Biomarkers Of Atherosclerosis Research Articles

Proteomics analysis of coronary atherosclerotic heart disease with different Traditional Chinese Medicine syndrome types before and after percutaneous coronary intervention.

To investigate the underlying protein molecular mechanisms of "Qi stagnation and blood stasis syndrome" (QS) and "Qi deficiency and blood stasis syndrome" (QD), as two subtypes of coronary artery disease (CAD) in Traditional Chinese Medicine (TCM), following percutaneous coronary intervention (PCI). In this study, a total of 227 CAD patients with QS and 211 CAD patients with QD were enrolled; all participants underwent PCI. Label-free quantification proteomics were employed to analyze the changes in serum in two subtypes of CAD patients before and 6 months after PCI, aiming to elucidate the intervention mechanism of PCI in treating CAD characterized by two different TCM syndromes. Biochemical analysis revealed significant changes in tumor necrosis factor-α, high density lipoprotein cholesterol, blood stasis clinical symptoms observation, and Gensini levels in both patient groups post-PCI; Proteomic analysis identified 79 and 95 differentially expressed proteins in the QS and QD patient groups, respectively, compared to their control groups. complement C8 alpha chain, complement factor H, apolipoprotein H, apolipoprotein B, plasminogen, carbonic anhydrase 2, and complement factor I were altered in both comparison groups. Furthermore, enrichment analysis demonstrated that cell adhesion and connectivity-related processes underwent changes in QS patients post-PCI, whereas lipid metabolism-related pathways, including the peroxisome proliferator-activated receptor signaling pathway and extracellular matrix receptor interaction, underwent changes in the QD group. The protein-protein interaction network analysis further enriched 52 node proteins, including apolipoprotein B, lipoprotein (a), complement C5, apolipoprotein A4, complement C8 alpha chain, complement C8 beta chain, complement C8 gamma chain, apolipoprotein H, apolipoprotein A-Ⅱ, albumin, complement C4-B, apolipoprotein C3, among others. The functional network of these proteins is posited to contribute to the pathophysiology of CAD characterized by TCM syndromes. The current quantitative proteomic study has preliminarily identified biomarkers of CAD in different TCM subtypes treated with PCI, potentially laying the groundwork for understanding the protein profiles associated with the treatment of various TCM subtypes of CAD.

Role of miR-128-3p and miR-195-5p as biomarkers of coronary artery disease in Indians: a pilot study

Coronary artery disease (CAD) imposes a significant economic burden in developing countries like India. Timely diagnosis and treatment should be prioritized to mitigate the disease. Current diagnostic tools being invasive and less specific raise the need to develop less invasive and more reliable molecular biomarkers. MicroRNAs (miRNAs) are an emerging class of molecules that can serve as a potential source of non-invasive biomarkers for CAD. The objective of this study was to determine the potential of circulatory miRNAs as diagnostic biomarkers in CAD. In this study, we have reported two microRNAs, miR-128-3p and miR-195-5p in the serum of CAD patients in Indian Population. A total of 124 subjects were recruited which included 89 angiographically proven CAD patients and 35 control subjects. Our results show a significant decrease in the levels of miR-128-3p in CAD patients while there were no significant changes in the levels of miR-195-5p. Further bioinformatics analysis revealed the potential role of miR-128-3p in cholesterol homeostasis. Altered homeostasis due to cholesterol accumulation in macrophages is the driving force behind formation of foam cells which in turn accelerates the progression of CAD. Here, we have shown that miR-128-3p increases cholesterol levels in macrophages by decreasing cholesterol efflux in-vitro.

