Quantitative Flow Ratio-Derived Index of Microcirculatory Resistance as a Novel Tool to Identify Microcirculatory Function in Patients with Ischemia and No Obstructive Coronary Artery Disease.

BACKGROUND: Coronary microvascular disease (CMVD) is associated with adverse cardiovascular outcomes. However, there is no reliable and noninvasive quantitative diagnostic method available for CMVD. The use of a pressure wire to measure the index of microcirculatory resistance (IMR) is possible, but it has inevitable practical restrictions. We hypothesized that computation of the quantitative flow ratio could be used to predict CMVD with symptoms of ischemia and no obstructive coronary artery disease (INOCA). METHODS: We retrospectively assessed the diagnostic efficiency of the quantitative flow ratio-derived index of microcirculatory resistance (QMR) in 103 vessels from 66 patients and compared it with invasive IMR using the thermodilution technique. RESULTS: Patients were divided into the CMVD group (41/66, 62.1%) and non-CMVD group (25/66, 37.9%). Pressure wire IMR measurements were made in 103 coronary vessels, including 44 left descending arteries, 18 left circumflex arteries, and 41 right coronary arteries. ROC curve analysis showed a good diagnostic performance of QMR for all arteries (area under the curve = 0.820, 95% confidence interval 0.736-0.904, p < 0.001) in predicting microcirculatory function. The optimal cut-off for QMR to predict microcirculatory function was 266 (sensitivity: 82.9%, specificity: 72.6%, and diagnostic accuracy: 76.7%). CONCLUSION: QMR is a promising tool for the assessment of coronary microcirculation. The assessment of the IMR without the use of a pressure wire may enable more rapid, convenient, and cost-effective assessment of coronary microvascular function.

The role of late reperfusion in ST-segment elevation myocardial infarction: a real-world retrospective cohort study.

BACKGROUND: Early reperfusion of the coronary artery has become the first choice for patients with ST-segment elevation myocardial infarction (STEMI). How to deal with patients who miss the time window for early reperfusion is still controversial. Based on real-world data, this study was conducted to explore whether percutaneous coronary intervention (PCI) has an advantage over standard drug therapy in patients who miss the optimal treatment window. METHODS: Consecutive patients who were diagnosed with STEMI and met the inclusion criteria between 2009 and 2018 in our center were retrospectively included in this cohort study. The primary endpoint events were major adverse cardiac events (MACEs), including heart failure, sudden cardiac death, malignant arrhythmia, thrombi and bleeding events during the period of admission. Secondary endpoint events were components of MACEs. At the same time, we also evaluated angina pectoris at admission and discharge through Canadian Cardiovascular Society (CCS) grading. RESULTS: This study enrolled 417 STEMI patients and divided them into four groups (PCI < 3 days, 14.87%; 3 days 7 days, 34.29%; MED, 29.74%). During the period of admission, MACEs occurred in 52 cases. The incidence of MACEs was 11.29, 7.95, 4.20 and 25.81% in the four respective groups (p < 0.0001). The MED group had higher rates of MACEs (OR = 3.074; 95% CI 0.1.116-8.469, p = 0.03) and cardiac death (OR = 3.027; 95% CI 1.121-8.169, p = 0.029) compared to the PCI group. Although both treatments were effective in improving CCS grade at discharge, the PCI group improved more significantly (p < 0.0001). CONCLUSIONS: In the real world, delayed PCI can be more effective in patients with angina symptoms at discharge and reduce the incidence of MACEs and cardiac death during hospitalization. The timing of intervention was independent of the occurrence of MACEs during hospitalization and of improvement in symptoms.

Role of stromal cell-derived factor-1 in patients with non-ST elevation acute coronary syndrome.

