significant differences in fibroatheroma with NV. Intraplaque NV could predict a high risk of plaque progression despite statin therapy [OR 6.521 (95% CI 2.457-17.308), p < 0.001]. CONCLUSIONS: NV might attenuate the benefits of statin therapy in plaque progression. This study may provide a new basis for anti-angiogenic strategies to prevent atherosclerotic plaque progression.

Small HDL subclass is associated with coronary plaque stability: An optical coherence tomography study in patients with coronary artery disease.

BACKGROUND: The role of high-density lipoprotein (HDL) subclasses in atherosclerotic diseases remains an open question. Previous clinical trials have attempted to explore the predictive effect of HDL subspecies on cardiovascular risk. However, no studies have assessed the connections between these subclasses and characteristics of plaque microstructure. OBJECTIVE: To investigate the relationship of HDL subclasses and coronary plaque stability assessed by optical coherence tomography (OCT). METHODS: Morphological characteristics of 160 nontarget lesions from 85 patients with coronary artery disease were assessed by OCT. HDL subclass profiles were analyzed using nondenaturing polyacrylamide gel electrophoresis. RESULTS: The plasma levels of small HDL subclass (percentage or concentration) were found to be positively associated with fibrous cap thickness (r = 0.232, P = .007; r = 0.243, P = .005) and negatively with maximum lipid arc (r = -0.240, P = .005; r = -0.252, P = .003) and lipid core length (r = -0.350, P < .001; r = -0.367, P < .001). Multivariate logistic regression analysis showed the small HDL subclass (percentage or concentration) (odds ratio [OR]: 0.457, 95% confidence interval [CI]: 0.214-0.974, P = .043; OR: 0.438, 95% CI: 0.204-0.938, P = .034) to be an independent factor in predicting OCT-detected thin-cap fibroatheroma of nontarget lesions. CONCLUSION: High levels of small HDL are associated with coronary nontarget plaque stability. Our findings suggest that the small HDL subtype might represent the atheroprotective activity of HDL.

Plasma trimethylamine N-oxide is associated with vulnerable plaque characteristics in CAD patients as assessed by optical coherence tomography.

BACKGROUND: Plaque vulnerability indicates the risk of a cardiovascular event. In the present study, we sought to analyze the relationship between trimethylamine N-oxide (TMAO), a gut microbiota metabolite from dietary phosphatidylcholine, and vulnerable plaque characteristics in patients with coronary artery disease (CAD). METHODS: One hundred eighty non-culprit plaques from 90 patients with ACS or with stable angina were assessed by optical coherence tomography (OCT). The plasma TMAO levels were measured using rapid resolution liquid chromatography quadrupole time-of-flight mass spectrometry (RRLC-QTOF/MS). RESULTS: Patients were divided into two groups (high TMAO group and low TMAO group) according to the median plasma TMAO level (114.73 µg/L). The non-culprit plaques in the high TMAO group exhibited a thinner fibrous cap thickness (FCT) (65.97 ±â€¯25.89 vs. 93.0 ±â€¯28.28 µm, P < 0.001), higher frequency of microvessels (75.6% vs. 31.1%, P < 0.001, per-patient) and increased incidence of thin-cap fibroatheroma (TCFA) (69.2% vs. 18.4%, P < 0.001, per-patient) compared with the low TMAO group. Moreover, the level of TMAO was negatively associated with FCT (r = -0.418, P < 0.001). Furthermore, multivariate regression analysis results showed that TMAO (OR: 7.455, 95% CI: 2.753-20.189, P < 0.001) had a significant association with TCFA, with a cut-off point of 118.34 µg/L, specificity of 72.6% and sensitivity of 79.5% in predicting the prevalence of TCFA. CONCLUSIONS: In conclusion, these findings suggest that the level of TMAO is significantly correlated with the incidence of TCFA. New biomarkers acquired through non-invasive means, such as TMAO, offer the potential to improve risk stratification and clinical management in patients with CAD.

Adipose-Derived Exosomes Exert Proatherogenic Effects by Regulating Macrophage Foam Cell Formation and Polarization.

