Search

Background: The purpose of this study was to explore the expression of miR-665 in acute myocardial infarction (AMI) and evaluate its significance in the diagnosis and prognosis of AMI., Methods: 100 patients with AMI were selected as the study group and 80 healthy subjects were chosen as the control group. The levels of miR-665 were detected by reverse transcription quantitative polymerase chain reaction (RT-qPCR) in the two groups. The diagnostic value of miR-665 expression level in AMI was analyzed by the receiver operator characteristic (ROC) curve. Kaplan-Meier curve and Cox regression were used to evaluate the predictive value of miR-665 for major adverse cardiovascular events (MACEs) in patients with AMI within 30 days after percutaneous coronary intervention (PCI)., Results: The serum miR-665 level of the study group was significantly lower than that of the control group. The level of miR-665 was significantly correlated with clinical indicators of patients with AMI. ROC curve showed that miR-665 has a high diagnostic value for AMI. Survival analysis showed that Gensini score and miR-665 were independent risk factors for the occurrence of MACEs within 30 days after PCI in patients with AMI., Conclusions: Abnormal decrease of serum miR-665 expression level in patients with AMI may increase the risk of MACEs occurrence after PCI., (© 2024. The Author(s).)

Background: Proprotein convertase subtilisins/kexin 6 (PCSK6) polymorphisms have been shown to be associated with atherosclerosis progression. This research aimed to evaluate the relationship of PCSK6 rs1531817 polymorphisms with coronary stenosis and the prognosis in premature myocardial infarction (PMI) patients., Methods: This prospective cohort analysis consecutively included 605 PMI patients who performed emergency percutaneous coronary intervention (PCI) at Tianjin Chest Hospital sequentially between January 2017 and August 2022, with major adverse cardiovascular events (MACEs) as the outcome. Analyses assessed the relationships among PCSK6 rs1531817 polymorphism, Gensini score (GS), triple vessel disease (TVD), and MACEs., Results: 92 (16.8%) patients experienced MACEs with an average follow-up of 25.7 months. Logistic analysis revealed that the PCSK6 rs1531817 CA + AA genotype was an independent protective factor against high GS and TVD. Cox analysis revealed that the PCSK6 rs1531817 CA + AA genotype was an independent protective factor against MACEs. The mediation effect results showed that apolipoprotein A1/apolipoprotein B (ApoA1/ApoB) partially mediated the association between PCSK6 rs1531817 polymorphism and coronary stenosis and that total cholesterol/high-density lipoprotein (TC/HDL) and TVD partially and in parallel mediated the association between the PCSK6 rs1531817 polymorphism and MACEs., Conclusion: Patients with the PCSK6 CA + AA genotype have milder coronary stenosis and a better long-term prognosis; according to the mediation model, ApoA1/ApoB and TC/HDL partially mediate. These results may provide a new perspective on clinical therapeutic strategy for anti-atherosclerosis and improved prognosis in PMI patients., (© 2024. The Author(s).)

Aim: To assess the levels of matrix metalloproteinases (MMP), vascular endothelial growth factor (VEGF), and miRNA-34a expression in patients with ischemic heart disease (IHD) and obstructive and nonobstructive coronary artery (CA) disease., Material and Methods: This cross-sectional observational study included 64 patients with IHD (diagnosis verified by coronary angiography or multislice computed tomography coronary angiography), of which 33 (51.6%) were men aged 64.9±8.1 years. 20 patients had nonobstructive CA disease (stenosis <50%), and 44 had hemodynamically significant stenoses. The control group consisted of 30 healthy volunteers. MMP-1, -9, -13, and -14, miRNA-34a, and VEGF were measured in all patients., Results: The concentration of MMP-1 was significantly higher in patients with ischemia and nonobstructive CA disease (INOCAD) (p=0.016), and the concentration of MMP-9 was the highest in the group with obstructive CA disease (p<0.001). The concentrations of MMP-13 and MMP-14 did not differ significantly between the groups. The highest VEGF concentrations were observed in the INOCAD group (p<0.001). The expression of miRNA-34a significantly differed between the IHD groups with different types of CA disease and controls (p <0.001). Patients with hemodynamically significant stenosis showed moderate relationships between the concentrations of MMP-14 and VEGF (ρ=0.418; p=0.024), as well as between VEGF and miRNA-34a (ρ=0.425; p=0.022). Patients with INOCAD had a significant negative correlation between the concentrations of MMP-13 and VEGF (ρ= -0.659; p=0.003). Correlation analysis showed in all IHD patients a moderate relationship of the concentrations of MMP-1 and MMP-14 with VEGF (ρ=0.449; p=0.002 and p=0.341; p=0.019, respectively). According to ROC analysis, a MMP-9 concentration above 4.83 ng/ml can be a predictor for the presence of hemodynamically significant CA obstruction in IHD patients; a VEGF concentration higher than 27.23 pg/ml suggests the absence of hemodynamically significant CA stenosis., Conclusion: IHD patients with INOCAD had the greatest increase in MMP-1, whereas patients with obstructive CA disease had the highest level of MMP-9. According to our data, concentrations of MMP-9 and VEGF can be used to predict the degree of CA obstruction. The expression of miRNA-34a was significantly higher in IHD patients with INOCAD and CA obstruction than in the control group, which suggested a miRNA-34a contribution to the development and progression of coronary atherosclerosis. In the future, it may be possible to use this miRNA as a diagnostic marker for IHD.

Our previous study finds that exosomal microRNA (miR)-186-5p promotes viability and invasion of vascular smooth muscle cells to accelerate atherosclerosis via inactivating phosphoinositide 3 kinase/protein kinase B/mammalian target of rapamycin pathway. Subsequently, this study aimed to identify the linkage of serum exosomal miR-186-5p with clinical features and major adverse cardiovascular events (MACE) in coronary heart disease (CHD) patients. Serum exosomal miR-186-5p was quantified in 175 CHD patients and 50 healthy controls (HCs) via reverse transcription quantitative polymerase chain reaction. Our study revealed that serum exosomal miR-186-5p was enhanced in CHD patients vs. HCs (P < 0.001). In CHD patients, serum exosomal miR-186-5p was positively correlated with total cholesterol (P = 0.002) and low-density lipoprotein cholesterol (P = 0.003). Elevated serum exosomal miR-186-5p was linked with increased Gensini score (P = 0.028) and stenosis degree categorized by the Gensini score (P = 0.018). Regarding MACE, the 1-year and 2-year accumulating MACE rate was 6.6% and 15.6%, respectively. Serum exosomal miR-186-5p was elevated in CHD patients with MACE vs. those without (P = 0.042). By Kaplan-Meier curves and log-rank analyses, serum exosomal miR-186-5p > 1.000 (P = 0.404) and > 1.610 (P = 0.328) was not related to accumulating MACE. While serum exosomal miR-186-5p > 3.390 exhibited a correlative trend with increased accumulating MACE, but not achieving statistical significance (P = 0.071). The 1-year and 2-year accumulating MACE rate of patients with serum exosomal miR-186-5p > 3.390 was 11.5% and 21.5%, respectively; while the rate was 3.3% and 11.5% in patients with serum exosomal miR-186-5p ≤ 3.390, accordingly. Conclusively, serum exosomal miR-186-5p positively associates with lipid level, coronary stenosis degree, and the risk of MACE in CHD patients.

Exosomal microRNAs (miRNAs/miRs) are potential biomarkers for the diagnosis and treatment of cardiovascular disease, and hyperglycemia serves an important role in the development of atherosclerosis. The present study aimed to investigate the expression profile of serum‑derived exosomal miRNAs in coronary heart disease (CHD) with hyperglycemia, and to identify effective biomarkers for predicting coronary artery lesions. Serum samples were collected from eight patients with CHD and hyperglycemia and eight patients with CHD and normoglycemia, exosomes were isolated and differentially expressed miRNAs (DEMIs) were filtered using a human miRNA microarray. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed using standard enrichment computational methods for the target genes of DEMIs. Receiver operating characteristic (ROC) curve analysis was applied to evaluate the values of the selected DEMIs in predicting the severity of coronary stenosis. A total of 10 DEMIs, including four upregulated miRNAs (hsa‑let‑7b‑5p, hsa‑miR‑4313, hsa‑miR‑4665‑3p and hsa‑miR‑940) and six downregulated miRNAs (hsa‑miR‑4459, hsa‑miR‑4687‑3p, hsa‑miR‑6087, hsa‑miR‑6089, hsa‑miR‑6740‑5p and hsa‑miR‑6800‑5p), were screened in patients with CHD and hyperglycemia. GO analysis showed that the 'cellular process', 'single‑organism process' and 'biological regulation' were significantly enriched. KEGG pathway analysis revealed that the 'mTOR signaling pathway', 'FoxO signaling pathway' and 'neurotrophin signaling pathway' were significantly enriched. Among these DEMIs, only hsa‑let‑7b‑5p expression was positively correlated with both hemoglobin A1C levels and Synergy between Percutaneous Coronary Intervention with Taxus and Cardiac Surgery score. ROC curves showed that hsa‑let‑7b‑5p could serve as an effective biomarker for differentiating the severity of coronary stenosis. In conclusion, the present study demonstrated that serum‑derived exosomal hsa‑let‑7b‑5p is upregulated in patients with CHD and hyperglycemia, and may serve as a noninvasive biomarker for the severity of coronary stenosis.