The predictive value of stromal cell-derived factor-1 (SDF-1) has not been established in patients with non-ST elevation acute coronary syndrome (non-STEACS). A total of 678 consecutive patients with non-STEACS and moderate to high TIMI (Thrombolysis In Myocardial Infarction) risk scores were recruited. All patients underwent an early invasive strategy and then were followed-up for 18 months for clinical events. Left ventricular remodeling was assessed by echocardiography. Plasma concentrations of SDF-1 and N-terminal pro-B-type natriuretic peptide (NT-proBNP) were analyzed. SDF-1 level was an independent predictor of left ventricular remodeling (OR = 2.95, 95% CI = 2.02-4.30, P < 0.001). Cox regression analysis demonstrated that both SDF-1 and NT-proBNP levels were significant independent predictors of death, myocardial infarction, or heart failure (HR = 2.45, 95% CI = 1.71-3.50, P < 0.001; HR = 3.71, 95% CI = 2.41-5.70, P < 0.001, respectively). The area under the ROC curves for SDF-1 (0.776) and NT-proBNP (0.817) were similar. The logistic model with both markers yielded a larger area under the ROC curve (0.862) than that of SDF-1 (P < 0.001) or NT-proBNP (P = 0.0001) alone. In patients stratified by NT-proBNP (above 615.4 pmol/L), SDF-1 (above 2175.1 pg/mL) was associated with poorer outcome (P < 0.001). Findings were similar for death and heart failure as individual endpoints. In non-STEACS, higher SDF-1 levels were a significant predictor of death, myocardial infarction, or heart failure independently of baseline clinical characteristics and NT-proBNP, and the combination of SDF-1 and NTproBNP significantly improved risk stratification. These data highlight the prognostic value of multiple, complementary biomarkers in non-ST elevation acute coronary syndrome.

Common variants in adiponectin gene are associated with coronary artery disease and angiographical severity of coronary atherosclerosis in type 2 diabetes.

BACKGROUND: Adiponectin, an adipokine facilitating insulin action, has antiatherogenic effects. This study investigated whether common single nucleotide polymorphisms (SNPs) in the adiponectin gene influenced plasma adiponectin level and whether they were associated with the risk of coronary artery disease (CAD) and its angiographical severity in type 2 diabetes in Chinese population. METHODS: 11 tagging SNPs were genotyped in 1110 subjects with or without CAD in type 2 diabetes. Variants of adiponectin gene were determined by Taqman polymerase chain reaction method. The plasma adiponectin concentrations were measured by sandwich enzyme-linked immunosorbent assay. The severity and extent of coronary atherosclerosis were assessed using the angiographic Gensini score and Sullivan Extent score. RESULTS: Among the 11 SNPs, the minor G allele of SNP rs266729 was significantly associated with higher odds of CAD (odds ratio (95% CI) = 1.49 (1.10 - 2.16), P = 0.022) after adjusting for covariates. In stepwise multivariate logistic regression, SNP rs266729 was a significant independent factor of CAD. Multivariate linear regression analysis revealed that rs266729 (ß = -0.101, P < 0.0001), rs182052 (ß = -0.044, P = 0.0035), and rs1501299 (ß = 0.073, P < 0.0001) were significantly associated with adiponectin level, and also indicated that the minor G allele of SNP rs266729 had higher Gensini score (ß = 0.139, P < 0.001) and Sullivan Extent score (ß = 0.107, P < 0.001). Haplotypes analysis revealed different haplotype distributions in case and control subjects (P = 0.0003), with two common haplotypes GGG and GAG of the rs266729, rs182052, and rs1501299 being associated in heterozygotes with a greater than threefold increase in cardiovascular risk (odds ratio (95% CI)=3.39 (1.83 - 6.30), P = 0.0001). CONCLUSIONS: In our population, genetic variants in the adiponectin gene influence plasma adiponectin levels, and one of them is a strong determinant of CAD susceptibility and its angiographical severity in type 2 diabetes. This study has provided further evidence for a role of adiponectin in the development of CAD.

[Curative effects on standardized management of community patients with coronary heart disease complicated with chronic heart failure].

OBJECTIVE: To explore the effects on the standardized management of patients with coronary atherosclerotic heart disease complicated with chronic heart failure. METHODS: A total of 823 patients discharged from our department were randomly enrolled. Among 734 patients with follow-up consents, they were divided into management and control groups (n = 440, 294). The management group received standardized out-of-hospital management, regular health education and follow-ups of telephone and outpatient visits. RESULTS: Compared with the control group, the management group had lower rates of all-cause mortality, cardiac death and readmission due to cardiovascular events (CVE) declining by 26.5%, 32.2% and 57.0% respectively. Over a 4-year period, the annular survival rate of management group was 92%, 85%, 83% and 82% while that of control group 95%, 89%, 82% and 75% respectively. Patient compliance of digoxin and diuretics in the control group was inferior to that in the management group. CONCLUSION: Through standardized out-of-hospital management, the patients with coronary atherosclerotic heart disease plus chronic heart failure may achieve significant benefits through reducing the rates of all-cause mortality, cardiac death and readmission due to CVE and improving survival rate.