BACKGROUND: Obesity is causally associated with atherosclerosis, and adipose tissue (AT)-derived exosomes may be implicated in the metabolic complications of obesity. However, the precise role of AT-exosomes in atherogenesis remains unclear. We herein aimed to assess the effect of AT-exosomes on macrophage foam cell formation and polarization and subsequent atherosclerosis development. METHODS AND RESULTS: Four types of exosomes isolated from the supernatants of ex vivo subcutaneous AT and visceral AT (VAT) explants that were derived from wild-type mice and high-fat diet (HFD)-induced obese mice were effectively taken up by RAW264.7 macrophages. Both treatment with wild-type VAT exosomes and HFD-VAT exosomes, but not subcutaneous AT exosomes, markedly facilitated macrophage foam cell generation through the downregulation of ATP-binding cassette transporter (ABCA1 and ABCG1)-mediated cholesterol efflux. Decreased expression of liver X receptor-α was also observed. Among the 4 types of exosomes, only HFD-VAT exosomes significantly induced M1 phenotype transition and proinflammatory cytokine (tumor necrosis factor α and interleukin 6) secretion in RAW264.7 macrophages, which was accompanied by increased phosphorylation of NF-κB-p65 but not the cellular expression of NF-κB-p65 or IκB-α. Furthermore, systematic intravenous injection of HFD-VAT exosomes profoundly exacerbated atherosclerosis in hyperlipidemic apolipoprotein E-deficient mice, as indicated by the M1 marker (CD16/32 and inducible nitric oxide synthase)-positive areas and the Oil Red O/Sudan IV-stained area, without affecting the plasma lipid profile and body weight. CONCLUSIONS: This study demonstrated a proatherosclerotic role for HFD-VAT exosomes, which is exerted by regulating macrophage foam cell formation and polarization, indicating a novel link between AT and atherosclerosis in the context of obesity.

Geraniin protects bone marrow­derived mesenchymal stem cells against hydrogen peroxide­induced cellular oxidative stress in vitro.

Administration of bone marrow­derived mesenchymal stem cells (MSCs) has emerged as a potential therapeutic approach for the treatment of myocardial infarction (MI). However, the increase in reactive oxygen species (ROS) in ischemic cardiac tissue compromises the survival of transplanted MSCs, thus resulting in limited therapeutic efficiency. Therefore, strategies that attenuate oxidative stress­induced damage and enhance MSC viability are required. Geraniin has been reported to possess potent antioxidative activity and exert protective effects on numerous cell types under certain conditions. Therefore, geraniin may be considered a potential drug used to modulate MSC­based therapy for MI. In the present study, MSCs were pretreated with geraniin for 24 h and were exposed to hydrogen peroxide (H2O2) for 4 h. Cell apoptosis, intracellular ROS levels and mitochondrial membrane potential were measured using Annexin V­fluorescein isothiocyanate/propidium iodide staining, the 2',7'­dichlorodihydrofluorescein diacetate fluorescent probe and the membrane permeable dye JC­1, respectively. Glutathione and malondialdehyde levels were also investigated. The expression levels of apoptosis­associated proteins and proteins of the phosphoinositide 3­kinase (PI3K)/protein kinase B (Akt) signaling pathway were analyzed by western blotting. The results demonstrated that geraniin could significantly attenuate H2O2­induced cell damage by promoting MSC survival, reducing cellular ROS production and maintaining mitochondrial function. Furthermore, geraniin modulated the expression levels of phosphorylated­Akt in a time­ and dose­dependent manner. The cytoprotective effects of geraniin were suppressed by LY294002, a specific PI3K inhibitor. In conclusion, the present study revealed that geraniin protects MSCs from H2O2­induced oxidative stress injury via the PI3K/Akt pathway. These findings indicated that cotreatment of MSCs with geraniin may optimize therapeutic efficacy for the clinical treatment of MI.

Association of Platelet to lymphocyte ratio with non-culprit atherosclerotic plaque vulnerability in patients with acute coronary syndrome: an optical coherence tomography study.