Proteomic Signatures of Coronary Artery Disease and Hypercholesterolemia

Background: Coronary artery disease (CAD) is the most common type of cardiovascular disease (CVD), it causes narrowing of the blood vessel lumen due to atherosclerotic plaque formation. Atherosclerosis, is strongly influenced by hypercholesterolemia (HC). Proteomics offers advantages over traditional studies that focus on individual biomarkers. This method provides a holistic view by examining the entire proteomic spectrum in a biological sample, making it an indispensable asset for spotting potential novel protein biomarkers directly linked to atherosclerosis occurrence, progression, and complications such as plaque instability or rupture. Methods: Slow Off-rate Modified Aptamer (SOMAmer)-based protein array was used to quantify proteins. Our cross-sectional study involved healthy controls (n=45), and patients diagnosed with HC (n=51) or CAD (n=32). Proteome data was analyzed using multiple statistical methods. Results: The orthogonal partial least square discriminant analysis (OPLS-DA) revealed a clear separation of the 3 study groups based on two principal components, with R2X= 0.267, R2Y= 0.9, and Q2= 0.28, indicating distinct protein alterations between groups. A total of 1,305 proteins were analyzed and 156 of them in CAD vs control, 140 of them in HC vs control, and 326 of the proteins in CAD vs HC comparisons, were significantly differentially expressed with a p-value<0.05. Among those, q-value<0.05 were determined. As a result, in CAD patients, 2 proteins exhibited significantly differential expressions compared to healthy controls. In contrast, HC patients had 15 significantly altered proteins compared to controls. Furthermore, a comparison between CAD and HC patients revealed 87 significantly regulated proteins. The receiver operating characteristic (ROC) was performed on proteins with distinct expressions ( q<0.05) in pairwise group comparisons. The AUC was calculated to identify potential biomarker candidates for the disease groups. In the CAD vs. control analysis, both significant proteins (PCSK9, SDF-1) exhibited an AUC of 0.75. In the comparison between HC and control groups, out of 15 significantly altered proteins, 7 had an AUC of 0.75 or higher (LRP1B, Apo E, QORL1, Apo E3, Apo B, Transferrin, MMP-3). Among the 87 proteins significantly differentially expressed in CAD versus HC, 59 had an AUC ≥ 0.75. Sixteen of these proteins had an AUC ≥ 0.80. Conclusion: Distinct protein patterns associated with each condition were identified. CAD patients showed a significant increase in the cholesterol-metabolizing protein PCSK9 and varying levels of the angiogenesis-related protein SDF-1. Several other proteins (LRP1B, VAV, CSRP3, HSP 60, and TAK1-TAB1) also exhibited unique expressions in disease groups, suggesting potential roles in atherosclerosis development. Moreover, a statistically significant correlation between SDF-1, ApoB levels, and LDL levels was found in CAD patients but not in healthy controls. This discovery phase cohort study unveils potential biomarkers for atherosclerosis within the HC context. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Cytomegalovirus Immunoglobulin G Levels and Subclinical Arterial Disease among People Living with HIV in Botswana: A Cross-Sectional Study.

Cytomegalovirus (CMV) has been linked with increased cardiovascular risk and monocyte activation in people living with HIV (PLWH). This cross-sectional study aimed to compare CMV immunoglobulin G (IgG) levels between combined antiretroviral therapy (cART)-treated PLWH versus ART-naïve PLWH and those without HIV, and to investigate their associations with biomarkers of endothelial injury and carotid atherosclerosis, in Gaborone, Botswana. All participants were between 30 and 50 years old. Carotid intimal media thickness (cIMT) and biomarkers of endothelial injury and monocyte activation were also assessed. The association between quantitative CMV IgG and cardiovascular disease risk was assessed in multivariate logistic regression analysis. The results showed that the mean CMV IgG level among ART-naïve participants was significantly higher than both the cART group and controls. However, CMV IgG levels did not differ significantly between the controls and cART groups. Among PLWH, CMV IgG levels were associated with ICAM-1 levels and cIMT. Increases in CMV IgG among ART-naïve participants were significantly associated with increases in log VCAM-1. In conclusion, CMV IgG levels are elevated among PLWH in sub-Saharan Africa, and higher levels are associated with biomarkers of endothelial injury and cIMT. Future research should investigate the long-term impact of elevated CMV IgG among PLWH.

Review and targeted lipidomic biomarkers in atherosclerosis

Ischemic cardiovascular events (ischemic stroke, myocardial infarction) are the most common complications of cardiovascular diseases. One of the leading mechanisms of these complications is atherosclerosis. Lipids play an important role in plaque development. Recently, the lipidome has been of greatest interest, since it may have a prognostic value in atherosclerosis development. With an increase in the circulation of proatherogenic lipidomic biomarkers, the risk of atheroscle­rosis destabilization and ischemic complications increases.The conducted studies made it possible to create additional risk stratification scales, for example, Cardiovascular Event Risk Test (CERT) 1 and 2. They make it possible to estimate the residual risk in patients taking statins. The lipidome examination in extracranial artery atherosclerosis can identify those plaques that have signs of instability, and therefore are dangerous for ischemic stroke development.The review describes the features of plasma lipidome in various cardiovascular diseases associated with atherosclerosis.