Background: The aim of the study was to assess the correlation between circulating long non-coding RNA (lncRNA) OTTHUMT00000387022 (named Coromarker) expression and disease severity, inflammatory cytokine levels, and plaque vulnerability in patients with coronary artery disease (CAD)., Methods: A total of 134 participants who received coronary angiography were enrolled and classified them as CAD patients (N = 89) and controls (N = 45). Blood samples were obtained from all subjects. Quantitative polymerase chain reaction was used to evaluate Coromarker expression. The enzyme-linked immunosorbent test was used to measure inflammatory cytokines including high sensitivity C reactive protein (hsCRP), interleukin (IL)-1β (IL-1β), IL-6, NOD-like receptor protein 3 (NLRP3), and markers of coronary plaque stability including matrix metallopeptidase 9 (MMP-9) and soluble CD40 ligand (sCD40L). The severity of coronary stenosis was determined from the Gensini Score., Results: LncRNA Coromarker expression was elevated to a greater extent in CAD patients than in control subjects before and after adjustments for age/gender (both p < 0.001); it was an independent predictor of CAD risk (area under curve: 0.824, 95% CI: 0.732-0.915). Additionally, Coromarker expression was significantly associated with Gensini Score (r = 0.574, p < 0.001), hsCRP (r = 0.221, p = 0.015), IL-1β (r = 0.351, p < 0.001), IL-6 (r = 0.286, p < 0.01), and NLRP3 levels (r = 0.312, p < 0.001). Coromarker expression was found to be linked with MMP-9 (r = 0.260, p < 0.01) and sCD40L (r = 0.441, p < 0.001)., Conclusion: Circulating lncRNA Coromarker expression correlates with increased disease severity and inflammation as well as plaque vulnerability in patients with CAD., (© 2022 The Authors. Journal of Clinical Laboratory Analysis published by Wiley Periodicals LLC.)

Circulating levels of microRNA-221 and 222 (miR-221/222) in patients with coronary artery disease (CAD) are elevated, yet the relationship between circulating miR-221/222 and the severity of coronary lesions in patients with acute coronary syndrome (ACS) remains unknown. In this study, the relative expression levels of circulating miR-221/222 in patients with ACS (n = 267) and controls (n = 71) were compared by real-time fluorescence quantitative-polymerase chain reaction (RT-qPCR). The ACS group was further divided into unstable angina pectoris (UA) group (n = 191) and acute myocardial infarction (AMI) group (n = 76). Significant upregulation of circulating miR-221/222 was observed in ACS. A positive linear correlation between circulating miR-221/222 and Gensini scores was demonstrated. The area under the curve (AUC) of circulating miR-221/222 in the diagnosis of coronary artery stenosis ≥50% was 0.605 and 0.643, respectively. The circulating miRNA-221/222 expression levels in ACS patients were elevated and positively associated with the severity of the coronary artery lesions. Circulating miR-221/222 may be novel biomarkers for the diagnosis of coronary artery stenosis ≥50% and the occurrence of ACS.

Background: Long noncoding RNA GAS5 (lnc-GAS5) and its target microRNA-21 (miR-21) regulate blood lipid, macrophages, Th cells, vascular smooth muscle cells to participate in atherosclerosis, and related coronary heart disease (CHD). The study aimed to further explore the linkage of their circulating expressions with common biochemical indexes, stenosis severity and inflammatory cytokines in CHD patients., Methods: Ninety-eight CHD patients and 100 controls confirmed by coronary angiography were enrolled. Plasma samples were collected for lnc-GAS5 and miR-21 detection by reverse transcription-quantitative polymerase chain reaction and inflammatory cytokines determination by enzyme-linked immunosorbent assay., Results: Lnc-GAS5 was increased in CHD patients compared with controls (2.270 (interquartile range [IQR]: 1.676-3.389) vs. 0.999 ([IQR: 0.602-1.409], p < 0.001), whereas miR-21 showed opposite tread (0.442 [IQR: 0.318-0.698] vs. 0.997 [IQR: 0.774-1.368], p < 0.001). In aspect of their intercorrelation, lnc-GAS5 negatively linked with miR-21 in CHD patients (p < 0.001) instead of controls (p = 0.211). Interestingly, among the common biochemical indexes, lnc-GAS5 related to decreased high-density lipoprotein cholesterol (p = 0.008) and increased C-reactive protein (CRP) (p < 0.001), while miR-21 correlated with lower total cholesterol (p = 0.024) and CRP (p < 0.001) in CHD patients. As stenosis degree, lnc-GAS5 positively correlated with Gensini score (p < 0.001), but miR-21 exhibited negative association (p = 0.003) in CHD patients. In terms of inflammatory cytokines, lnc-GAS5 positively related to tumor necrosis factor α (TNF-α) and interleukin (IL)-17A, while miR-21 negatively linked with TNF-α, IL-1β, IL-6, and IL-17 in CHD patients (all p < 0.05)., Conclusion: Circulating lnc-GAS5 and its target miR-21 exhibit potency to serve as biomarkers for CHD management., (© 2022 The Authors. Journal of Clinical Laboratory Analysis published by Wiley Periodicals LLC.)

Background: Although the presence of physical signs [tendon xanthomas and/or corneal arcus (TX/CA)], are associated with the risk of coronary artery disease in patients with heterozygous familial hypercholesterolemia (HeFH), their relationship with genotypes and clinical characteristics has not been fully determined. This study aimed to examine the association of TX/CA with genetic mutation, lipid- and inflammation-related markers, the severity of coronary stenosis or calcification, and cardiovascular events (CVEs) in patients with HeFH., Methods: LDLR, APOB, and PCSK9 genes were screened in 523 HeFH patients, and patients with TX/CA (n = 50) were 1:4 propensity score-matched to patients without TX/CA (n = 200) to adjust for age and sex. Laboratory markers (proprotein convertase subtilisin/kexin type 9 [PCSK9], lipoprotein(a) and high-sensitivity C-reactive protein [hsCRP]), computed tomography angiography, coronary angiography, and follow-up for CVEs were performed., Results: Patients with physical signs had significantly higher low-density lipoprotein cholesterol levels; higher PCSK9 or hsCRP concentrations; more LDLR positive mutations; and higher prevalence of high tertiles of Gensini, SYNTAX and Jeopardy scores as well as coronary artery calcium scores than did those without. Over an average follow-up of 3.7 years, the incidence of CVEs was significantly higher in patients with TX/CA (log-rank p < 0.001). Patients with physical signs and mutation positivity had threefold higher risks of CVEs (adjusted hazard ratio 3.34, 95% confidence interval 1.04-10.72, p = 0.024)., Conclusions: Physical signs were associated with genotypes and phenotypes, and worse outcomes in patients with HeFH, suggesting that these signs may help in risk stratification in these patients., (© 2021. The Author(s).)

Coronary atherosclerotic heart disease (CAD) is a chronic disease caused by multiple risk factors. Aberrant expression of long non-coding RNAs (lncRNAs) has been regarded as an independent risk factor of CAD. This study evaluated lncRNA myocardial infarction-associated transcription (MIAT) expression in CAD patients and its clinical significance. Totally, 155 CAD patients and 76 non-CAD controls were enrolled. MIAT expression was detected using reverse transcription quantitative polymerase chain reaction. The clinical diagnostic significance of MIAT was evaluated by plotting the receiver operating characteristic (ROC) curve. The levels of inflammatory cytokines were detected using enzyme-linked immunosorbent assay. microRNA (miR)-29b-3p expression and pregnancy-associated plasma protein A (PAPPA) level were detected. MIAT expression in CAD patients (4.23 [1.22-6.50]) was higher than that in non-CAD controls (1.64 [0.05-2.93]) (p < 0.01) and had an independent correlation with CAD. The area under ROC curve of predicting CAD was calculated as 0.790, the specificity as 71.40%, and the sensitivity as 70.00%. MIAT expression was positively correlated with the C-reactive protein level (r = 0.769, p < 0.0001) and pro-inflammatory cytokines tumor necrosis factor-α (TNF-α), interleukin 6 (IL-6), and IL-8 levels, while negatively correlated with the anti-inflammatory cytokine IL-10. MIAT was positively correlated with Gensini score and had an independent correlation with it. LncRNA MIAT sponged miR-29b-3p and miR-29b-3p targeted PAPPA. In conclusion, lncRNA MIAT was upregulated in the peripheral blood of CAD patients and elicited clinical diagnostic significance. MIAT participated in the development of CAD via miR-29b-3p/PAPPA axis. This study provides insights into a potential target for the diagnosis and treatment of CAD., (© 2021 The Authors. The Kaohsiung Journal of Medical Sciences published by John Wiley & Sons Australia, Ltd on behalf of Kaohsiung Medical University.)

Background: In-stent restenosis usually occurs by platelet activation, neointima formation, VSMC migration, and proliferation in the position of the vessel stent. The monocytes have a magnificent role in neointimal hyperplasia since these cells recruit to the site of vessel injury through chemokines and other secretion proteins. This study is focused on the investigation of vitronectin, miR-193, miR-34, and miR-520 expression levels in PBMCs isolated from stenosed patients., Methods: A total of sixty subjects undergoing coronary artery angiography containing patients with stent no restenosis (n = 20), in-stent restenosis (n = 20), and healthy participants (n = 20) participated in the study. The vitronectin, miR-193, miR-34, and miR-520 expression levels were measured by the RT-qPCR technique. Data were analyzed by SPSS software., Results: The vitronectin, miR-34, and miR-520 expression levels changed significantly in patients with vessel in-stent restenosis (p = 0.02, p = 0.02, and p = 0.01, respectively). Furthermore, there were inverse correlations between the expression levels of vitronectin gene and miR-34 (r =  - 0.44, p = 0.04) as well as miR-520 (r =  - 0.5, p=0.01)., Conclusions: The molecular events in the vessel stenosis may be affected by targeting vitronectin with miR-520 and miR-34., (© 2021. The Author(s), under exclusive licence to Springer Nature B.V.)