BACKGROUND: The platelet to lymphocyte ratio (PLR), an indirect inflammatory biomarker, has been recently demonstrated to be associated with severity of coronary artery disease. In the present study, we sought to investigate whether PLR is associated with vulnerable plaque characteristics of non-culprit lesions in patients with acute coronary syndrome (ACS). METHODS: The patients in our study were divided into two groups (high PLR group and low PLR group). A total of 119 non-culprit plaques from 71 patients with ACS were assessed by optical coherence tomography (OCT). RESULTS: The non-culprit plaques in high PLR group exhibited thinner fibrous cap thickness (FCT) (88.60 ± 44.70 vs. 119.28 ± 50.22 µm, P = 0.001), greater maximum lipid arc (271.73 ± 71.66 vs. 240.60 ± 76.69°, P = 0.027) and increased incidence of thin-cap fibroatheroma (TCFA) (34.0% vs. 15.9%, P = 0.022) compared with those in low PLR group. Meanwhile, PLR was negatively associated with FCT (r = -0.329, P < 0.001). Furthermore, multivariate regression analysis showed that PLR [OR: 1.023 (95% CI: 1.005-1.041), P = 0.012] and LDL-C [OR: 1.892 (95% CI: 1.106-3.239), P = 0.020] were significant predictors of TCFA. CONCLUSIONS: High level of PLR may be associated with vulnerable plaque features of non-culprit lesions in patients with ACS. PLR, a cheap and easily available index, may surve as a useful inflammatory marker in reflecting plaque vulnerability.

MicroRNA-182 prevents vascular smooth muscle cell dedifferentiation via FGF9/PDGFRß signaling.

The abnormal phenotypic transformation of vascular smooth muscle cells (SMCs) causes various proliferative vascular diseases. MicroRNAs (miRNAs or miRs) have been established to play important roles in SMC biology and phenotypic modulation. This study revealed that the expression of miR­182 was markedly altered during rat vascular SMC phenotypic transformation in vitro. We aimed to investigate the role of miR­182 in the vascular SMC phenotypic switch and to determine the potential molecular mechanisms involved. The expression of miR­182 gene was significantly downregulated in cultured SMCs during dedifferentiation from a contractile to a synthetic phenotype. Conversely, the upregulation of miR­182 increased the expression of SMC-specific contractile genes, such as α-smooth muscle actin, smooth muscle 22α and calponin. Additionally, miR­182 overexpression potently inhibited SMC proliferation and migration under both basal conditions and under platelet-derived growth factor-BB stimulation. Furthermore, we identified fibroblast growth factor 9 (FGF9) as the target gene of miR­182 for the phenotypic modulation of SMCs mediated through platelet-derived growth factor receptor ß (PDGFRß) signaling. These data suggest that miR­182 may be a novel SMC phenotypic marker and a modulator that may be used to prevent SMC dedifferentiation via FGF9/PDGFRß signaling.

Relation between baseline plaque features and subsequent coronary artery remodeling determined by optical coherence tomography and intravascular ultrasound.

Atherosclerosis often leads to myocardial infarction and stroke. We examined the influence of baseline plaque characteristics on subsequent vascular remodeling in response to changes in plaque size. Using optical coherence tomography (OCT) and intravascular ultrasound (IVUS), we examined 213 plaques from 138 patients with acute coronary syndrome at baseline and repeated IVUS at the 12-month follow-up. The change in external elastic membrane (EEM) area for each 1 mm2 change in plaque area (i.e., the slope of the regression line) was calculated as a measure of vascular remodeling capacity. In plaques with static positive remodeling, the slope was smaller than in plaques without static positive remodeling. In addition, the slope of the regression line for lesions with a large plaque burden was much smaller than that for lesions with a small plaque burden. Multivariate linear regression analysis showed that diabetes, calcification and static positive remodeling were inversely and independently associated with the level of change in EEM area/change in plaque area. Lesions with a large plaque burden, calcifications or static positive remodeling had less remodeling capacity, and calcification and static positive remodeling were independent predictors of reduced subsequent remodeling. Therefore, calcifications and static positive remodeling could be used as morphological biomarkers to predict decreased subsequent arterial remodeling.

Comparison of coronary arterial lumen dimensions on angiography and plaque characteristics on optical coherence tomography images and their changes induced by statin.