Development and Validation of a Nomogram for Predicting Radial Artery Spasm During Coronary Angiography.

This study describes an attempt to develop a user-friendly nomogram incorporating psychological factors to individually predict the risk of radial artery spasm. Patients consecutively recruited between June 2020 and June 2021 constituted the development cohort for retrospective analysis of the development of a prediction model. Least absolute shrinkage and selection operator regression combined with clinical significance was employed to screen out appropriate independent variables. The model's discrimination and calibration were subsequently evaluated and calibrated by using the C-index, receiver operating characteristic (ROC) curve, and calibration plot. Decision curve analysis was also performed to evaluate the net benefit with the nomogram, and internal validation was assessed using bootstrapping validation. The predictors included in the risk nomogram included "body mass index ," "anxiety score," "duration of interventional surgery," "latency time (time spent waiting in the catheterization laboratory)," "vascular circuity (substantial changes in the curvature of vessels)," and "puncture number." The derived model showed good discrimination with an area under the ROC curve of .77, a C-index of .771 (95% CI: .72-.822) and good calibration. Decision curve analysis indicated that the nomogram provided a better net benefit than the alternatives.

Association of exposures to serum terpenes with the prevalence of dyslipidemia: a population-based analysis.

This study sought to examine hitherto unresearched relationships between serum terpenes and the prevalence of dyslipidemia. Serum terpenes such as limonene, α-pinene, and ß-pinene from the 2013-2014 National Health and Nutrition Examination Survey (NHANES) were used as independent variables in this cross-sectional study. Continuous lipid variables included total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), non-HDL-C, triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), residual cholesterol (RC), and apolipoprotein B (Apo B). Binary lipid variables (elevated TC, ≥5.18 mmol/L; lowered HDL-C, <1.04 mmol/L in men, and <1.30 mmol/L in women; elevated non-HDL-C, ≥4.2 mmol/L; elevated TG, ≥1.7 mmol/L; elevated LDL-C, ≥3.37 mmol/L; elevated RC, ≥1.0 mmol/L; and elevated Apo B, ≥1.3 g/L) suggest dyslipidemia. The relationships between the mixture of serum terpenes with lipid variables were investigated using weighted quantile sum (WQS) regression and Bayesian kernel machine regression (BKMR). The study for TC, HDL-C, and non-HDL-C included a total of 1,528 people, whereas the analysis for TG, LDL-C, RC, and Apo B comprised 714 participants. The mean age of the overall participants was 47.69 years, and 48.77% were male. We found that tertiles of serum terpene were positively associated with binary (elevated TC, non-HDL-C, TG, LDL-C, RC, Apo B, and lowered HDL-C) and continuous (TC, non-HDL-C, TG, LDL-C, RC, and Apo B, but not HDL-C) serum lipid variables. WQS regression and BKMR analysis revealed that the mixture of serum terpenes was linked with the prevalence of dyslipidemia. According to our data, the prevalence of dyslipidemia was correlated with serum concentrations of three terpenes both separately and collectively.

The Importance of Integrated Regulation Mechanism of Coronary Microvascular Function for Maintaining the Stability of Coronary Microcirculation: An Easily Overlooked Perspective.

Coronary microvascular dysfunction (CMD) refers to a group of disorders affecting the structure and function of coronary microcirculation and is associated with an increased risk of major adverse cardiovascular events. At present, great progress has been made in the diagnosis of CMD, but there is no specific treatment for it because of the complexity of CMD pathogenesis. Vascular dysfunction is one of the important causes of CMD, but previous reviews mostly considered microvascular dysfunction as a whole abnormality so the obtained conclusions are skewed. The coronary microvascular function is co-regulated by multiple mechanisms, and the mechanisms by which microvessels of different luminal diameters are regulated vary. The main purpose of this review is to revisit the mechanisms by which coronary microvessels at different diameters regulate coronary microcirculation through integrated sequential activation and briefly discuss the pathogenesis, diagnosis, and treatment progress of CMD from this perspective.

Impact of epicardial adipose tissue volume on hemodynamically significant coronary artery disease in Chinese patients with known or suspected coronary artery disease.