Background: Complex coronary atherosclerotic lesions often lead to coronary occlusion, clinically represented as a single-vessel disease (SVD) and multivessel disease (MVD). These occlusions could hinder the blood flow in coronary arteries that affects appropriate management of the CVD. The current study intended to genotype interleukin (IL)-18 promoter's hotspots (rs187238, rs1946518, and rs1946519) and their possible association with coronary artery stenosis., Material and Methods: The IL-18 promoter genotyping was performed by the Sanger method along with the examination of biochemical parameters in 125 study subjects categorized into three groups, viz. controls, SVD and MVD., Results: The current study observed a significant association of diabetes, hypertension, and dyslipidemia between the studied group's viz. healthy controls, SVD, and MVD. Fasting blood sugar and glycosylated hemoglobin (HBA1C) were also significantly enhanced from 4.82 vs. 8.01 and 4.33 vs. 8.27, in SVD, and MVD respectively. Despite the visible differences in the pattern of genotypic and allelic expressions, the current study did not show any statistically significant correlation with IL-18 promoter polymorphism at its hotspots with controls, SVD, and MVD subjects. The only exception of the above results was the distribution of allelic frequency at the rs1946519 hotspot, where a significant change (P < 0.05) was observed., Conclusion: This study is of additional value to our previous reports, revealing the pattern of genotypes and allelic frequency of IL-18 promoters in a small cohort of Saudi ethnicity. Further investigations on larger sample size are recommended to envisage the presence of functional mutations in the IL-18 gene that could establish or rule out the possible association of IL-18 polymorphism with SVD and MVD., (© 2021. The Author(s), under exclusive licence to Springer Nature B.V.)

Objective: There is a need to identify genetic factors that may produce coronary artery atherosclerotic disease (CAD) that are not involved in the usual risk factors leading to CAD. Previous studies have often equated coronary artery calcification (CAC) with CAD with coronary stenosis or its sequelae. The objective of this study was to examine the relationship between phosphatase and actin regulator 1 (PHACTR1) single nucleotide polymorphisms (SNPs) and the type of coronary artery disease CAD versus CAC., Method: A systematic review of the literature was conducted to answer the question of whether PHACTR1 gene polymorphisms are associated with coronary artery disease expressed as coronary artery atherosclerosis or CAC., Results: Eighteen studies spanning seven PHACTR1 SNPs were identified and evaluated for the relationship between PHACTR1 and coronary artery disease. There were significant relationships between rs9349379, rs12526453, and CAD with odds ratios (ORs) (confidence interval) of, respectively, 1.15 (1.13-1.17), 1.13 (1.09-1.17) but not for rs2026458, 1.03 (0.88-1.19). The OR for CAC was 1.22 (1.18-1.26) for rs9349379 and 1.28 (1.21-1.38) for rs12526453., Conclusions: Several PHACTR1 specifically rs9349379 and rs12526453 polymorphisms but not rs2026458, are associated with CAD. There are differences in the association of PHACTR1 SNPs with CAC. PHACTR1 warrants more attention and study for the prevention and treatment of CAD., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Polygenic risk scores (PRSs) are associated with coronary artery disease (CAD), but the clinical potential of using PRSs at the single-patient level for risk stratification has yet to be established. We investigated whether adding a PRS to clinical risk factors (CRFs) improves risk stratification in patients referred to coronary computed tomography angiography on a suspicion of obstructive CAD., Methods: In this prespecified diagnostic substudy of the Dan-NICAD trial (Danish study of Non-Invasive testing in Coronary Artery Disease), we included 1617 consecutive patients with stable chest symptoms and no history of CAD referred for coronary computed tomography angiography. CRFs used for risk stratification were age, sex, symptoms, prior or active smoking, antihypertensive treatment, lipid-lowering treatment, and diabetes. In addition, patients were genotyped, and their PRSs were calculated. All patients underwent coronary computed tomography angiography. Patients with a suspected ≥50% stenosis also underwent invasive coronary angiography with fractional flow reserve. A combined end point of obstructive CAD was defined as a visual invasive coronary angiography stenosis >90%, fractional flow reserve <0.80, or a quantitative coronary analysis stenosis >50% if fractional flow reserve measurements were not feasible., Results: The PRS was associated with obstructive CAD independent of CRFs (adjusted odds ratio, 1.8 [95% CI, 1.5-2.2] per SD). The PRS had an area under the curve of 0.63 (0.59-0.68), which was similar to that for age and sex. Combining the PRS with CRFs led to a CRF+PRS model with area under the curve of 0.75 (0.71-0.79), which was 0.04 more than the CRF model ( P =0.0029). By using pretest probability (pretest probability) cutoffs at 5% and 15%, a net reclassification improvement of 15.8% ( P =3.1×10 -4 ) was obtained, with a down-classification of risk in 24% of patients (211 of 862) in whom the pretest probability was 5% to 15% based on CRFs alone., Conclusions: Adding a PRS improved risk stratification of obstructive CAD beyond CRFs, suggesting a modest clinical potential of using PRSs to guide diagnostic testing in the contemporary clinical setting. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02264717.

Background and Aims: Novel genetic determinants associated with coronary artery disease (CAD) have been discovered by genome wide association studies. Variants encompassing the CELSR2- PSRC1-SORT1 gene cluster have been associated with CAD. This study is aimed to investigate the rs629301 polymorphism association with the extent of CAD evaluated by coronary angiography (CAG), and to evaluate its associations with an extensive panel of lipid and lipoprotein measurements in a large Italian cohort of 2429 patients., Methods and Results: The patients were collected by four Intensive Care Units located in Palermo and Verona (Italy). Clinical Records were filed, blood samples were collected, lipids and apolipoproteins (apo) were measured in separate laboratories. CAD was defined by the presence of stenotic arteries (>50% lumen diameter) by CAG. The presence of CAD was associated with the rs629301 genotype. Patients with CAD were 78% and 73% (p = 0.007) of the T/T vs. T/G + G/G genotype carriers respectively. T/T genotype was also correlated with the number of stenotic arteries, with a 1.29 (1.04-1.61) risk to have a three-arteries disease. T/T genotype correlated with higher levels of LDL-, non-HDL cholesterol, apoB, apoE and apoCIII, and lower HDL-cholesterol. Logistic Regression confirmed that rs629301was associated with CAD independently from the common risk factors, with a risk similar to that conferred by ten years of age [odds ratios were 1.43 (1.04-1.96) and 1.39 (1.22-1.58) respectively]., Conclusions: rs629301 risk allele was independently associated with the extension and severity of CAD and positively with apoE and apoB containing lipoproteins., Competing Interests: Declaration of competing interest The authors have no conflict of interests to declare., (Copyright © 2021 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Cellular senescence is an irreversible arrest of cell proliferation triggered by different stimuli, including DNA damage, telomere shortening and oncogenic stress. Senescent cells, by releasing the senescence-associated-secretory-phenotype (SASP), contribute to various diseases pathogenesis. Human atherosclerotic plaque contains cells with multiple markers of senescence that associate with disease severity. We characterized the frequency of senescent cTfh cells and genes expressions before and after treatment with Dasatinib in patients with different degrees of stenosis. Twelve high (≥50%), and twelve low (<50%) stenosis patients and six healthy controls were enrolled. The percentage of senescent CD3 + CD4 + CXCR5 + CD153 + CD57 + cells was significantly decreased in Dasatinib treated cells from individuals with low and high stenosis (P = 0.0007 and P = 0.0002, respectively). However, the frequency of total lymphocytes, CD3 + and CD4 + T cells were not significantly different between the groups before and after treatment. The expression levels of P53 (P = 0.0003 and P = 0.0001), P16 (P = 0.0005 and P = 0.0002), p21 (P = 0.0002 and P < 0.0001), SENEX (P = 0.0005 and P < 0.0001) and BCL-2 (P = 0.0005 and P = 0.0002) were decreased in PBMCs of low and high stenosis groups after treatment with Dasatinib, respectively. The percentage of senescent cTfh cells positively correlated with cholesterol (P = 0.034; r = 0.671), C-reactive protein (CRP) (P = 0.029; r = 0.707), Erythrocyte sedimentation rate (ESR) levels (P = 0.030; r = 0.598) and neutrophil counts (P = 0.021; r = 0.799) in patients with high stenosis. The decreased frequency of senescent cTfh cells and the expression levels of senescence genes after Dasatinib treatment in patients with atherosclerosis suggest a role for Dasatinib in partial clearance or rejuvenation of senescent cTfh cells, which may decrease inflammatory mediators and attenuate disease progression., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Abstract: Cardiovascular disease (CAD) is a devastating illness, but to date there are limited means of predicting a person's coronary stenosis severity and their prognosis. The study was performed to investigate the relationship between dipeptidyl peptidase 4(DPP4) gene polymorphisms and serum lipid profiles, as well as the severity of coronary artery stenosis in patients with CAD and type 2 diabetes (T2DM) for the first time.Herein, 201 patients with CAD and T2DM were enrolled in the Department of Cardiology, Shandong Provincial Qianfoshan Hospital. DPP4 rs3788979 and rs7608798 single nucleotide polymorphisms (SNPs) were genotyped. The general information of all patients was collected, and the associations between DPP4 SNPs and lipid profiles were detected. At the same time, association between SNP polymorphisms and the degree of coronary artery stenosis were analyzed.There was a significant difference in apolipoprotein B (ApoB) levels (P = .011) for the rs3788979 polymorphism, while no difference was identified in other blood lipids or with other mutations. SNP mutation of A to G in rs3788979 was associated with a reduced percentage of severe coronary artery stenosis in female patients (P = .023) as well as those with nosmoking (P = .030), nodrinking (P = 0.007), and nocardiovascular family history (P = 0.015).G allele of rs3788979 is associated with a reduced ApoB level. Besides, we suggest that G allele in rs3788979 may have a cardioprotective effect and prove to be a useful and specific measure when predicting a patient's coronary stenosis severity if diagnosed with CAD and T2DM., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