BACKGROUND: Coronary angiography (CAG) is widely used to assess lumen dimensions, and optical coherence tomography (OCT) is used to evaluate the characteristics of atherosclerotic plaque. This study was aimed to compare coronary lumen dimensions using CAG and plaque characteristics using OCT and their changes during statin therapy. METHODS: We identified 97 lipid-rich plaques from 69 statin-naïve patients, who received statin therapy in the following 12 months. CAG and OCT examinations were conducted at baseline and 12-month follow-up period. RESULTS: Lesion length, as measured by CAG, was closely correlated with lipid length by OCT (baseline: r = 0.754, p < 0.001; follow-up: r = 0.639, p < 0.001). However, no significant correlations were found between the other findings on OCT and data on CAG. With 12-month statin therapy, microstructures of lipid-rich plaques were significantly improved, but CAG-derived lumen dimensions were not improved. Moreover, we found no significant relationship between changes in OCT measurements and changes in CAG data over time. CONCLUSION: Lipid length on OCT and lesion length on CAG were closely correlated. However, plaque microstructural characteristics on OCT showed no significantly statistically correlations with lumen dimensions on CAG, neither did their evolutionary changes induced by statin over time. A RETROSPECTIVELY REGISTERED STUDY: Clinical trial registry: ClinicalTrial.gov. Registered number: NCT01023607 . Registered 1 December 2009.

Patterns of coronary plaque progression: phasic versus gradual. A combined optical coherence tomography and intravascular ultrasound study.

OBJECTIVE: Some plaques grow slowly in a linear manner, whereas others undergo a rapid phasic progression. However, the detailed in-vivo relationship between plaque characteristics and plaque progression pattern has not been reported. The current study aimed to investigate the plaque progression patterns with serial intravascular ultrasound (IVUS) examinations, and to correlate baseline plaque characteristics assessed by optical coherence tomography and IVUS with plaque progression patterns. METHODS: A total of 248 coronary lesions from 157 patients were identified and imaged by both optical coherence tomography and IVUS at baseline. IVUS examination was repeated at 6 and 12 months. Plaque progression was defined as greater than or equal to 5% increase in percent atheroma volume by IVUS. The progression patterns were divided into three groups: no progression, rapid phasic progression, and gradual progression. RESULTS: Among 248 lesions, 190 (77%) showed no progression. Among 58 lesions with progression, 20 (34%) showed gradual progression, whereas 38 (66%) showed rapid phasic progression. Multivariate analysis indicated that thin-cap fibroatheroma [odds ratio (OR)=5.24, 95% confidence interval (CI) 2.04-13.4; P=0.001], microvessel (OR=2.20, 95% CI 1.10-4.79; P=0.045), and positive remodeling (OR=2.64, 95% CI 1.19-5.81; P=0.016) were associated independently with rapid phasic progression. CONCLUSION: Three-quarters of coronary plaques did not progress over time with contemporary medical treatment. Among the lesions with progression, one-third showed a gradual pattern and two-thirds showed a rapid phasic pattern. The presence of thin-cap fibroatheroma, microvessel, and positive remodeling were the independent predictors for rapid phasic pattern progression of coronary atherosclerotic plaques.

Statin-induced improvements in vulnerable plaques are attenuated in poorly controlled diabetic patients with coronary atherosclerosis disease: a serial optical coherence tomography analysis.

AIMS: The incidence of cardiac events is increased in diabetic patients even after lipid-lowering therapy. This study aimed to compare the statin-induced changes in the characteristics of vulnerable plaques in patients without diabetes mellitus (DM) and in those with better- or poorly controlled DM, measured by optical coherence tomography (OCT). METHODS: This was a retrospective study of 99 non-culprit lipid-rich plaques from 75 patients who underwent intensive OCT imaging examination. Thirty-four non-diabetic patients were assigned to Group A. According to the average HbA1c level, 22 diabetic patients were assigned to Group B, and 19, to Group C (average HbA1c < 8 and ≥8 %, respectively). RESULTS: Following 12 months of statin therapy, similar improvements in serum lipid levels were observed in the three groups. However, the increase in fibrous-cap thickness of plaques was the highest in Group A (Group A, 183 %; Group B, 104 %; and Group C, 53 %). Significant reductions in lipid volume index were observed in Groups A and B (Group A: -12 %, P < 0.001; Group B: -13 %, P = 0.038; Group C: 7 %, P = 0.948). Percent changes in OCT measurements were significantly correlated with average HbA1c in patients. CONCLUSIONS: Improved glucose control may enhance the statin-induced reduction in characteristics of vulnerable plaque in diabetic patients.

Relationship between serum angiopoietin-like protein 2 and plaque vulnerability in patients with coronary artery disease and diabetes.

