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1.
Int J Mol Sci ; 25(10)2024 May 11.
Article in English | MEDLINE | ID: mdl-38791267

ABSTRACT

Cardiovascular diseases, among which includes coronary artery disease, represent one of the most important causes of mortality and morbidity worldwide. Research aimed at determining the risk factors involved recognizes a group of "traditional" risk factors, but also more recent studies identified over 100 "novel" ones which may have a role in the disease. Among the latter is the thrombophilia profile of a patient, a pathology well-established for its involvement in venous thromboembolism, but with less studied implications in arterial thrombosis. This paper reviews the literature, explaining the pathophysiology of the thrombophilia causes associated most with coronary thrombosis events. Results of several studies on the subject, including a meta-analysis with over 60,000 subjects, determined the significant involvement of factor V Leiden, prothrombin G20210A mutation, plasminogen activator inhibitor-1 and antiphospholipid syndrome in the development of coronary artery disease. The mechanisms involved are currently at different stages of research, with some already established and used as therapeutic targets.


Subject(s)
Coronary Artery Disease , Factor V , Thrombophilia , Thrombosis , Humans , Coronary Artery Disease/genetics , Coronary Artery Disease/etiology , Coronary Artery Disease/pathology , Thrombophilia/genetics , Thrombophilia/etiology , Thrombosis/genetics , Thrombosis/etiology , Thrombosis/pathology , Factor V/genetics , Prothrombin/genetics , Prothrombin/metabolism , Plasminogen Activator Inhibitor 1/genetics , Plasminogen Activator Inhibitor 1/metabolism , Risk Factors , Genetic Predisposition to Disease , Mutation
2.
PLoS One ; 19(5): e0302547, 2024.
Article in English | MEDLINE | ID: mdl-38820294

ABSTRACT

INTRODUCTION: The natural outcome of coronary plaque in acute coronary syndrome (ACS) patients with chronic kidney disease (CKD) is unique, which can be analyzed quantitatively by optical flow ratio (OFR) software. METHODS: A total of 184 ACS patients with at least one nonculprit subclinical atherosclerosis (NSA) detected by optical coherence tomography (OCT) at baseline and 1-year follow-up were divided into non-CKD group (n = 106, estimated glomerular filtration rate (eGFR)> 90 mL/(min×1.73 m2)) and mild CKD group (n = 78, 60≤eGFR<90 mL/(min×1.73 m2)). Changes of normalized total atheroma volume (TAVn) of NSA was the primary endpoint at the 1-year follow-up. RESULTS: Patients with mild CKD showed more TAVn progression of NSA than non-CKD (p = 0.019) from baseline to the 1-year follow-up, which was mainly due to an increase in calcium TAVn (p<0.001). The morphological change in the maximal calcification thickness (p = 0.026) was higher and the change in the distance from the calcified surface to the contralateral coronary media membrane (ΔC-to-M) at the maximal cross-sectional calcium area was lower (p<0.001) in mild CKD group than in non-CKD group. Mild CKD had more NSA related MACEs at the 5-year follow-up than non-CKD (30.8% vs. 5.8%, p = 0.045). CONCLUSIONS: Mild CKD patients had more plaque progression of NSA which showed the increase of calcium component with more protrusion into the lumen morphologically at the 1-year follow-up and a higher corresponding incidence of NSA-related MACEs at the 5-year follow-up. TRIAL REGISTRATION: Clinical Trial registration ClinicalTrials.gov. NCT02140801. https://classic.clinicaltrials.gov/ct2/show/NCT02140801.


Subject(s)
Acute Coronary Syndrome , Glomerular Filtration Rate , Renal Insufficiency, Chronic , Tomography, Optical Coherence , Humans , Male , Female , Acute Coronary Syndrome/pathology , Acute Coronary Syndrome/diagnostic imaging , Renal Insufficiency, Chronic/pathology , Renal Insufficiency, Chronic/complications , Middle Aged , Follow-Up Studies , Aged , Plaque, Atherosclerotic/diagnostic imaging , Plaque, Atherosclerotic/pathology , Disease Progression , Atherosclerosis/pathology , Atherosclerosis/diagnostic imaging , Atherosclerosis/complications , Coronary Artery Disease/pathology , Coronary Artery Disease/diagnostic imaging , Coronary Artery Disease/complications , Clinical Relevance
3.
Biomed Phys Eng Express ; 10(4)2024 Jun 05.
Article in English | MEDLINE | ID: mdl-38806008