The current study aims to explore the miRNA changes that occur in the serum of patients with coronary heart disease (CHD) and healthy controls using a microarray technique, thereby exploring the potential biomarkers in the diagnosis of CHD and the underlying mechanism. Clinical data were reviewed, and venous blood samples were collected from 66 cases of CHD and 58 cases of healthy controls. MicroRNA-wide expression profiling identified 16 miRNAs that were aberrantly decreased by ~2-fold in the serum of patients with CHD compared to that of healthy controls. RT-PCR analysis indicated that the expression of miR-3129-5p was increased the most in patients with CHD compared with that of controls. Moreover, serum miR-3129-5p was found to be highest in the severe stenosis group, followed by the moderate stenosis group and mild stenosis group. ROC analysis showed that serum miR-3129-5p could differentiate patients with CHD from controls. Further study showed that mTOR was a target gene of miR-3129-5p. Western blot assays demonstrated that miR-3129-5p significantly suppressed the phosphorylation of S6 but increased LC3II/LC3I and Beclin1 levels. Consistently, GFP-LC3 and TEM assays indicated that miR-3129 increased autophagy puncta in H9C2 cells. More importantly, silencing mTOR significantly decreased the expression of p-S6 but increased LC3II/LC3I and Beclin expression even in H9C2 cells transfected with miR-3129-5p inhibitor, indicating that miR-3129-5p-induced cell autophagy was mediated via mTOR in H9C2 cells. In summary, elevated serum miR-3129-5p contributes to CHD by targeting mTOR signaling and may be a therapeutic target in the treatment of CHD., (© 2020 The Authors. The Kaohsiung Journal of Medical Sciences published by John Wiley & Sons Australia on behalf of Kaohsiung Medical University.)

[Figure: see text].

Background: Coronary Artery Disease (CAD) is the narrowing or blockage of the coronary arteries. It is closely associated with numerous genetics and environmental factors that have been extensively evaluated in various populations. In recent studies, severe phenotypes have been strongly linked to genetic risk factors., Methods: This study investigated the association of clinical, demographic, and genetic factors with severe coronary artery stenosis phenotypes in our population composed of 1734 individuals with severe coronary stenosis (≥ 50% in coronary vessels) and comparing them to 757 controls with no evidence of stenosis on angiography. We performed generalized linear model (GLM) genome-wide association studies to evaluate three stratification models and their associations to characteristics of the clinical disease. In model 1, patients were not stratified. In model 2, patients were stratified based on presence or absence of CAD family history (FxCAD). In model 3, patients were stratified by young age of CAD onset., Results: Eight SNPs (single nucleotide polymorphism) were significantly associated with severe CAD phenotypes in the various models [Formula: see text], four of these SNPs were associated with severe CAD and the four others were specifically significant for young CAD patients. While these SNPs were not previously reported for association with CAD, six of them are present in genes that have already been linked to coronary disease., Conclusion: In conclusion, this study presents new genetic factors associated with severe stenosis and highlights different risk factors associated with a young age at diagnosis of CAD.

Adrenomedullin (AM) is a peptide hormone with multiple physiological functions, which are regulated by its receptor activity-modifying proteins, RAMP2 and RAMP3. We previously reported that AM or RAMP2 knockout (KO) (AM-/-, RAMP2-/-) is embryonically lethal in mice, whereas RAMP3-/- mice are apparently normal. AM, RAMP2, and RAMP3 are all highly expressed in the heart; however, their functions there are not fully understood. Here, we analyzed the pathophysiological functions of the AM-RAMP2 and AM-RAMP3 systems in hearts subjected to cardiovascular stress. Cardiomyocyte-specific RAMP2-/- (C-RAMP2-/-) and RAMP3-/- showed no apparent heart failure at base line. After 1 week of transverse aortic constriction (TAC), however, C-RAMP2-/- exhibited significant cardiac hypertrophy, decreased ejection fraction, and increased fibrosis compared with wild-type mice. Both dP/dtmax and dP/dtmin were significantly reduced in C-RAMP2-/-, indicating reduced ventricular contractility and relaxation. Exposing C-RAMP2-/- cardiomyocytes to isoproterenol enhanced their hypertrophy and oxidative stress compared with wild-type cells. C-RAMP2-/- cardiomyocytes also contained fewer viable mitochondria and showed reduced mitochondrial membrane potential and respiratory capacity. RAMP3-/- also showed reduced systolic function and enhanced fibrosis after TAC, but those only became apparent after 4 weeks. A reduction in cardiac lymphatic vessels was the characteristic feature in RAMP3-/-. These observations indicate the AM-RAMP2 system is necessary for early adaptation to cardiovascular stress through regulation of cardiac mitochondria. AM-RAMP3 is necessary for later adaptation through regulation of lymphatic vessels. The AM-RAMP2 and AM-RAMP3 systems thus play separate critical roles in the maintenance of cardiovascular homeostasis against cardiovascular stress., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: ATP-binding cassette transporter A1 (ABCA1) plays a major role in high-density lipoprotein (HDL) metabolism and reverse cholesterol transport (RCT) and exerts anti-inflammatory effects. Increased ABCA1 promoter methylation level may result in the progression of coronary artery disease. Thus, the present study investigated the association between promoter methylation status of ABCA1 and inflammation in the development of premature coronary artery disease (pCAD)., Methods: PCAD patients and healthy individuals (n = 90 each) were recruited from the Characteristic Medical Center of the Chinese People's Armed Police Force from June to December 2019. Using pyrosequencing, the levels of ABCA1 promoter methylation in their blood samples were evaluated. Serum concentrations of lipids, interleukin 1β (IL-1β), C-reactive protein (CRP), and circulating free DNA/Neutrophil extracellular traps (cfDNA/NETs) were also routinely measured and compared between the two groups. P values < 0.05 were considered statistically significant., Results: The mean ABCA1 promoter methylation levels were significantly higher in the pCAD group than in the control group (44.24% ± 3.66 vs. 36.05% ± 2.99, P < 0.001). Based on binary logistic regression analysis, ABCA1 promoter methylation level was identified as an independent risk factor for pCAD development (odds ratio = 2.878, 95% confidence interval: 1.802-4.594, P < 0.001). Furthermore, ABCA1 promoter methylation levels were negatively correlated with HDL levels (r =  - 0.488, P < 0.001) and positively correlated with the levels of CRP, cfDNA/NETs, and IL-1β (r = 0.389, 0.404, 0.385, respectively; P < 0.001). Multiple regression analysis showed that the serum levels of CRP, IL-1β, and cfDNA/NETs independently affect ABCA1 promoter methylation., Conclusions: Our findings indicate that high methylation levels at the ABCA1 promoter are associated with low HDL cholesterol levels and an increased risk of pCAD. Inflammatory factors and NETs may be involved in the progression of pCAD by affecting ABCA1 promoter methylation levels.

Background: We aimed to examine the role of the rs6060566 polymorphism of the reactive oxygen species modulator 1 (ROMO1) gene in the development of myocardial infarction (MI) in Caucasians with type 2 diabetes (T2DM)., Methods: A total of 1072 subjects with T2DM were enrolled in this cross-sectional case-control study: 335 subjects with MI and 737 subjects without clinical signs of coronary artery disease (CAD). The genetic analysis of the rs6060566 polymorphism was performed in all subjects. To assess the degree of coronary artery obstruction, a subpopulation of 128 subjects with T2DM underwent coronary computed tomography angiography. Next, endarterectomy samples were obtained during myocardial revascularization from diffusely diseased coronary arteries in 40 cases, which were analysed for ROMO1 expression according to their genotype., Results: There were no statistically significant associations between different genotypes or alleles of the rs6060566 polymorphism and MI in subjects with T2DM. The carriers of the C allele of the ROMO1 rs6060566 had a threefold increased likelihood of having 50-75% coronary artery stenosis (Adjusted OR = 3.27, 95% CI 1.16-9.20). Subjects with two affected coronary arteries had a 3.72 fold higher prevalence of MI (OR = 3.72, 95% CI 1.27-10.84). With CAD in LMCA or LAD, MI prevalence was about 3.5-fold higher (p = 0.07 for LMCA and p = 0.01 for LAD). Furthermore, the carriers of the rs6060566 C allele showed higher number of positive cells for ROMO1 expression in endarterectomy samples of coronary arteries., Conclusions: According to our study, the rs6060566 polymorphism of the ROMO1 gene is not a risk factor for MI in Caucasians with T2DM. However, we found that subjects carrying the C allele were at a 3.27-fold increased risk of developing severe CAD compared with those who had non-obstructive CAD. Moreover, C allele carriers showed a statistically higher number of cells positive for ROMO1 compared with T allele carriers in coronary endarterectomy samples.

Myocardial infarction (MI), the leading cause of mortality and disability worldwide, is a disease in which multiple environmental and genetic factors are involved. Recently, researches suggested that insertion/deletion (ins/del) variation of NFKB1 gene rs28362491 is a functional polymorphism. In the present study, we aimed to explore the relation between variation of NFKB1 gene rs28362491 and MI by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) in 359 MI patients and 1085 control participants. Gensini score was used to evaluate the degree of coronary artery stenosis in MI patients. The plasma levels of interleukin-6 (IL-6), IL-8, malonaldehyde (MDA) and superoxide dismutase (SOD) were randomly measured by ELISA both in MI patients and control participants. We found that the detected frequencies of D allele (41.2% vs. 36.4%, P = 0.021) and DD genotype (17.5% vs. 12.0%, P = 0.022) were significantly higher in MI patients than in control participants. Compared with II or ID genotype carriers, the Gensini score in MI patients with DD genotype was 32-43% higher (both P < 0.001). Moreover, DD genotype carries had more diseased coronary arteries (P = 0.001 vs. II or ID genotype). Of note, IL-6 levels in MI patients carrying DD genotype were significantly higher than that in control participants and other genotype carriers in MI patients (both P < 0.05). In conclusion, NFKB1 gene rs28362491 DD genotype was associated with a higher risk of MI and more severe coronary artery lesion, which also had a potential influence on the level of inflammatory cytokine IL-6.