Fisetin Suppresses Atherosclerosis by Inhibiting Ferroptosis-Related Oxidative Stress in Apolipoprotein E Knockout Mice

Introduction: Fisetin has been demonstrated to inhibit the occurrence of atherosclerosis; however, the mechanism of fisetin suppressing atherosclerosis remains elusive. Methods: The function of fisetin in the inhibition of atherosclerosis was evaluated by hematoxylin and eosin and Oil Red O staining in ApoE−/− mice. Molecular biomarkers of atherosclerosis progression were detected by Western blot and qPCR. Moreover, the inhibition of atherosclerosis on oxidative stress and ferroptosis was evaluated by immunofluorescence staining, qPCR, and Western blot assays. Results: The obtained results showed that serum lipid was attenuated and consequentially the formation of atherosclerosis was also suppressed by fisetin in ApoE−/− mice. Exploration of the mechanism revealed that molecular biomarkers of atherosclerosis were decreased under fisetin treatment. The level of reactive oxygen species and malondialdehyde declined, while the activity of superoxide dismutases and glutathione peroxidase was increased under the fisetin treatment. Additionally, the suppressor of ferroptosis, glutathione peroxidase 4 proteins, was elevated. The ferritin was decreased in the aortic tissues treated with fisetin. Conclusions: In summary, fisetin attenuated the formation of atherosclerosis through the inhibition of oxidative stress and ferroptosis in the aortic tissues of ApoE−/− mice.

Identification of diagnostic biomarkers and immune cell infiltration in coronary artery disease by machine learning, nomogram, and molecular docking.

Coronary artery disease (CAD) is still a lethal disease worldwide. This study aims to identify clinically relevant diagnostic biomarker in CAD and explore the potential medications on CAD. GSE42148, GSE180081, and GSE12288 were downloaded as the training and validation cohorts to identify the candidate genes by constructing the weighted gene co-expression network analysis. Functional enrichment analysis was utilized to determine the functional roles of these genes. Machine learning algorithms determined the candidate biomarkers. Hub genes were then selected and validated by nomogram and the receiver operating curve. Using CIBERSORTx, the hub genes were further discovered in relation to immune cell infiltrability, and molecules associated with immune active families were analyzed by correlation analysis. Drug screening and molecular docking were used to determine medications that target the four genes. There were 191 and 230 key genes respectively identified by the weighted gene co-expression network analysis in two modules. A total of 421 key genes found enriched pathways by functional enrichment analysis. Candidate immune-related genes were then screened and identified by the random forest model and the eXtreme Gradient Boosting algorithm. Finally, four hub genes, namely, CSF3R, EED, HSPA1B, and IL17RA, were obtained and used to establish the nomogram model. The receiver operating curve, the area under curve, and the calibration curve were all used to validate the accuracy and usefulness of the diagnostic model. Immune cell infiltrating was examined, and CAD patients were then divided into high- and low-expression groups for further gene set enrichment analysis. Through targeting the hub genes, we also found potential drugs for anti-CAD treatment by using the molecular docking method. CSF3R, EED, HSPA1B, and IL17RA are potential diagnostic biomarkers for CAD. CAD pathogenesis is greatly influenced by patterns of immune cell infiltration. Promising drugs offers new prospects for the development of CAD therapy.

Development of a CD163-Targeted PET Radiotracer That Images Resident Macrophages in Atherosclerosis.

Tissue-resident macrophages are complementary to proinflammatory macrophages to promote the progression of atherosclerosis. The noninvasive detection of their presence and dynamic variation will be important to the understanding of their role in the pathogenesis of atherosclerosis. The goal of this study was to develop a targeted PET radiotracer for imaging CD163-positive (CD163+) macrophages in multiple mouse atherosclerosis models and assess the potential of CD163 as a biomarker for atherosclerosis in humans. Methods: CD163-binding peptide was identified using phage display and conjugated with a NODAGA chelator for 64Cu radiolabeling ([64Cu]Cu-ICT-01). CD163-overexpressing U87 cells were used to measure the binding affinity of [64Cu]Cu-ICT-01. Biodistribution studies were performed on wild-type C57BL/6 mice at multiple time points after tail vein injection. The sensitivity and specificity of [64Cu]Cu-ICT-01 in imaging CD163+ macrophages upregulated on the surface of atherosclerotic plaques were assessed in multiple mouse atherosclerosis models. Immunostaining, flow cytometry, and single-cell RNA sequencing were performed to characterize the expression of CD163 on tissue-resident macrophages. Human carotid atherosclerotic plaques were used to measure the expression of CD163+ resident macrophages and test the binding specificity of [64Cu]Cu-ICT-01. Results: [64Cu]Cu-ICT-01 showed high binding affinity to U87 cells. The biodistribution study showed rapid blood and renal clearance with low retention in all major organs at 1, 2, and 4 h after injection. In an ApoE-/- mouse model, [64Cu]Cu-ICT-01 demonstrated sensitive and specific detection of CD163+ macrophages and capability for tracking the progression of atherosclerotic lesions; these findings were further confirmed in Ldlr-/- and PCSK9 mouse models. Immunostaining showed elevated expression of CD163+ macrophages across the plaques. Flow cytometry and single-cell RNA sequencing confirmed the specific expression of CD163 on tissue-resident macrophages. Human tissue characterization demonstrated high expression of CD163+ macrophages on atherosclerotic lesions, and ex vivo autoradiography revealed specific binding of [64Cu]Cu-ICT-01 to human CD163. Conclusion: This work reported the development of a PET radiotracer binding CD163+ macrophages. The elevated expression of CD163+ resident macrophages on human plaques indicated the potential of CD163 as a biomarker for vulnerable plaques. The sensitivity and specificity of [64Cu]Cu-ICT-01 in imaging CD163+ macrophages warrant further investigation in translational settings.