Background: Epicardial adipose tissue (EAT) is directly related to coronary artery disease (CAD), but little is known about its role in hemodynamically significant CAD. Therefore, our goal is to explore the impact of EAT volume on hemodynamically significant CAD. Methods: Patients who underwent coronary computed tomography angiography (CCTA) and received coronary angiography within 30 days were retrospectively included. Measurements of EAT volume and coronary artery calcium score (CACs) were performed on a semi-automatic software based on CCTA images, while quantitative flow ratio (QFR) was automatically calculated by the AngioPlus system according to coronary angiographic images. Results: This study included 277 patients, 112 of whom had hemodynamically significant CAD and showed higher EAT volume. In multivariate analysis, EAT volume was independently and positively correlated with hemodynamically significant CAD [per standard deviation (SD) cm3; odds ratio (OR), 2.78; 95% confidence interval (CI), 1.86-4.15; P < 0.001], but negatively associated with QFRmin (per SD cm3; ß coefficient, -0.068; 95% CI, -0.109 to -0.027; P = 0.001) after adjustment for traditional risk factors and CACs. Receiver operating characteristics curve analysis demonstrated a significant improvement in predictive value for hemodynamically significant CAD with the addition of EAT volume to obstructive CAD alone (area under the curve, 0.950 vs. 0.891; P < 0.001). Conclusion: In this study, we found that EAT volume correlated substantially and positively with the existence and severity of hemodynamically significant CAD in Chinese patients with known or suspected CAD, which was independent of traditional risk factors and CACs. In combination with obstructive CAD, EAT volume significantly improved diagnostic performance for hemodynamically significant CAD, suggesting that EAT could be a reliable noninvasive indicator of hemodynamically significant CAD.

Impact of plaque characteristics on percutaneous coronary intervention-related microvascular dysfunction: insights from angiographic microvascular resistance and intravascular ultrasound.

Background: The correlation between percutaneous coronary intervention (PCI)-related microvascular dysfunction (MVD) and plaque characteristics remains unclear. To investigate this correlation and its prognosis, we assessed changes in MVD by angiographic microvascular resistance (AMR) and intracoronary ultrasound scans after PCI. Methods: We conducted a retrospective study that enrolled 250 patients with coronary artery disease between July 2016 and December 2018. We collected demographic characteristics, laboratory tests, coronary angiography (CAG) and intracoronary ultrasound findings. We calculated quantitative flow ratio (QFR) and AMR by CAG. The endpoint was vessel-oriented composite outcomes (VOCOs). Results: After 47 exclusions, we divided 203 cases into a deteriorated group (n=139) and an improved group (n=64) based on AMR change after PCI. Compared with the improved group, the deteriorated group had smaller lumen area [3.03 (interquartile range, 2.20-3.91) vs. 3.55 mm2 (interquartile range, 2.45-4.57), P=0.033], higher plaque burden [78.92% (interquartile range, 73.95-82.61%) vs. 71.93% (interquartile range, 62.70-77.51%), P<0.001], and higher proportion of lipidic components (13.86%±4.67% vs. 11.78%±4.41%, P=0.024). Of 186 patients who completed 4.81±1.55 years follow-up, 56 developed VOCOs. Receiver-operating characteristic (ROC) curve analysis showed post-PCI AMR and VOCOs correlation (area under the curve: 0.729, P<0.001). Multivariate regression analysis showed post-PCI AMR >285 mmHg·s/m correlated with adverse outcome (hazard ratio =4.350; 95% confidence interval: 1.95-9.703; P<0.001). Conclusions: Intravascular ultrasound (IVUS) imaging and AMR revealed an association of post-PCI MVD with a smaller lumen area, more severe plaque burden, and a higher percentage of lipidic components. Post-PCI MVD was an independent risk factor for poor prognosis.

Integrated Bioinformatic Analyses Reveal Immune Molecular Markers and Regulatory Networks for Cerebral Ischemia-Reperfusion.