Fractional flow reserve (FFR) assessed during adenosine-induced maximal hyperemia has emerged as a useful tool for the guidance of percutaneous coronary interventions (PCI). However, interindividual variability in the response to adenosine has been claimed as a major limitation to the use of adenosine for the measurement of FFR, carrying the risk of underestimating the severity of coronary stenoses, with potential negative prognostic consequences. Genetic variants of the adenosine receptor A2a (ADORA2A gene), located in the coronary circulation, have been involved in the modulation of the hyperemic response to adenosine. However, no study has so far evaluated the impact of the single nucleotide polymorphism rs5751876 of ADORA2A on the measurement of FFR in patients undergoing percutaneous coronary intervention that was, therefore, the aim of our study. We included patients undergoing coronary angiography and FFR assessment for intermediate (40-70%) coronary lesions. FFR measurement was performed by pressure-recording guidewire (Prime Wire, Volcano), after induction of hyperemia with intracoronary boli of adenosine (from 60 to 1440 μg, with dose doubling at each step). Restriction fragment length polymorphism (RFLP) analysis was performed to assess the presence of rs5751876 C>T polymorphism of ADORA2a receptor. We included 204 patients undergoing FFR measurement of 231 coronary lesions. A total of 134 patients carried the polymorphism (T allele), of whom 41 (30.6%) in homozygosis (T/T).Main clinical and angiographic features did not differ according to ADORA2A genotype. The rs5751876 C>T polymorphism did not affect mean FFR values (p = 0.91), the percentage of positive FFR (p = 0.54) and the duration of maximal hyperemia. However, the time to recovery to baseline FFR values was more prolonged among the T-allele carriers as compared to wild-type patients (p = 0.04). Based on these results, in patients with intermediate coronary stenoses undergoing FFR assessment with adenosine, the polymorphism rs5751876 of ADORA2A does not affect the peak hyperemic response to adenosine and the results of FFR. However, a more prolonged effect of adenosine was observed in T-carriers.

Objective: Experimental evidence suggests a close link between PARP (poly[ADP-ribose] polymerase) activation and diabetic endothelial dysfunction. Here, we tested whether PARP activity in circulating leukocytes was associated with coronary artery disease (CAD) among patients with type 2 diabetes mellitus (T2DM). Approach and Results: We performed observational and bidirectional Mendelian randomization studies of 3149 Chinese individuals with T2DM who underwent coronary angiography, with leukocyte PARP activity, 16 tag single-nucleotide polymorphisms in PARP1 and PARP2 , and 17 CAD risk single-nucleotide polymorphisms analyzed. Of 3149 participants, 1180 who further received percutaneous coronary intervention were prospectively followed for 1 year to track major adverse cardiovascular and cerebrovascular events. Overall, greater PARP activity was cross-sectionally associated with an odds ratio of 1.23 for obstructive CAD, and prospectively with a hazard ratio of 1.34 for 1-year major adverse cardiovascular and cerebrovascular events after percutaneous coronary intervention (both P <0.001). Using a genetic score of 5 screened single-nucleotide polymorphisms in PARP1 and PARP2 as the instrumental variable, genetically predicted elevation in PARP activity showed a causal association with obstructive CAD (odds ratio=1.35, P <0.001). In contrast, the genetic risk of CAD had no significant effect on PARP activity. Ex vivo and in vitro cultures of human monocytes showed that rs747657, as the lead single-nucleotide polymorphism strongly associated with PARP activity, caused the differential binding of transcription factor GATA2 (GATA-binding protein 2) to an intronic regulatory region in PARP1 , thus modulating PARP1 expression and PARP activity., Conclusions: Greater PARP activity may have causal roles in the development of obstructive CAD among patients with diabetes mellitus.

Exosomes are nanosized vesicles secreted by most cells, which can deliver a variety of functional lipids, proteins, and RNAs into the target cells to participate in complex intercellular communications. Cells respond to certain physical, chemical, and biological stimuli by releasing exosomes. Exosomes are rich in small molecules of RNA, including miRNAs and mRNAs, which have been demonstrated to have certain functions in recipient cells. Recent studies on single-cell RNA sequences have revealed the transcription and the heterogeneity of macrophages in Ldlr-/-mice fed with a high-fat diet. Five macrophage populations were found in the atherosclerotic plaques. It is worth noting that these subset populations of macrophages seem to be endowed with different functions in lipid metabolism and catabolism. A total of 100 differentially expressed mRNAs were selected for these subset populations. Importantly, these macrophage populations were also present in human advanced atherosclerosis. To clarify the specific functions and the regulatory mechanism of these macrophage populations, we extracted exosome RNAs from the plasma of patients with chronic coronary artery disease (CAD) and performed RNA sequencing analysis. Compared with the healthy control, a total of 14 miRNAs were significantly expressed in these patients. A total of 5,248 potential mRNAs were predicted by the bioinformatics platform. Next, we determined the outcome of the intersection of these predicted mRNAs with 100 mRNAs expressed in the above-mentioned five macrophage populations. Based on the screening of miRNA-mRNA pairs, a co-expression network was drawn to find out the key RNAs. Three down-regulated miRNAs and five up-regulated mRNAs were selected for validation by real-time RT-PCR. The results showed that the expression of miR-4498 in plasma exosomes was lower than that in the healthy control, and the expressions of Ctss, Ccr2 and Trem2 mRNA in peripheral blood mononuclear cells isolated from CAD patients were higher. In order to clarify the regulatory mechanism, we established a co-culture system in vitro . Studies have shown that the uptake of exosomes from CAD patients can up-regulate the expression of Ctss, Trem2, and Ccr2 mRNA in THP-1 cells induced by lipopolysaccharide. Our findings revealed a unique relationship between the transcriptional signature and the phenotypic heterogeneity of macrophage in the atherosclerotic microenvironment., (Copyright © 2020 Li, He, Wang, Wang, Cong, Zhu and Chen.)

Aims: Immune endothelial inflammation, underlying coronary heart disease (CHD) related phenotypes, could provide new insight into the pathobiology of the disease. We investigated DNA methylation level of the unique CpG island of HLA-G gene in CHD patients and evaluated the correlation with cardiac computed tomography angiography (CCTA) features., Methods: Thirty-two patients that underwent CCTA for suspected CHD were enrolled for this study. Obstructive CHD group included fourteen patients, in which there was a stenosis greater than or equal to 50% in one or more of the major coronary arteries detected; whereas subjects with Calcium (Ca) Score = 0, uninjured coronaries and with no obstructive CHD (no critical stenosis, NCS) were considered as control subjects (n = 18). For both groups, DNA methylation profile of the whole 5'UTR-CpG island of HLA-G was measured. The plasma soluble HLA-G (sHLA-G) levels were detected in all subjects by specific ELISA assay. Statistical analysis was performed using R software., Results: For the first time, our study reported that 1) a significant hypomethylation characterized three specific fragments (B, C and F) of the 5'UTR-CpG island (p = 0.05) of HLA-G gene in CHD patients compared to control group; 2) the hypomethylation level of one specific fragment of 161bp (+616/+777) positively correlated with coronary Ca score, a relevant parameter of CCTA (p<0.05) between two groups evaluated and was predictive for disease severity., Conclusions: Reduced levels of circulating HLA-G molecules could derive from epigenetic marks. Epigenetics phenomena induce hypomethylation of specific regions into 5'UTR-CpG island of HLA-G gene in CHD patients with obstructive non critical stenosis vs coronary stenosis individuals., Competing Interests: The authors have declared that no competing interests exist.

Genome-wide association studies (GWAS) of coronary artery disease (CAD) have revealed multiple genetic risk loci. We assessed the association of 47 genome-wide significant single-nucleotide polymorphisms (SNPs) at 43 CAD loci with coronary stenosis in a Pakistani sample comprising 663 clinically ascertained and angiographically confirmed cases. Genotypes were determined using the iPLEX Gold technology. All statistical analyses were performed using R software. Linkage disequilibrium (LD) between significant SNPs was determined using SNAP web portal, and functional annotation of SNPs was performed using the RegulomeDB and Genotype-Tissue Expression (GTEx) databases. Genotyping comparison was made between cases with severe stenosis (≥70%) and mild/minimal stenosis (<30%). Five SNPs demonstrated significant associations: three with additive genetic models PLG /rs4252120 ( p = 0.0078), KIAA1462 /rs2505083 ( p = 0.005), and SLC22A3 /rs2048327 ( p = 0.045) and two with recessive models SORT1 /rs602633 ( p = 0.005) and UBE2Z /rs46522 ( p = 0.03). PLG /rs4252120 was in LD with two functional PLG variants (rs4252126 and rs4252135), each with a RegulomeDB score of 1f. Likewise, KIAA1462 /rs2505083 was in LD with a functional SNP, KIAA1462 /rs3739998, having a RegulomeDB score of 2b. In the GTEx database, KIAA1462 /rs2505083, SLC22A3 /rs2048327, SORT1 /rs602633, and UBE2Z /rs46522 SNPs were found to be expression quantitative trait loci (eQTLs) in CAD-associated tissues. In conclusion, five genome-wide significant SNPs previously reported in European GWAS were replicated in the Pakistani sample. Further association studies on larger non-European populations are needed to understand the worldwide genetic architecture of CAD., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2020 Asma Naseer Cheema et al.)