MicroRNAs and Oxidative Stress Markers as Additional Diagnostic Criteria for Coronary Heart Disease

The aim. To examine the significance of microribonucleic acids (miRNAs) and oxidative stress markers in predicting the onset of atherosclerosis and the connection between oxidative stress levels and miRNAs in individuals with coronary heart disease.
 Materials and methods. Initially, 40 patients were divided as follows: 10 subjects without any lesions in coronary arteries (group 0), 4 patients with non-stenotic atherosclerosis (group 1), and 26 patients with significant multivessel atherosclerotic lesions (group 2). Various biochemical parameters were analyzed, including miRNA expression levels and common oxidative stress markers.
 Results. The groups were comparable in terms of the patients’ age, but there was unequal distribution of males and females in the angio-groups as per Fisher’s exact test. We also analyzed the data separately for females, but no significant difference was found. There were significant differences in miRNA-122 levels, N-terminal prohormone of brain natriuretic peptide levels, lipid profiles, and oxidative stress markers between group 0 and groups with atherosclerotic lesions. Specifically, miRNA-122 levels were elevated in group 0, along with N-terminal prohormone of brain natriuretic peptide, triglycerides, ratio of triglycerides to high-density lipoprotein cholesterol, and oxidative stress markers. Conversely, compared to group 0, total cholesterol, high-density lipoprotein cholesterol, bilirubin, and specific glutathione levels decreased in patients with coronary lesions.
 Conclusions. The study demonstrated the potential of miRNAs, particularly miRNA-122, as predictive biomarkers for atherosclerosis. Further research with larger cohorts is warranted to validate these findings and explore additional miRNA candidates and therapeutic interventions for cardiovascular diseases.

Abstract 55: Associations Between Cardiovascular Disease, Cognition, Kidney Function and Polyepigenetic Scores of Atherosclerosis in the Health and Retirement Study

Introduction: Atherosclerosis, characterized by the accumulation of arterial fatty and fibrous materials, underlies various morbidities, particularly cardiovascular disease (CVD). Epigenetic processes, like DNA methylation (DNAm), may function as mediators or biomarkers of atherosclerosis. In this study, we estimated polyepigenetic scores, which are risk-profile scores calculated from the results of an external epigenome-wide association study, for coronary artery calcification (DNAm-CAC) and carotid plaque (DNAm-cPlaque). We assessed the hypothesis that these scores are associated CVD, cognitive function, and renal function. Methods: We utilized data from the Health and Retirement Study, a longitudinal survey of U.S. adults over age 50. DNAm was measured on a representative sample of respondents aged 56 years and older who consented to blood draws in 2016 (N=3,875). We defined CVD based on self-reported physician diagnoses, cognitive function/dementia status using the Langa-Weir classification, and kidney function using serum cystatin C. We used weighted linear regression for modeling associations with cognitive and kidney function, logistic regression for prevalent CVD, and Cox proportional hazards models for incident CVD and dementia over a four-year follow-up period. Results: In 2016, the sample had a mean age of 67.4 years (SD=8.5). Most participants were females (57%), with Whites/Caucasians comprising 75% and Blacks/African Americans 17% of the sample. Both DNAm-CAC and DNAm-cPlaque were higher in smokers, individuals with a history of stroke, and those of Black/African American ancestry, while participants with higher education and greater wealth had lower scores (p<0.05). In unadjusted models, DNAm-CAC was linked to higher CVD (Odds ratio: 1.16, 95% CI: 1.07-1.26, p = 3.7х10 -4 ), worse cognitive function (Beta: -0.50, 95%CI: -0.68 - -0.32, p=8.0х10 -9 for DNAm-CAC and -0.38, 95% CI: -0.56 - -0.20, p=1.1х10 -5 for DNAm-cPlaque), and declining kidney function (1.02 fold-increase, 95% CI: 1.01-1.03, p=0.004). Adjusting for comorbidities/lifestyle factors attenuated CVD and kidney function associations but not cognition (Beta = -0.30, 95% CI: -0.14 - -0.30 for DNAm-CAC; -0.23, 95% CI:-0.05- -0.23 for DNAm-cPlaque). DNAm-cPlaque was associated with dementia/cognitive impairment incidence (hazard ratio: 1.16, 95% CI: 1.01-1.32, p=0.03) after adjusting for comorbidities/lifestyle factors including APOE -E4 genotype. For both cognitive function and dementia/cognitive impairment incidence, adjusting for race/ethnicity, education, and wealth fully attenuated the associations. Conclusions: Our findings highlight the significance of polyepigenetic scores of atherosclerosis as potential biomarkers for associated morbidities in a representative U.S. sample and underscore the role of social factors as a pathway influencing these associations.