ABSTRACT

Atherosclerosis is a cardiovascular disease mainly caused by plaque deposition in blood vessels. Plaque comprises components such as thrombosis, fibrin, collagen, and lipid core. It plays an essential role in inducing rupture in a blood vessel. Generally, Plaque could be described as three kinds of elastic models: cellular Plaque, hypocellular Plaque, and calcified Plaque. The present study aimed to investigate the behavior of atherosclerotic plaque rupture according to different lipid cores using Fluid-Structure Interaction (FSI). The blood vessel was also varied with different thicknesses (0.05, 0.25, and 0.5 mm). In this study, FSI simulation with a cellular plaque model with various thicknesses was investigated to obtain information on plaque rupture. Results revealed that the blood vessel with Plaque having a lipid core represents higher stresses than those without a lipid core. Blood vessels' thin thickness, like a thin cap, results in more considerable than Von Mises stress. The result also suggests that even at low fracture stress, the risk of rupture due to platelet decomposition at the gap was more significant for cellular plaques.


Subject(s)
Computer Simulation , Coronary Artery Disease , Models, Cardiovascular , Plaque, Atherosclerotic , Stress, Mechanical , Humans , Plaque, Atherosclerotic/pathology , Coronary Artery Disease/pathology , Blood Vessels/pathology , Lipids/chemistry , Coronary Vessels/pathology , Elasticity
4.
Arterioscler Thromb Vasc Biol ; 44(5): 1135-1143, 2024 May.
Article in English | MEDLINE | ID: mdl-38572648

ABSTRACT

BACKGROUND: Acute coronary syndrome (ACS) involves plaque-related thrombosis, causing primary ischemic cardiomyopathy or lethal arrhythmia. We previously demonstrated a unique immune landscape of myeloid cells in the culprit plaques causing ACS by using single-cell RNA sequencing. Here, we aimed to characterize T cells in a single-cell level, assess clonal expansion of T cells, and find a therapeutic target to prevent ACS. METHODS: We obtained the culprit lesion plaques from 4 patients with chronic coronary syndrome (chronic coronary syndrome plaques) and the culprit lesion plaques from 3 patients with ACS (ACS plaques) who were candidates for percutaneous coronary intervention with directional coronary atherectomy. Live CD45+ immune cells were sorted from each pooled plaque samples and applied to the 10× platform for single-cell RNA sequencing analysis. We also extracted RNA from other 3 ACS plaque samples and conducted unbiased TCR (T-cell receptor) repertoire analysis. RESULTS: CD4+ T cells were divided into 5 distinct clusters: effector, naive, cytotoxic, CCR7+ (C-C chemokine receptor type 7) central memory, and FOXP3 (forkhead box P3)+ regulatory CD4+ T cells. The proportion of central memory CD4+ T cells was higher in the ACS plaques. Correspondingly, dendritic cells also tended to express more HLAs (human leukocyte antigens) and costimulatory molecules in the ACS plaques. The velocity analysis suggested the differentiation flow from central memory CD4+ T cells into effector CD4+ T cells and that from naive CD4+ T cells into central memory CD4+ T cells in the ACS plaques, which were not observed in the chronic coronary syndrome plaques. The bulk repertoire analysis revealed clonal expansion of TCRs in each patient with ACS and suggested that several peptides in the ACS plaques work as antigens and induced clonal expansion of CD4+ T cells. CONCLUSIONS: For the first time, we revealed single cell-level characteristics of CD4+ T cells in patients with ACS. CD4+ T cells could be therapeutic targets of ACS. REGISTRATION: URL: https://upload.umin.ac.jp/cgi-open-bin/icdr_e/ctr_view.cgi?recptno=R000046521; Unique identifier: UMIN000040747.