Objective: This study aimed to investigate the role of long non-coding RNA (lncRNA) THRIL in coronary heart disease (CHD) patients., Methods: A total of 420 patients who underwent coronary arteriography due to suspected symptoms of CHD were enrolled, in which 220 were diagnosed as CHD and 200 were set as control subjects. LncRNA THRIL in plasma samples of CHD patients and control subjects was detected by reverse transcription-quantitative polymerase chain reaction. Gensini score and biochemical indexes were evaluated in CHD patients and control subjects. Plasma inflammatory cytokines were detected, and major adverse cardiovascular events (MACE) were recorded in CHD patients., Results: Both before and after adjustment by age/gender, lncRNA THRIL was increased in CHD patients compared with control subjects (both P < .001), and it well predicted enhanced CHD risk by receiver operating characteristic curves. For coronary artery stenosis, it was positively correlated with Gensini score (P < .001, r = .430). For clinical characteristics, lncRNA THRIL was positively correlated with diabetes mellitus occurrence (P < .001) and fasting blood glucose (FBG) level (P = .029, r = .147). For inflammation, it was positively associated with CRP (P < .001, r = .374), TNF-α (P < .001, r = .249), IL-1β (P = .001, r = .222), IL-8 (P < .001, r = .254), and IL-17 (P = .011, r = .172), while negatively correlated with IL-10 (P < .001, r = -.244). For prognosis, lncRNA THRIL was positively associated with MACE accumulating rate (P = .037) in CHD patients., Conclusion: Long non-coding RNA THRIL was increased in CHD patients and well predicted elevated CHD risk. Moreover, it was correlated with enhanced coronary stenosis, systematic inflammation, FBG level, and MACE risk in CHD patients., (© 2020 The Authors. Journal of Clinical Laboratory Analysis Published by Wiley Periodicals, Inc.)

Purpose: Previous studies have reported controversial results regarding the risk of restenosis with polymorphisms of endothelial nitric oxide synthase (eNOS), matrix metalloproteinase 3 (MMP-3), angiotensinogen (AGT), and angiotensin II type 1 receptor (AT1R) after percutaneous coronary intervention (PCI). This study aimed to summarize the association between these polymorphisms and risk of restenosis after PCI., Methods: We searched the electronic databases of PubMed, Embase, Cochrane's Library, and ClinicalTrials.gov for studies on the association of eNOS, MMP-3, AGT, and AT1R polymorphisms with restenosis., Findings: A total of 17 studies (7781 patients) were analyzed, including 5 studies on eNOS G298A (n = 912), 5 studies on MMP3 5A/6A (n = 4519), 6 studies on AGT M235T (n = 1801), and 7 studies on AT1R A1166C (n = 2477). For the G298A variant of the eNOS gene, the allele odds ratio (OR) was 1.685 (95% CI, 1.269-2.338; P < 0.001), the heterozygote OR was 2.144 (95% CI, 1.490-3.085; P < 0.001), the dominant OR was 2.078 (95% CI, 1.462-2.954; P < 0.001), and the overdominant OR was 0.496 (95% CI, 0.348-0.706; P < 0.001). For the 5A/6A variant of the MMP3 gene, the heterozygote OR was 0.839 (95% CI, 0.722-0.975; P = 0.022), the dominant OR was 0.846 (95% CI, 0.733-0.976; P = 0.022), and the overdominant OR was 1.141 (95% CI, 1.001-1.301; P = 0.049). For the M235T variant of the AGT gene, the heterozygote OR was 1.594 (95% CI, 1.179-2.155; P = 0.002), the dominant OR was 1.437 (95% CI, 1.077-1.918; P = 0.014), and the overdominant OR was 0.694 (95% CI, 0.555-0.869; P = 0.001). Positive results were observed in the AT1R gene A1166C polymorphism under 3 models (homozygote OR = 2.009; 95% CI, 1.433-2.816; P < 0.001; recessive OR 1.874; 95% CI, 1.353-2.595; P < 0.001; and dominant OR = 1.350; 95% CI, 1.105-1.649; P = 0.003)., Implications: The G298A variant of eNOS, the 5A/6A variant of MMP3, the M235T variant of AGT, and the A1166C variant of A1TR may increase the risk of restenosis after PCI., Competing Interests: Disclosures The authors have indicated that they have no conflicts of interest regarding the content of this article., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Type 2 diabetes increases the risk of coronary heart disease (CHD), yet the mechanisms involved remain poorly described. Polygenic risk scores (PRS) provide an opportunity to understand risk factors since they reflect etiologic pathways from the entire genome. We therefore tested whether a PRS for CHD influenced risk of CHD in individuals with type 2 diabetes and which risk factors were associated with this PRS., Methods: We tested the association of a CHD PRS with CHD and its traditional clinical risk factors amongst individuals with type 2 diabetes in UK Biobank (N = 21,102). We next tested the association of the CHD PRS with atherosclerotic burden in a cohort of 352 genome-wide genotyped participants with type 2 diabetes who had undergone coronary angiograms., Results: In the UK Biobank we found that the CHD PRS was strongly associated with CHD amongst individuals with type 2 diabetes (OR per standard deviation increase = 1.50; p = 1.5 × 10 - 59 ). But this CHD PRS was, at best, only weakly associated with traditional clinical risk factors, such as hypertension, hyperlipidemia, glycemic control, obesity and smoking. Conversely, in the angiographic cohort, the CHD PRS was strongly associated with multivessel stenosis (OR = 1.65; p = 4.9 × 10 - 4 ) and increased number of major stenotic lesions (OR = 1.35; p = 9.4 × 10 - 3 )., Conclusions: Polygenic predisposition to CHD is strongly associated with atherosclerotic burden in individuals with type 2 diabetes and this effect is largely independent of traditional clinical risk factors. This suggests that genetic risk for CHD acts through atherosclerosis with little effect on most traditional risk factors, providing the opportunity to explore new biological pathways.

Fibronectin-splice variant containing extra domain A (Fn-EDA) is associated with smooth muscle cells (SMCs) following vascular injury. The role of SMC-derived Fn-EDA in SMC phenotypic switching or its implication in neointimal hyperplasia remains unclear. Herein, using human coronary artery sections with a bare metal stent, we demonstrate the expression of Fn-EDA in the vicinity of SMC-rich neointima and peri-strut areas. In mice, Fn-EDA colocalizes with SMCs in the neointima of injured carotid arteries and promotes neointima formation in the comorbid condition of hyperlipidemia by potentiating SMC proliferation and migration. No sex-based differences were observed. Mechanistic studies suggested that Fn-EDA mediates integrin- and TLR4-dependent proliferation and migration through activation of FAK/Src and Akt1/mTOR signaling, respectively. Specific deletion of Fn-EDA in SMCs, but not in endothelial cells, reduced intimal hyperplasia and suppressed the SMC synthetic phenotype concomitant with decreased Akt1/mTOR signaling. Targeting Fn-EDA in human aortic SMCs suppressed the synthetic phenotype and downregulated Akt1/mTOR signaling. These results reveal that SMC-derived Fn-EDA potentiates phenotypic switching in human and mouse aortic SMCs and neointimal hyperplasia in the mouse. We suggest that targeting Fn-EDA could be explored as a potential therapeutic strategy to reduce neointimal hyperplasia.

Background: This study aimed to investigate the correlation of pro-angiogenic microRNA (miRNA) expressions with rapid angiographic stenotic progression (RASP) and restenosis risks in coronary artery disease (CAD) patients underwent percutaneous coronary intervention (PCI) with drug-eluting stents (DES)., Methods: A total of 286 CAD patients underwent PCI with DES were consecutively recruited in this study. Plasma samples were collected before PCI operation, and 14 pro-angiogenic miRNAs were measured by real-time quantitative reverse transcription-polymerase chain reaction. Rapid angiographic stenotic progression at nontarget lesions and restenosis at stented lesions were evaluated by quantitative coronary angiography at 12 months after PCI operation., Results: The occurrence rates of RASP and restenosis were 39.5% and 22.4%, respectively. Let-7f, miR-19a, miR-19b-1, miR-92a, miR-126, miR-210, and miR-296 were decreased in RASP patients than non-RASP patients, among which let-7f, miR-19a, miR-126, miR-210, and miR-296 independently correlated with lower RASP occurrence by multivariate analysis, followed by receiver-operating characteristic (ROC) curve exhibited that these five miRNAs showed great value in predicting RASP risk with area under curve (AUC) 0.879 (95% CI: 0.841-0.917). Besides, let-7f, miR-19a, miR-92a, miR-126, miR-130a, and miR-210 were reduced in restenosis patients than non-restenosis patients, among them miR-19a, miR-126, miR-210, and miR-378 independently correlated with lower restenosis occurrence by multivariate analysis, followed by ROC curve disclosed that these four miRNAs had good value in predicting restenosis risk with AUC 0.776 (95% CI: 0.722-0.831)., Conclusions: Circulating let-7f, miR-19a, miR-126, miR-210, and miR-296 independently correlate with reduced RASP risk, while miR-19a, miR-126, miR-210, and miR-378 independently correlate with decreased restenosis risk in CAD patients underwent PCI with DES., (© 2019 The Authors. Journal of Clinical Laboratory Analysis Published by Wiley Periodicals, Inc.)