Iron Status and Risk of Heart Disease, Stroke, and Diabetes: A Mendelian Randomization Study in European Adults.

The relevance of iron status biomarkers for coronary artery disease (CAD), heart failure (HF), ischemic stroke (IS), and type 2 diabetes (T2D) is uncertain. We compared the observational and Mendelian randomization (MR) analyses of iron status biomarkers and hemoglobin with these diseases. Observational analyses of hemoglobin were compared with genetically predicted hemoglobin with cardiovascular diseases and diabetes in the UK Biobank. Iron biomarkers included transferrin saturation, serum iron, ferritin, and total iron binding capacity. MR analyses assessed associations with CAD (CARDIOGRAMplusC4D [Coronary Artery Disease Genome Wide Replication and Meta-Analysis Plus The Coronary Artery Disease Genetics], n=181 522 cases), HF (HERMES [Heart Failure Molecular Epidemiology for Therapeutic Targets), n=115 150 cases), IS (GIGASTROKE, n=62 100 cases), and T2D (DIAMANTE [Diabetes Meta-Analysis of Trans-Ethnic Association Studies], n=80 154 cases) genome-wide consortia. Observational analyses demonstrated J-shaped associations of hemoglobin with CAD, HF, IS, and T2D. In contrast, MR analyses demonstrated linear positive associations of higher genetically predicted hemoglobin levels with 8% higher risk per 1 SD higher hemoglobin for CAD, 10% to 13% for diabetes, but not with IS or HF in UK Biobank. Bidirectional MR analyses confirmed the causal relevance of iron biomarkers for hemoglobin. Further MR analyses in global consortia demonstrated modest protective effects of iron biomarkers for CAD (7%-14% lower risk for 1 SD higher levels of iron biomarkers), adverse effects for T2D, but no associations with IS or HF. Higher levels of iron biomarkers were protective for CAD, had adverse effects on T2D, but had no effects on IS or HF. Randomized trials are now required to assess effects of iron supplements on risk of CAD in high-risk older people.

Profiling of differentially expressed MicroRNAs in familial hypercholesterolemia via direct hybridization