BACKGROUND: Cerebral ischemia-reperfusion injury (CIR) following a stroke results in secondary damage and is a leading cause of adult disability. The present study aimed to identify hub genes and networks in CIR to explore potential therapeutic agents for its treatment. METHODS: Differentially expressed genes based on the GSE23163 dataset were identified, and weighted gene co-expression network analysis was performed to explore co-expression modules associated with CIR. Hub genes were identified by intersecting immune gene profiles, differentially expressed genes, and modular genes. Gene Ontology, Kyoto Encyclopedia of Genes and Genomes pathway, and transcription factor-microRNA-gene regulatory network analyses were then conducted in selected crucial modules. Subsequently, their expression levels in animal models were verified using real-time quantitative polymerase chain reaction and Western blotting. Finally, potential drug molecules were screened for, and molecular docking simulations were performed to identify potential therapeutic targets. RESULTS: Seven hub genes-namely, Ccl3, Ccl4, Ccl7, Cxcl1, Hspa1a, Cd14, and Socs3-were identified. Furthermore, we established a protein interaction network using the STRING database and found that the core genes selected through the cytohubba plugin remained consistent. Animal experiments showed that at the transcriptional level, all seven genes showed significant differences (p < 0.001, fold change vs sham, 5-200). At the translational level, however, only Ccl3, Ccl4, Ccl7, Hspa1a, and Socs3 showed significant differences, while Cxcl1 and Cd14 did not. Nifedipine, with the highest predicted score, was identified as a therapeutic agent and successfully docked with the protein encoded by the hub genes. CONCLUSIONS: The expression of Ccl3, Ccl4, Ccl7, Hspa1a, and Socs3 was significantly different in CIR tissues compared to normal tissues both at the transcriptional and translational levels. Systems biology approaches indicated that these could be possible CIR marker genes, providing a stepping stone for further experimental studies.

Secondary prevention of antithrombotic therapy in patients with stable cardiovascular disease at high ischemic risk: A network meta-analysis of randomized controlled trials.

Aims: Antithrombotic secondary prevention in stable cardiovascular disease (SCVD) patients at high ischemic risk remains unclear. We compared the efficacy and safety of aspirin monotherapy, clopidogrel monotherapy, ticagrelor monotherapy, rivaroxaban monotherapy, clopidogrel plus aspirin, ticagrelor plus aspirin, and rivaroxaban plus aspirin in the high-risk ischemic cohorts. Methods and results: Eleven randomized controlled trials were included (n = 111737). The primary outcomes were major cardiovascular and cerebrovascular events (MACEs) and major bleeding. A random effects model was used for frequentist network meta-analysis. Odds ratio (OR) and 95% credible intervals (CI) were reported as a summary statistic. Compared with aspirin monotherapy, rivaroxaban plus aspirin [OR 0.79 (95% CI, 0.69, 0.89)], ticagrelor plus aspirin [0.88 (0.80, 0.98)], clopidogrel plus aspirin [0.56 (0.41, 0.77)] were associated with a reduced risk of MACEs, but rivaroxaban monotherapy [0.92 (0.79, 1.07)], ticagrelor monotherapy [0.68 (0.45, 1.05)], and clopidogrel monotherapy [0.67 (0.43, 1.05)] showed no statistically significant difference. However, rivaroxaban monotherapy and all dual antithrombotic strategies increased the risk of major bleeding to varying degrees, with ticagrelor plus aspirin associated with the highest risk of major bleeding. The net clinical benefit favored clopidogrel or ticagrelor monotherapy, which have a mild anti-ischemic effect without an increase in bleeding risk. Conclusion: The present network meta-analysis suggests that clopidogrel or ticagrelor monotherapy may be recommended first in this cohort of SCVD at high ischemic risk. But clopidogrel plus aspirin or rivaroxaban plus aspirin can still be considered for use in patients with recurrent MACEs.

A clinical trial for computed tomography myocardial perfusion based non-invasive index of microcirculatory resistance (MPBIMR): rationale and trial design.

INTRODUCTION: Accurate and rapid assessment of the coronary microcirculation has become an important medical challenge. However, reliable and non-invasive quantitative methods to diagnose coronary microvascular disease (CMVD), select treatments for coronary artery disease (CAD), and therefore improve coronary microcirculation are lacking. Current detection methods have limitations. Therefore, we will assess whether a new detection method, the non-invasive index of microcirculatory resistance (IMR), based on computed tomography (CT) perfusion and hydrodynamics (CT-IMR), can effectively evaluate the function of coronary microvessels. METHODS: We will conduct a multicenter, randomized, open-label study, including a Phase I single-center and Phase II multicenter trial, to assess the accuracy of the non-invasive CT-IMR coronary measurement of microcirculation function. The study will enroll 295 patients who will undergo coronary CT angiography (CCTA), dynamic CT-myocardial perfusion imaging (CT-MPI), invasive coronary angiography (ICA), and invasive IMR. This study will identify the key influencing factors when calculating myocardial microcirculation perfusion and develop an accurate three-dimensional coronary reconstruction method and a non-invasive coronary IMR calculation method based on computational fluid dynamics (CFD). This will facilitate the development of a non-invasive system to detect and measure coronary microcirculation. CONCLUSION: The clinical trial for computed tomography myocardial perfusion based non-invasive index of microcirculatory resistance (MPBIMR) will establish the key influencing factors when calculating myocardial microcirculation perfusion and create a non-invasive CT-IMR calculation method based on CFD. This method may diagnose patients with simple coronary microvascular lesions and those with coronary microvascular lesions combined with coronary vascular lesions.