Background and Aims: We aimed to identify a blood-based gene expression score (GES) to predict the severity of coronary artery stenosis in patients with known or suspected coronary artery disease (CAD) by integrative use of gene network construction, Support Vector Machine (SVM) algorithm, and multi-cohort validation., Methods: In the discovery phase, a public blood-based microarray dataset of 110 patients with known CAD was analyzed by weighted gene coexpression network analysis and protein-protein interaction network analysis to identify candidate hub genes. In the training set with 151 CAD patients, bioinformatically identified hub genes were experimentally verified by real-time polymerase chain reaction, and statistically filtered with the SVM algorithm to develop a GES. Internal and external validation of GES was performed in patients with suspected CAD from two validation cohorts (n = 209 and 206)., Results: The discovery phase screened 15 network-centric hub genes significantly correlated with the Duke CAD Severity Index. In the training cohort, 12 of 15 hub genes were filtered to construct a blood-based GES12, which showed good discrimination for higher modified Gensini scores (AUC: 0.798 and 0.812), higher Sullivan Extent scores (AUC: 0.776 and 0.778), and the presence of obstructive CAD (AUC: 0.834 and 0.792) in two validation cohorts. A nomogram comprising GES12, smoking status, hypertension status, low density lipoprotein cholesterol level, and body mass index further improved performance, with respect to discrimination, risk classification, and clinical utility, for prediction of coronary stenosis severity., Conclusions: GES12 is useful in predicting the severity of coronary artery stenosis in patients with known or suspected CAD., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Kawasaki disease (KD) patients could develop coronary artery lesion (CAL) which threatens children's life. A previous study identified KD biomarker miRNAs that could discriminate KD patients from febrile non-KD patients. We wonder whether these KD prediction biomarkers could be further applied to predict CAL formation in KD patients., Methods: To examine this hypothesis, we conducted a meta-analysis, miRNA mimic transfection, in vitro cell model and microarray assays., Results: We first showed that miR-182-5p and miR-183-5p kept higher levels in the KD patients with CAL than those without CAL (p < .05). Further machine learning alignment confirmed that CAL formation could be predicted, with an auROC value of 0.86. We further treated neutrophil cells with miR-182-5p mimic, followed by in vitro transendotherial migration assay. As a result, miR-182-5p overexpression significantly (p < .05) enhanced neutrophil cells to infiltrate the endothelial layer composed of human coronary artery endothelium cells. Further microarray assay and pathway enrichment analysis showed that the genes activated with miR-182-5p overexpression were significantly enriched in the leukocyte transendothelial migration pathway (kegg&#95;pathway&#95;194, p < .05)., Conclusion: Therefore, our study suggested that miR-182-5p enhanced in vitro leukocyte infiltration by activating the leukocyte transendothelial migration pathway in CAL formation in KD., (© 2019 Kaohsiung Veterans General Hospital / Kaohsiung Chang Gung Memorial Hospital. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc.)

Aim: To investigated the potential differences between probable and definite heterozygous familial hypercholesterolemia (HeFH) patients diagnosed by Dutch Lipid Clinic Network criteria. Methods: Clinical characteristics, lipid profile, severity of coronary artery stenosis and gene mutations were compared. Kaplan-Meier curve was performed to evaluate the cardiovascular events. Results: Overall, 325 participants were included and divided into two groups: probable (n = 233) and definite HeFH (n = 92). Definite HeFH patients had higher low-density lipoprotein cholesterol (LDL-C), oxidized-LDL and proprotein convertase subtilisin/kexin 9 levels, and higher prevalence of tendon xanthomas. The incidence of genetic mutations was statistically higher in definite HeFH than probable HeFH patients. The coronary stenosis calculated by Gensini score was statistically severer in definite HeFH patients. The best LDL-C threshold for predicting mutations was 5.14 mmol/l. Definite HeFH had lower event-free survival rates. Conclusion: Definite HeFH patients had higher severity of phenotype and genotype, and higher risk of cardiovascular events.

Coronary artery disease (CAD) is primarily caused by atherosclerosis, which is a series of chronic inflammatory processes leading to the initiation and progression of vascular endothelial cell injury enhancing plaque formation. As critical components of the immune system, peripheral blood mononuclear cells (PBMCs) actively cross-talk with pathophysiological conditions induced by endothelial cell injury, reflecting in altered PBMC expression pattern. This study explored PBMC expression levels of miR-21, miR-25 and PTEN in patients with angiographically proven significant coronary stenosis (the CAD group), patients with insignificant coronary stenosis (the ICAD group) and healthy subjects, and assessed potentials of PBMC expressions in discriminating groups of study subjects. In-silico analysis was also performed to obtain insights into CAD-related pathways and biological processes that may be influenced by altered miRNA expressions. A reduced level of PBMC miR-21 was observed in the ICAD group compared to the CAD group (P: 0.004) or healthy controls (P: 0.0001). PBMC miR-21 level was negatively correlated with the PTEN expression (Spearman r: -0.43, P: 3.9e-09). The PTEN expression was increased in the CAD or ICAD group compared to the control group (CAD vs. controls P: 0.0003, ICAD vs. controls P: 0.03). A stepwise increase in PBMC miR-25 levels was observed from healthy controls to ICADs and CAD patients (Kruskal-Wallis P: 7.68e-12). PBMC gene expressions had reasonable power to discriminate between pairs of study groups. PBMC miR-21 levels were able to discriminate ICADs from both CADs and controls and miR-25 levels had potentials to differentiate among all pairs of study groups (i.e. CADs-ICADs, CADs-controls, CADs-all other subjects, ICADs-controls). PBMC PTEN expression was able to discriminate patients with CAD or ICAD from control subjects. Overrepresentation enrichment analysis of experimentally validated targets of miR-21 and miR-25 highlighted key biological processes and pathways, such as "angiogenesis" and "leukocyte cell-cell adhesion", that may be influenced by dysregulation of PBMC miR-21 and miR-25. In conclusion, these findings suggest that patients with insignificant coronary stenosis may have a distinct PBMC miRNA expression profile than those with significant stenosis or healthy controls., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Due to being stable in the circulatory system plasma miRNAs have been detected in various diseases including coronary artery disease (CAD) which is the major cause of mortality and morbidity worldwide. Atherosclerosis is the major cause of CAD. The first and most important event in the progression of atherosclerosis is endothelial dysfunction and accumulation of the lipids in the arterial wall. Recent studies have shown that different expression levels of lipid metabolism-related miRNAs associated with the pathogenesis of atherosclerosis. Therefore, in this current study, we aimed to investigate the possible effects of lipid metabolism-related miRNAs in plasma of patients with CAD. miRNA analysis was performed by high throughput quantitative PCR method using RNA samples isolated from 46 patients with CAD and 43 non-CAD or control. Data were analyzed using SPSS software version 17 and GeneGlobe Data Analysis Center by Qiagen. Among 40 miRNAs, 4 miRNAs were markedly up-regulated while 4 miRNAs were down-regulated in patients with CAD compared to the control group. The results have shown that, hsa-mir-144-3p, hsa-miR-222-5p and hsa-miR-133a-5p were statistically different in the patient with CAD compared to the control (p = 0.040, 0.030 and 0.005 respectively). Increased expression of hsa-mir-144-3p, hsa-miR-222-5p and hsa-miR-133a-5p would have associated with presence of the CAD. Furthermore, we suggested that these miRNAs might have been useful markers for early detection of the CAD.

Vascular remodeling is mainly caused by excessive proliferation of vascular smooth muscle cells (VSMCs). Noncoding RNAs (ncRNAs) have emerged as important regulators in diverse pathological processes. Previous work has shown the functions and mechanisms of long noncoding RNA H19 (LncRNA H19) on VSMCs. As long noncoding RNAs (lncRNAs) are complex in their mechanisms of action, the aim of the study is to identify if there are any other molecular mechanisms of LncRNA H19 on VSMCs. In vivo studies demonstrated that cyclin D1 was overexpressed in neointima of balloon-injured artery. In vitro studies identified that the overexpression of LncRNA H19 promoted VSMCs proliferation and cyclin D1 upregulation. On the contrary, cellular proliferation and expression of cyclin D1 were inhibited in VSMCs after infection with let-7a. Furthermore, luciferase reporter assays and RNA pull-down assays were used to explore the regulatory mechanism, we found that LncRNA H19 functioned as a competing endogenous RNA (ceRNA) by sponging let-7a to promote the expression of the target gene cyclin D1. In conclusion, LncRNA H19 positively regulated cyclin D1 expression through directly binding to let-7a in VSMCs. Our findings provide new insight into the mechanism of LncRNA H19 in VSMCs proliferation and vascular remodeling, and further indicate the implications of LncRNA H19 in the diagnosis and treatment of vascular proliferative diseases., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Introduction: Coronary stenosis is a consequence of atherosclerotic plaque progression that is associated with impaired fibrinolysis. Thrombin-activatable fibrinolysis inhibitor (TAFI) and plasminogen activator inhibitor 1 (PAI-1) are fibrinolysis inhibitors whose levels are influenced by acquired conditions and by polymorphisms. This study therefore aimed to investigate the association of TAFI and PAI-1 gene polymorphisms with severity of coronary stenosis in subjects with stable coronary artery disease (CAD)., Materials and Methods: A total of 327 subjects suspected with CAD who underwent a coronary angiogram were recruited. Gensini score was applied to stratify the severity of coronary stenosis. Based on the Gensini score, the subjects were categorized into low-medium (<20) or high (≥20) groups. The study polymorphisms included TAFI Ala147Thr (505G/A), Thr325Ile (1040C/T), +1542C/G, +1583T/A and PAI-1 -675 4G/5G. Most polymorphisms were genotyped by allele-specific polymerase chain reaction, except for TAFI Thr325Ile that was genotyped by polymerase chain reaction-restriction fragment length polymorphism., Results: A significant increase in the Gensini score was found in TAFI 505A and +1583A allele carriers. Binary regression analysis revealed the independent association of the TAFI 505G/A and +1583T/A polymorphisms with a high Gensini score [adjusted OR = 1.67 (95% CI: 1.03, 2.73) and 1.69 (95% CI: 1.04, 2.76), respectively]. Neither the homozygous PAI-1 -675 4G/4G nor the heterozygous 4G/5G was associated with a high Gensini score., Conclusions: The results indicated the contribution of TAFI polymorphisms to atherosclerosis progression and severity of coronary stenosis in stable CAD., (Copyright © 2018. Published by Elsevier Ltd.)