BackgroundIndividuals with homozygous familial hypercholesterolemia (HoFH) have a severe clinical problem in their first decade of life, which is not usually present in heterozygous FH (HeFH) individuals. For this latter group of patients, FH diagnosis is mostly severely delayed with a significant increase in the risk of angina, myocardial infarction, peripheral artery disease, stroke, and cardiovascular and all-cause mortality. MethodsThis study used various bioinformatics tools to analyze microarray data and identify critical miRNAs and their target genes associated with FH and its severity. Differentially expressed serum miRNAs from direct hybridization microarray data in three groups of subjects: healthy, HeFH, and HoFH. The differential expressed miRNAs were determined according to a log of fold-change (LFC) <-0.5 or >0.5 and of p < 0.05. Then, we assessed their target genes in silico. Gene ontology (GO) enrichment was applied by Cytoscape. The protein-protein interaction and co-expression network were analyzed by the STRING and GeneMANIA plugins of Cytoscape, respectively. ResultsWe identified increased expression of circulating hsa-miR-604, hsa-miR-652-5p, and hsa-miR-4451 as well as reduced expression of hsa-miR-3140-3p, hsa-miR-550a-5p, and hsa-miR-363-3p in both group of FH vs. healthy subjects. Higher levels of hsa-miR-1183, hsa-miR-1185-1-3p, hsa-miR-122-5p, hsa-miR-19a-3p, hsa-miR-345-3p, and hsa-miR-34c-5p were detected in HeFH in respect to HoFH when compared to healthy subjects. Most upregulated miRNAs mainly affected gene related to cardiac myofibrillogenesis, cholesterol synthesis, RNA editing for apolipoprotein B, and associated with LDL-cholesterol levels. In contrast, down-regulated miRNAs mainly affected gene related to plasma biomarker for coronary artery disease, lipids metabolism, cell adhesion and migration, genetic predictors of type 2 diabetes and cholesterol metabolism. The essential genes were primarily enriched in GO regarding biological regulation, intracellular nucleic acid binding, and the KEGG pathway of TGF-β signaling. ConclusionsThe case-control nature of this study precluded the possibility of assessing the predictive role of the identified differentially expressed miRNAs for cardiovascular events. Therefore, the signature of miRNAs reflecting the pathogenesis of both HeFH and HoFH.

Decreased circulating CTRP3 levels in acute and chronic cardiovascular patients

C1q/TNF-related protein 3 (CTRP3) represents an adipokine with various metabolic and immune-regulatory functions. While circulating CTRP3 has been proposed as a potential biomarker for cardiovascular disease (CVD), current data on CTRP3 regarding coronary artery disease (CAD) remains partially contradictory. This study aimed to investigate CTRP3 levels in chronic and acute settings such as chronic coronary syndrome (CCS) and acute coronary syndrome (ACS). A total of 206 patients were classified into three groups: CCS (n = 64), ACS having a first acute event (ACS-1, n = 75), and ACS having a recurrent acute event (ACS-2, n = 67). The control group consisted of 49 healthy individuals. ELISA measurement in peripheral blood revealed decreased CTRP3 levels in all patient groups (p < 0.001) without significant differences between the groups. This effect was exclusively observed in male patients. Females generally exhibited significantly higher CTRP3 plasma levels than males. ROC curve analysis in male patients revealed a valuable predictive potency of plasma CTRP3 in order to identify CAD patients, with a proposed cut-off value of 51.25 ng/mL. The sensitivity and specificity of prediction by CTRP3 were congruent for the subgroups of CCS, ACS-1, and ACS-2 patients. Regulation of circulating CTRP3 levels in murine models of cardiovascular pathophysiology was found to be partly opposite to the clinical findings, with male mice exhibiting higher circulating CTRP3 levels than females. We conclude that circulating CTRP3 levels are decreased in both male CCS and ACS patients. Therefore, CTRP3 might be useful as a biomarker for CAD but not for distinguishing an acute from a chronic setting.Key messagesCTRP3 levels were found to be decreased in both male CCS and ACS patients compared to healthy controls. Plasma CTRP3 has a valuable predictive potency in order to identify CAD patients among men and is therefore proposed as a biomarker for CAD but not for distinguishing between acute and chronic settings.Regulation of circulating CTRP3 levels in murine models of cardiovascular pathophysiology was found to be partly opposite to the clinical findings in men.

Pharmacogenomic biomarkers in coronary artery disease: a narrative review.

Coronary artery disease (CAD) has a high mortality rate. Despite various therapeutic targets, non-responsiveness to drugs remains a prevalent issue. Pharmacogenomics assesses the way an individual's genetic attributes affect their likely response to drug therapy. Single-nucleotide polymorphisms play a crucial role in determining these outcomes. This review offers an overview of single-nucleotide polymorphisms investigated in clinical studies and their associations with drug response/nonresponse in the treatment of CAD. A total of 104 studies of whole sets of chromosomes and several genes were explored. A total of161 polymorphisms exhibited associations with drug response/nonresponse in CAD across diverse ethnic populations. This pool can serve as a pharmacogenomic biomarker for predicting response to drug therapy in patients with CAD.