AIMS: Obesity is characterized by low-grade inflammation state and excessive inflammatory cytokine production of adipose tissue. Angiopoietin-like protein 2 (ANGPTL2), a novel proinflammatory adipokine, has recently been suggested to be involved in the pathogenesis of atherosclerosis in animal studies. However, no data regarding the relationship between ANGPTL2 and morphologic characteristics of coronary plaques in humans are available. The aim of the current study was to investigate the in vivo association between serum ANGPTL2 level and plaque vulnerability in patients with coronary artery disease (CAD) and diabetes. METHODS AND RESULTS: 72 consecutive patients with clinically proven CAD and diabetes were enrolled between October 2013 and December 2014. Circulating ANGPTL2 concentration was measured using a human ANGPTL2 sandwich enzyme-linked immunosorbent assay (ELISA) kit. The morphologic characteristics of non-culprit lipid-rich plaques were assessed by optical coherence tomography. Fibrous cap thickness was significantly and negatively correlated with serum ANGPTL2 levels (r = -0.29, P = 0.005). A significant and positive correlation was observed between mean lipid core arc and serum ANGPTL2 concentration (r = 0.32, P = 0.01). In addition, levels of serum ANGPTL2 were significantly higher in patients with thin-cap fibroatheroma (TCFA) than those without TCFA (P < 0.001). Multivariate logistic regression analysis showed that a higher serum ANGPTL2 concentration was a powerful predictor of TCFA (odds ratio: 3.18, P = 0.002). CONCLUSION: Serum ANGPTL2 level is significantly associated with plaque vulnerability in patients with CAD and diabetes. Systemic ANGPTL2 comprises an inflammatory adipokine that links the adipose tissue and coronary plaque.

Roles of microRNA-34a targeting SIRT1 in mesenchymal stem cells.

INTRODUCTION: Mesenchymal stem cell (MSC)-based therapies have had positive outcomes both in animal models of cardiovascular diseases and in clinical patients. However, the number and function of MSCs decline during hypoxia and serum deprivation (H/SD), reducing their ability to contribute to endogenous injury repair. MicroRNA-34a (miR-34a) is originally identified as a TP53-targeted miRNA that modulates cell functions, including apoptosis, proliferation, and senescence via several signaling pathways, and hence is an appealing target for MSC-based therapy for myocardial infarction. METHODS: Bone marrow-derived MSCs were isolated from 60-80 g male donor rats. Expression levels of miR-34a were determined by qRT-PCR. The roles of miR-34a in regulating cell vitality, apoptosis and senescence were investigated using the cell counting kit (CCK-8) assay, flow cytometric analysis of Annexin V-FITC/PI staining and senescence-associated ß-galactosidase (SA-ß-gal) staining, respectively. The expression of silent information regulator 1 (SIRT1) and forkhead box class O 3a (FOXO3a) and of apoptosis- and senescence-associated proteins in MSCs were analyzed by western blotting. RESULTS: The results of the current study showed that miR-34a was significantly up-regulated under H/SD conditions in MSCs, while overexpression of miR-34a was significantly associated with increased apoptosis, impaired cell vitality and aggravated senescence. Moreover, we found that the mechanism underlying the proapoptotic function of miR-34a involves activation of the SIRT1/FOXO3a pathway, mitochondrial dysfunction and finally, activation of the intrinsic apoptosis pathway. Further study showed that miR-34a can also aggravate MSC senescence, an effect which was partly abolished by the reactive oxygen species (ROS) scavenger, N-acetylcysteine (NAC). CONCLUSIONS: Our study demonstrates for the first time that miR-34a plays pro-apoptotic and pro-senescence roles in MSCs by targeting SIRT1. Thus, inhibition of miR-34a might have important therapeutic implications in MSC-based therapy for myocardial infarction.

Association of circulating levels of neopterin with non-culprit plaque vulnerability in CAD patients an angiogram, optical coherent tomography and intravascular ultrasound study.

BACKGROUND: Neopterin is a pteridine derivative secreted by activated macrophages. Previous studies have shown that neopterin plays a pivotal role in coronary artery disease (CAD); however, the relationship between circulating neopterin and non-culprit plaque vulnerability in patients with CAD remains unclear. In this study, we investigated the correlation of neopterin and vulnerable plaque features in patients with CAD. METHODS: One hundred and thirty non-culprit plaques from 81 patients with CAD were assessed by angiogram and optical coherence tomography (OCT) as well as intravascular ultrasound (IVUS) imaging. According to the median value of serum neopterin (10.61 nmol/L), patients were divided into a low neopterin group (n = 40,