Efficacy and Safety of Long-Term Antithrombotic Strategies in Patients With Chronic Coronary Syndrome: A Network Meta-analysis of Randomized Controlled Trials.

Background Long-term antithrombotic strategies for patients with chronic coronary syndrome with high-risk factors represent an important treatment dilemma in clinical practice. Our aim was to conduct a network meta-analysis to evaluate the efficacy and safety of long-term antithrombotic strategies in patients with chronic coronary syndrome. Methods and Results Four randomized studies were included (n=75167; THEMIS [Ticagrelor on Health Outcomes in Diabetes Mellitus Patients Intervention Study], COMPASS [Cardiovascular Outcomes for People Using Anticoagulation Strategies], PEGASUS-TIMI 54 [Prevention of Cardiovascular Events in Patients With Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin-Thrombolysis in Myocardial Infarction 54], and DAPT [Dual Anti-platelet Therapy]). The odds ratios (ORs) and 95% CIs) were calculated as the measure of effect size. The results of the network meta-analysis showed that, compared with aspirin monotherapy, the ORs for trial-defined major adverse cardiovascular and cerebrovascular events were 0.86; (95% CI, 0.80-0.93) for ticagrelor plus aspirin, 0.89 (95% CI, 0.78-1.02) for rivaroxaban monotherapy, 0.74 (95% CI, 0.64-0.85) for rivaroxaban plus aspirin, and 0.72 (95% CI, 0.60,-0.86) for thienopyridine plus aspirin. Compared with aspirin monotherapy, the ORs for trial-defined major bleeding were 2.15 (95% CI, 1.78-2.59]) for ticagrelor plus aspirin, 1.51 (95% CI, 1.23-1.85) for rivaroxaban monotherapy, and 1.68 (95% CI, 1.37-2.05) for rivaroxaban plus aspirin. For death from any cause, the improvement effect of rivaroxaban plus aspirin was detected versus aspirin monotherapy (OR, 0.76; 95% CI, 0.65-0.90), ticagrelor plus aspirin (OR, 0.79; 95% CI, 0.66-0.95), rivaroxaban monotherapy (OR, 0.82; 95% CI, 0.69-0.97), and thienopyridine plus aspirin (OR, 0.58; 95% CI, 0.41-0.82) regimens. Conclusions All antithrombotic strategies combined with aspirin significantly reduced the incidence of major adverse cardiovascular and cerebrovascular events and increased the risk of major bleeding compared with aspirin monotherapy. Considering the outcomes of all ischemic and bleeding events and all-cause mortality, rivaroxaban plus aspirin appears to be the preferred long-term antithrombotic regimen for patients with chronic coronary syndrome and high-risk factors.

Neferine inhibits angiotensin II-stimulated proliferation in vascular smooth muscle cells through heme oxygenase-1.