Orosomucoid 2 as a biomarker of carotid artery atherosclerosis plaque vulnerability through its generation of reactive oxygen species and lipid accumulation in vascular smooth muscle cells

BackgroundOrosomucoid (ORM) has been reported as a biomarker of carotid atherosclerosis, but the role of ORM 2, a subtype of ORM, in carotid atherosclerotic plaque formation and the underlying mechanism have not been established. MethodsPlasma was collected from patients with carotid artery stenosis (CAS) and healthy participants and assessed using mass spectrometry coupled with isobaric tags for relative and absolute quantification (iTRAQ) technology to identify differentially expressed proteins. The key proteins and related pathways were identified via western blotting, immunohistochemistry, and polymerase chain reaction of carotid artery plaque tissues and in vitro experiments involving vascular smooth muscle cells (VSMCs). ResultsWe screened 33 differentially expressed proteins out of 535 proteins in the plasma. Seventeen proteins showed increased expressions in the CAS groups relative to the healthy groups, while 16 proteins showed decreased expressions during iTRAQ and bioinformatic analysis. The reactive oxygen species metabolic process was the most common enrichment pathway identified by Gene Ontology analysis, while ORM2, PRDX2, GPX3, HP, HBB, ANXA5, PFN1, CFL1, and S100A11 were key proteins identified by STRING and MCODE analysis. ORM2 showed increased expression in patients with CAS plaques, and ORM2 was accumulated in smooth muscle cells. Oleic acid increased the lipid accumulation and ORM2 and PRDX6 expressions in the VSMCs. The recombinant-ORM2 also increased the lipid accumulation and reactive oxygen species (ROS) in the VSMCs. The expressions of ORM2 and PRDX-6 were correlated, and MJ33 (an inhibitor of PRDX6-PLA2) decreased ROS production and lipid accumulation in VSMCs. ConclusionORM2 may be a biomarker for CAS; it induced lipid accumulation and ROS production in VSMCs during atherosclerosis plaque formation. However, the relationships between ORM2 and PRDX-6 underlying lipid accumulation-induced plaque vulnerability require further research.

ApoB100 and Atherosclerosis: What's New in the 21st Century?

ApoB is the main protein of triglyceride-rich lipoproteins and is further divided into ApoB48 in the intestine and ApoB100 in the liver. Very low-density lipoprotein (VLDL) is produced by the liver, contains ApoB100, and is metabolized into its remnants, intermediate-density lipoprotein (IDL) and low-density lipoprotein (LDL). ApoB100 has been suggested to play a crucial role in the formation of the atherogenic plaque. Apart from being a biomarker of atherosclerosis, ApoB100 seems to be implicated in the inflammatory process of atherosclerosis per se. In this review, we will focus on the structure, the metabolism, and the function of ApoB100, as well as its role as a predictor biomarker of cardiovascular risk. Moreover, we will elaborate upon the molecular mechanisms regarding the pathophysiology of atherosclerosis, and we will discuss the disorders associated with the APOB gene mutations, and the potential role of various drugs as therapeutic targets.

Predicting Lipid-Rich Plaque Progression in Coronary Arteries Using Multimodal Imaging and Wall Shear Stress Signatures.

Plaque composition and wall shear stress (WSS) magnitude act as well-established players in coronary plaque progression. However, WSS magnitude per se does not completely capture the mechanical stimulus to which the endothelium is subjected, since endothelial cells experience changes in the WSS spatiotemporal configuration on the luminal surface. This study explores WSS profile and lipid content signatures of plaque progression to identify novel biomarkers of coronary atherosclerosis. Thirty-seven patients with acute coronary syndrome underwent coronary computed tomography angiography, near-infrared spectroscopy intravascular ultrasound, and optical coherence tomography of at least 1 nonculprit vessel at baseline and 1-year follow-up. Baseline coronary artery geometries were reconstructed from intravascular ultrasound and coronary computed tomography angiography and combined with flow information to perform computational fluid dynamics simulations to assess the time-averaged WSS magnitude (TAWSS) and the variability in the contraction/expansion action exerted by WSS on the endothelium, quantifiable in terms of topological shear variation index (TSVI). Plaque progression was measured as intravascular ultrasound-derived percentage plaque atheroma volume change at 1-year follow-up. Plaque composition information was extracted from near-infrared spectroscopy and optical coherence tomography. Exposure to high TSVI and low TAWSS was associated with higher plaque progression (4.00±0.69% and 3.60±0.62%, respectively). Plaque composition acted synergistically with TSVI or TAWSS, resulting in the highest plaque progression (≥5.90%) at locations where lipid-rich plaque is exposed to high TSVI or low TAWSS. Luminal exposure to high TSVI, solely or combined with a lipid-rich plaque phenotype, is associated with enhanced plaque progression at 1-year follow-up. Where plaque progression occurred, low TAWSS was also observed. These findings suggest TSVI, in addition to low TAWSS, as a potential biomechanical predictor for plaque progression, showing promise for clinical translation to improve patient prognosis.