Aim: Messenger RNAs (mRNAs) play an important role in the pathogenesis of coronary artery disease (CAD). We evaluated the association of selected increase in mRNAs from monocytes with the risk of CAD., Methods: Chip data (GSE9820) retrieved from Gene Expression Omnibus (GEO) was re-analyzed, and the selected candidate genes, meeting specific conditions, were up-regulated and verified for specific biomarkers of CAD within a prospective cohort study that recruited 194 individuals and subdivided into two groups: group Non-CAD (GN), n = 68 and group CAD (GC), n = 126. The patients in GC were further categorized into three sub-units according to the extent of coronary stenosis shown during coronary angiography, coded as single-vessel stenosis (GC1, n = 53), 2-vessel stenosis (GC2, n = 50), or ≥ 3-vessel stenosis (GC3, n = 23). All candidate mRNAs expressions were analyzed from patients' monocytes with quantitative PCR (q-PCR). Receiver-operating characteristic (ROC) curves and the area under the ROC curves (AUCs) were used to evaluate the mRNAs' feasibility for CAD prediction. AUCs ≥0.8 were accounted as highly specific association with CAD., Results: GBA2, CSTF3, ZNF606 and MPP5 were selected as mRNAs candidates from chip data reanalysis. GBA2 (P = .002) and ZNF606 (P < .001) expressions were significantly increased in GC. ZNF606 showed significant increase after adjusting the risk factors with logistic regression analysis (OR = 3.804, 95% CI: 1.923, 7.798, P < .001), and its expression level was positively correlated with age (β = 0.04 × 10 -3 , P < .001). The AUCs (and 95% CI) of ZNF606 expression in GC2 and GC3 were ≥0.8., Conclusion: These findings suggest that it is novel and specific for the association of ZNF606 gene expression from monocytes with the risk of CAD, especially in patients with multiple coronary artery stenosis., (Copyright © 2018. Published by Elsevier Inc.)

Background: This study aims to investigate the relationship between polymorphism of adiponectin (ADIPOQ) gene SNPS+276 and the severity of coronary heart disease (CHD) and coronary artery disease (CAD)., Methods: A total of 582 inpatients were enrolled and divided into Group CHD (342 cases) and the control group (CON, 240 cases), according to their angiographic results from June 2014 to April 2016 for the genotype (G/T) analysis of ADIPOQ SNPs+276 by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP)., Results: Group CHD: GG 110 (32%), GT 205 (59%), and TT27 (8%); Group CON: GG 36 (15%), GT 161 (67%), and TT 43 (18%) (P < .05). The frequency of allele G in group CHD was 62.1% and 48.5% in group CON (P < .05). The frequencies of genotype GG, GT, and TT were 67 (33.3%), 107 (53.2%), and 27 (13.5%), respectively, in the group with single vascular lesion, and 64 (45.4%), 53 (37.6%), and 24 (17%), respectively, in the group with multiple vascular lesions. There was statistical significance between the two groups (P < .05)., Conclusions: The 276G gene of adiponectin may be a susceptibility gene of CHD, and the genotype GG may be related to the severity of this disease.

Background and Aims: Lipoprotein(a) [Lp(a)] is an emerging genetic risk factor for cardiovascular disease (CVD). We examined whether plasma Lp(a) concentration and apolipoprotein(a) [apo(a)] isoform size are associated with extent and severity of coronary artery disease (CAD), and the presence of carotid artery plaque., Methods: We included in our study male participants (n = 263) from a cohort with angiographically defined premature CAD (Carotid Ultrasound in Patients with Ischemic Heart Disease). The angiographic extent and severity of CAD were determined by the modified Gensini and Coronary Artery Stenosis≥20% (CAGE) scores. Carotid artery plaque was assessed by bilateral carotid B-mode ultrasound. Apo(a) isoform size was determined by LPA Kringle IV-2 copy number (KIV-2 CN)., Results: Lp(a) concentration, but not KIV-2 CN, was positively associated with the Gensini score. The association remained significant following adjustment for conventional CVD risk factors (all p < 0.05). Lp(a) concentration and elevated Lp(a) [≥50 mg/dL] were positively associated with the CAGE≥20 score, independent of conventional CVD risk factors. KIV-2 C N Q1 (lowest KIV-2 CN quartile) was associated with CAGE≥20 score and KIV-2 CN, with the CAGE≥20 score in those without diabetes. In multivariate models that included phenotypic familial hypercholesterolemia or low-density lipoprotein cholesterol, Lp(a) concentration, but not KIV-2 CN, was independently associated with the Gensini and CAGE≥20 scores. No significant associations between Lp(a) concentration and KIV-2 CN with carotid artery plaque were observed., Conclusions: Lp(a) concentration, but not apo(a) isoform size, is independently associated with angiographic extent and severity of CAD. Neither Lp(a) nor apo(a) isoform size is associated with carotid artery plaque., (Copyright © 2018. Published by Elsevier B.V.)

Background: Alterations in gene expression in peripheral blood cells play a curtail role in the presence and extent of coronary artery disease (CAD), but its severity reflected by gene expression alterations in peripheral blood cells is still unknown in Xinjiang population in China., Methods: Global gene expression profiling in peripheral blood was used to explore differentially expressed genes in coronary artery stenosis patients. RNA was extracted from peripheral blood of 9 controls without coronary stenosis and 21 cases with angiographically CAD. The extent of CAD severity was categorized angiographically as no CAD, mild CAD (20 to 50% luminal diameter stenosis [LDS]), moderate CAD (50 to 75% LDS) and severe CAD (≥75% LDS). Differentially expressed genes related with CAD severity from peripheral blood cells were screened by linear mixed effects analysis using the lme4 package in R. Then the differentially expressed genes that gradually up-regulated or down-regulated were enriched by Gene Ontology (GO) functional annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis., Results: The most significantly enrichments were toll-like receptor signaling pathway, immune responses, translational processes, cellular growth, inflammation and metabolic processes. Combined with NCBI-GeneRIF and PubMed analysis, we focused on the 12 genes associated with toll-like receptor signaling pathway in the extent of coronary artery stenosis patients. Receiver operating characteristic (ROC) analysis of 12 genes associated with toll-receptor signaling pathway in the 236 CAD patients from GEO database demonstrated that 12 genes expression could predict severe CAD with an area under the curve of 0.67, sensitivity of 77.65% and specificity of 51.52%., Conclusion: These results suggest that 12 genes associated with toll-like receptor signaling pathway in peripheral-blood cells reflect the presence and extent of CAD severity in Xinjiang population in China.

Objective: To investigate the association of CXCL12 and CXCR4 polymorphisms with the genetic risk and severity of coronary stenosis in patients with coronary artery disease (CAD)., Methods: Competitive allele specific PCR(KASP) was performed to identify the genotypes of rs2297630 and rs2322864 polymorphisms in 302 CAD patients and 302 age-and gender-matched healthy controls. The severity of CAD patients was assessed by the Gensini scoring system according to the results of coronary arteriography. The association of rs2297630 and rs2322864 polymorphisms with genetic risk of CAD and Gensini scores were analyzed by unconditional logistic regression and multivariate linear regression respectively., Results: There were significant differences in the genotype and allele frequencies of both rs2297630 and rs2322864 between the CAD group and healthy control (all P <0.01). Regression analysis showed that rs2297630 polymorphism was associated with genetic risk of CAD and Gensini scores (all P <0.01). People who carried the AA genotype suffered higher risk of CAD susceptibility and more serious coronary stenosis (all P <0.01), compared with GG genotype carriers. There was also significant association between rs2322864 polymorphism and genetic risk of CAD ( P <0.01); those who carried the CT genotype had higher risk of CAD ( P <0.01), compared with TT genotype carriers. However, rs2322864 polymorphism was not associated with the severity of coronary stenosis ( P >0.05)., Conclusions: Gene polymorphism of CXCL12 rs2297630 is associated with the genetic risk of CAD and the severity of coronary stenosis. Moreover, the gene polymorphism of CXCR4 rs2322864 is associated with genetic risk of CAD, but not with the severity of coronary stenosis.

Background: Ossabaw pigs are unique miniature swine with genetic predisposition to develop metabolic syndrome and coronary atherosclerosis after extended periods receiving atherogenic diets. We have hypothesized that transgenic Ossabaw swine expressing chimp PCSK9 (proprotein convertase subtilisin-like/kexin type 9) containing the D374Y gain of function would develop familial hypercholesterolemia and coronary artery plaques more rapidly than Landrace swine with the same transgene., Methods and Results: Ossabaw and Landrace PCSK9 gain-of-function founders were generated by Sleeping Beauty transposition and cloning. Histopathologic findings in the Ossabaw founder animal showed more advanced plaques and higher stenosis than in the Landrace founder, underscoring the Ossabaw genetic predisposition to atherosclerosis. We chose to further characterize the Ossabaw PCSK9 gain-of-function animals receiving standard or atherogenic diets in a 6-month longitudinal study using computed tomography, magnetic resonance (MR) imaging, intravascular ultrasound, and optical coherence tomography, followed by pathological analysis of atherosclerosis focused on the coronary arteries. The Ossabaw model was consistently hypercholesterolemic, with or without dietary challenge, and by 6 months had consistent and diffuse fibrofatty or fibroatheromatous plaques with necrosis, overlying fibrous caps, and calcification in up to 10% of coronary plaques., Conclusions: The Ossabaw PCSK9 gain-of-function model provides consistent and robust disease development in a time frame that is practical for use in preclinical therapeutic evaluation to drive innovation. Although no animal model perfectly mimics the human condition, this genetic large-animal model is a novel tool for testing therapeutic interventions in the context of developing and advanced coronary artery disease., (© 2018 The Authors and Recombinetics. Published on behalf of the American Heart Association, Inc., by Wiley.)