AIM: To explore the effect of neferine on angiotensin II (Ang II)-induced vascular smooth muscle cell (VSMC) proliferation. METHODS: Human umbilical vein smooth muscle cells (HUVSMCs) were used. Cell proliferation was determined by using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and flow cytometry analysis. Heme oxygenase (HO)-1 protein expression was tested by Western blot analysis. Extracellular signal-regulated protein kinase 1/2 (ERK1/2) activation was determined by using immunoblotting. RESULTS: Pre-incubation of HUVSMCs with neferine (0.1, 0.5, 1.0, and 5.0 micromol/L) significantly inhibited Ang II-induced cell proliferation in a concentration-dependent manner and neferine 5.0 micromol/L increased HO-1 expression by 259% compared with control. The antiproliferative effect of neferine was significantly attenuated by coapplication of zinc protoporphyrin IX (ZnPP IX, an HO-1 inhibitor) with neferine. Ang II-enhanced ERK1/2 phosphorylation was markedly reversed by neferine. By inhibiting HO-1 activity with ZnPP IX, the inhibitive effect of neferine on ERK1/2 phosphorylation was significantly attenuated. Cobalt-protoporphyrin (CoPP), an HO-1 inducer, significantly decreased Ang II-induced ERK1/2 phosphorylation and inhibited Ang II-induced cell proliferation. The ERK1/2 pathway inhibitor PD98059 significantly blocked Ang II-enhanced ERK1/2 phosphorylation and inhibited cell proliferation. CONCLUSION: These findings suggest that neferine can inhibit Ang II-induced HUVSMC proliferation by upregulating HO-1, leading to the at least partial downregulation of ERK1/2 phosphorylation.

[Management of coronary atherosclerotic heart disease through an alliance of community and hospital].

OBJECTIVE: To evaluate the effect of out-hospital normalized management of coronary heart disease (CAD) on the end point events such as mortality, readmission, etc, and on the compliance of patients through normalized management by an alliance of community and hospital. METHODS: The samples were comprised of a total of 2000 patients in 15 communities. And 1642 patients agreed to a follow-up and signed a consent form. Ten communities were chosen as the intensive management group in which community clinicians were trained and the patient management plan was proposed and carried out. The remaining 5 communities were taken as the control group in which the community clinicians were not trained and the patients received only general management. Both groups received a follow-up of 23 months. RESULTS: Compared with the control group, the intensive manage group showed a lower risk of all-cause death, cardiac death and readmission due to cardiovascular events (CVE). They declined by 36.5% (OR 0.635, 95%CI 0.478-0.854), 41.5% (OR 0.585, 95%CI 0.428-0.800) and 56.1% (OR 0.439, 95%CI 0.315-0.612) respectively. The proportion of patients with NYHA III in the intensive management and control groups increased by 3.6% and 7.7% while that of the counterparts of NYHAIV in two groups increased by 1.6% and 6.4% respectively. The cardiac function in the patients of intensive management group was significantly superior to that in control group. Patients in both groups displayed an acceptable compliance to cardiac medications except for aspirin. The proportion of aspirin in the intensive management and control groups increased by 8.4% and 8.7% respectively (P<0.05). CONCLUSION: Through normalized management provided by an alliance of community and hospital, the rates of all-cause death and readmission due to CVE decrease significantly concurrently with an improvement of cardiac function and quality of life in CAD patients.

Coronary plaque tissue characterization in patients with premature coronary artery disease.

Premature coronary artery disease (CAD) studies rarely involve coronary plaque characterization. We characterize coronary plaque tissue by radiofrequency intravascular ultrasound (IVUS) in patients with premature CAD. From July 2015 to December 2017, 220 patients from the Department of Cardiology, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine with first occurrence of angina or myocardial infarction within 3 months were enrolled. Patients with premature CAD (n = 47, males aged < 55 years, and females aged < 65 years) or later CAD (n = 155) were retrospectively compared for cardiovascular risk factors, laboratory examination findings, coronary angiography data, gray-scale IVUS, and iMap-IVUS. The mean age was 53.53 ± 7.24 vs. 70.48 ± 8.74 years (p < 0.001). The groups were similar for traditional coronary risk factors except homocysteine (18.60 ± 5.15 vs. 17.08 ± 4.27 µmol/L, p = 0.043). After matching for baseline characteristics, LDL cholesterol (LDL-C) was higher for premature CAD than later CAD (2.50 ± 0.96 vs. 2.17 ± 0.80 mmol/L, p = 0.019). Before the matching procedure, the premature CAD group had shorter target lesion length [18.50 (12.60-32.00) vs. 27.90 (18.70-37.40) mm, p = 0.002], less plaque volume [175.59 (96.60-240.50) vs. 214.73 (139.74-330.00) mm3, p = 0.013] than the later CAD group. After the matching procedure, the premature CAD group appeared to be less plaque burden (72.69 ± 9.99 vs. 74.85 ± 9.80%, p = 0.005), and positive remodeling (1.03 ± 0.12 vs. 0.94 ± 0.18, p = 0.034), and lower high risk feature incidence (p = 0.006) than the later CAD group. At the plaque's minimum lumen, premature CAD had more fibrotic (p < 0.001), less necrotic (p = 0.001) and less calcified areas (p = 0.012). Coronary plaque tissue was more fibrotic with less necrotic and calcified components in premature than in later CAD, and the range and degree of atherosclerosis were significantly lower.