Plasma proteomics for prediction of subclinical coronary artery calcifications in primary prevention

Recent developments in high-throughput proteomic technologies enable the discovery of novel biomarkers of coronary atherosclerosis. The aims of this study were to test if plasma protein subsets could detect coronary artery calcifications (CAC) in asymptomatic individuals and if they add predictive value beyond traditional risk factors. Using proximity extension assays, 1,342 plasma proteins were measured in 1,827 individuals from the Impaired Glucose Tolerance and Microbiota (IGTM) study and 883 individuals from the Swedish Cardiopulmonary BioImage Study (SCAPIS) aged 50-64 years without history of ischaemic heart disease and with CAC assessed by computed tomography. After data-driven feature selection, extreme gradient boosting machine learning models were trained on the IGTM cohort to predict the presence of CAC using combinations of proteins and traditional risk factors. The trained models were validated in SCAPIS. The best plasma protein subset (44 proteins) predicted CAC with an area under the curve (AUC) of 0.691 in the validation cohort. However, this was not better than prediction by traditional risk factors alone (AUC = 0.710, P = .17). Adding proteins to traditional risk factors did not improve the predictions (AUC = 0.705, P = .6). Most of these 44 proteins were highly correlated with traditional risk factors. A plasma protein subset that could predict the presence of subclinical CAC was identified but it did not outperform nor improve a model based on traditional risk factors. Thus, support for this targeted proteomics platform to predict subclinical CAC beyond traditional risk factors was not found.

Dysregulation of micro-RNA 143-3p as a Biomarker of Carotid Atherosclerosis and the Associated Immune Reactions During Disease Progression.

Atherosclerosis commonly remains undiagnosed until disease manifestations occur. The disease is associated with dysregulated micro(mi)RNAs, but how this is linked to atherosclerosis-related immune reactions is largely unknown. A mouse model of carotid atherosclerosis, human APOB100-transgenic Ldlr-/- (HuBL), was used to study the spatiotemporal dysregulation of a set of miRNAs. Middle-aged HuBL mice with established atherosclerosis had decreased levels of miR-143-3p in their carotid arteries. In young HuBL mice, early atherosclerosis was observed in the carotid bifurcation, which had lower levels of miR-15a-5p, miR-143-3p, and miR-199a-3p, and higher levels of miR-155-5p. The dysregulation of these miRNAs was reflected by specific immune responses during atheroprogression. Finally, levels of miR-143-3p were 70.6% lower in extracellular vesicles isolated from the plasma of patients with carotid stenosis compared to healthy controls. Since miR-143-3p levels progressively decrease when transitioning between early and late experimental carotid atherosclerosis, we propose it as a biomarker for atherosclerosis.

The positive association between the atherogenic index of plasma and the risk of new-onset hypertension: a nationwide cohort study in China

ABSTRACT Background The atherogenic index of plasma (AIP) is a novel metabolic biomarker of atherosclerosis. Nevertheless, the association between the AIP and new-onset hypertension has not been elucidated in the Chinese population. Methods Prospective data were obtained from 3150 participants aged ≥ 18 years in the China Health and Nutrition Survey from 2009 to 2015. The AIP is a logarithmically transformed ratio of triglycerides to high-density lipoprotein cholesterol in molar concentration. Cox regression analysis was used to determine the association of AIP index with new-onset hypertension. Results After the six-year follow-up, 1054 (33.4%) participants developed new-onset hypertension. The participants were divided into AIP quartile groups (Q1-Q4). Compared with those in Q1, subjects in Q3–4 had nearly 1.35 times the risk of new-onset hypertension after full adjustment [Q3: hazard ratio (HR): 1.35, 95% confidence interval (CI): 1.13–1.62; Q4: HR: 1.35, 95% CI: 1.13–1.64]. The risks of new-onset hypertension were nearly 1.30 times higher in subjects in Q2–4 than in subjects in Q1 (p < .01) after the full adjustment when we excluded subjects with diabetes and/or chronic kidney diseases. There was a significant difference [HR (CI): 1.27 (1.04–1.54) vs. 0.90 (0.69–1.18)] when subjects were divided into two groups according to body mass index (BMI) level (<24 vs. ≥24 kg/m2). Conclusions The present study suggested that individuals with a higher AIP index are associated with new-onset hypertension, independent of kidney function and glucose levels. The association was stronger in subjects with normal BMI, which may provide early screening of metabolomics in hypertension prevention.