[Mechanism of cardioprotection induced by noninvasive limb ischemic preconditioning].

OBJECTIVE: To verify the inhibitory effect of mitochondrial calcium uniporter in remote preconditioning-induced cardioprotection. METHODS: By occlusion and reperfusion of left anterior descending artery, the rat hearts were subjected to 30 min regional ischemia and 120 min reperfusion in vivo. Thus the ischemic reperfusion model was established. The rats were randomly assigned to undergo one of the following maneuvers: (1) remote preconditioning; (2) ruthenium red (an inhibitor of mitochondrial calcium uniporter); (3) spermine or SB202190 (an opener of mitochondrial calcium uniporter). Remote preconditioning was elicited by three cycles of 5 min of right femoral artery occlusion interspersed with 5 min of reperfusion. The mean arterial blood pressure, heart rate and lactate dehydrogenase released in plasma were measured during reperfusion but the infarct size was measured after reperfusion. RESULTS: In comparison with I/R group, remote preconditioning limited infarct size [(20.4 +/- 2.5)% vs (51.0 +/- 6.0)%] and lactate dehydrogenase release [(271 +/- 9) U/L vs (339 +/- 39)U/L] during reperfusion. On the contrary, spermine or SB202190 attenuated the reduction of infarct size and lactate dehydrogenase release induced by remote preconditioning. The group of spermine was [(40.8 +/- 9.2)% vs (20.4 +/- 2.5)%] and [(383 +/- 43) U/L vs (271 +/- 9) U/L] while the group of SB202190 was [(44.3 +/- 6.8)% vs (20.4 +/- 2.5)%] and [(356 +/- 26) U/L vs (271 +/- 9) U/L]. CONCLUSION: Inhibition of mitochondrial calcium uniporter opening is involved in the remote preconditioning-induced cardioprotection.

Long non-coding RNA FOXD3-AS1 aggravates ischemia/reperfusion injury of cardiomyocytes through promoting autophagy.

We aimed to investigate the role of long non-coding RNA (lncRNA) FOXD3 antisense RNA 1 (FOXD3-AS1) in myocardial Ischemia/reperfusion (I/R) injury. In our study, H9C2 cells were treated with oxygen-glucose deprivation and reoxygenation (OGD/R). RT-qPCR was performed to detect the expression level of lncRNA FOXD3-AS1 in OGD/R induced H9C2 cells. Then, pcDNA-lncRNA FOXD3-AS1 was transfected into H9C2 cells. The level of LC3 II was measured by immunofluorescence assay. And the expression of autophagy related genes were detected using western blot. In addition, 3-methyladenine (3 M), an autophagy inhibitor, was recruited to treat with H9C2 cells. The contents of creatine kinase (CK), CK isoenzymes (CK-MB), cardiac troponin I (cTnI), inflammation associated factors, reactive oxygen (ROS) and NO were evaluated by kits. Moreover, cell apoptosis was measured by a flow cytometry assay and the expression levels of apoptosis associated proteins were evaluated by western blot. Furthermore, the expression of NF-κB/iNOS/COX2 signaling were measured in our study. The results indicated that FOXD3-AS1 expression was increased in OGD/R-treated H9C2 cells and overexpression of FOXD3-AS1 upregulated the expression of LC3 II, Beclin1, ATG5 accompanied by a downregulated expression of p62. In addition, FOXD3-AS1 overexpression increased the levels of CK, CK-MB, cTnI, TNF-α, IL-1ß, IL-6, ROS and NO, whereas the increase of above factors were reversed following treatment with 3 M. Moreover, FOXD3-AS1 overexpression enhanced the rate of apoptosis cells coupled with a decrease of Bcl-2 expression and an increase of Bax and cleaved caspase 3 expression, which were reversed by 3 M. Furthermore, FOXD3-AS1 overexpression promoted the activation of NF-κB/iNOS/COX2 signaling, which was blocked following treatment with 3 M. These findings demonstrate that overexpression of lncRNA FOXD3-AS1 aggravates myocardial I/R injury through promoting autophagy, which was regulated by activating NF-κB/iNOS/COX2 signaling.