Subject(s)
Acute Coronary Syndrome , CD4-Positive T-Lymphocytes , Plaque, Atherosclerotic , Single-Cell Analysis , Humans , Acute Coronary Syndrome/immunology , Acute Coronary Syndrome/genetics , CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/metabolism , Male , Middle Aged , Female , Aged , RNA-Seq , Receptors, Antigen, T-Cell/genetics , Receptors, Antigen, T-Cell/metabolism , Receptors, Antigen, T-Cell/immunology , Coronary Vessels/immunology , Coronary Vessels/pathology , Sequence Analysis, RNA , Coronary Artery Disease/immunology , Coronary Artery Disease/genetics , Coronary Artery Disease/pathology , Phenotype
5.
Methods Mol Biol ; 2803: 219-226, 2024.
Article in English | MEDLINE | ID: mdl-38676896

ABSTRACT

Coronary artery dissection (CAD) is the intimal tearing of the coronary arterial wall and can be iatrogenic, spontaneous, or traumatic in origin. CAD is a rare but challenging condition that can cause significant hemodynamic compromise. Management strategies for CAD, such as the use of mechanical circulatory support devices, are available in the clinical setting. However, the incidence, etiology, and optimal management of CAD are not well-defined, emphasizing the need for adequate animal models in preclinical studies. Large animal models provide the human-like conditions necessary for testing and development of potential treatment strategies. In this chapter, we describe a method for the creation of a CAD swine model.


Subject(s)
Aortic Dissection , Coronary Vessels , Disease Models, Animal , Vascular Diseases/congenital , Animals , Swine , Coronary Vessels/pathology , Humans , Coronary Vessel Anomalies , Vascular Diseases/etiology , Vascular Diseases/pathology , Vascular Diseases/therapy , Coronary Artery Disease/pathology
6.
Arterioscler Thromb Vasc Biol ; 44(6): 1330-1345, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38602103

ABSTRACT

BACKGROUND: CALCRL (calcitonin receptor-like) protein is an important mediator of the endothelial fluid shear stress response, which is associated with the genetic risk of coronary artery disease. In this study, we functionally characterized the noncoding regulatory elements carrying coronary artery disease that risks single-nucleotide polymorphisms and studied their role in the regulation of CALCRL expression in endothelial cells. METHODS: To functionally characterize the coronary artery disease single-nucleotide polymorphisms harbored around the gene CALCRL, we applied an integrative approach encompassing statistical, transcriptional (RNA-seq), and epigenetic (ATAC-seq [transposase-accessible chromatin with sequencing], chromatin immunoprecipitation assay-quantitative polymerase chain reaction, and electromobility shift assay) analyses, alongside luciferase reporter assays, and targeted gene and enhancer perturbations (siRNA and clustered regularly interspaced short palindromic repeats/clustered regularly interspaced short palindromic repeat-associated 9) in human aortic endothelial cells. RESULTS: We demonstrate that the regulatory element harboring rs880890 exhibits high enhancer activity and shows significant allelic bias. The A allele was favored over the G allele, particularly under shear stress conditions, mediated through alterations in the HSF1 (heat shock factor 1) motif and binding. CRISPR deletion of rs880890 enhancer resulted in downregulation of CALCRL expression, whereas HSF1 knockdown resulted in a significant decrease in rs880890-enhancer activity and CALCRL expression. A significant decrease in HSF1 binding to the enhancer region in endothelial cells was observed under disturbed flow compared with unidirectional flow. CALCRL knockdown and variant perturbation experiments indicated the role of CALCRL in mediating eNOS (endothelial nitric oxide synthase), APLN (apelin), angiopoietin, prostaglandins, and EDN1 (endothelin-1) signaling pathways leading to a decrease in cell proliferation, tube formation, and NO production. CONCLUSIONS: Overall, our results demonstrate the existence of an endothelial-specific HSF (heat shock factor)-regulated transcriptional enhancer that mediates CALCRL expression. A better understanding of CALCRL gene regulation and the role of single-nucleotide polymorphisms in the modulation of CALCRL expression could provide important steps toward understanding the genetic regulation of shear stress signaling responses.


Subject(s)
Calcitonin Receptor-Like Protein , Coronary Artery Disease , Endothelial Cells , Enhancer Elements, Genetic , Polymorphism, Single Nucleotide , Stress, Mechanical , Humans , Endothelial Cells/metabolism , Coronary Artery Disease/genetics , Coronary Artery Disease/metabolism , Coronary Artery Disease/pathology , Calcitonin Receptor-Like Protein/genetics , Calcitonin Receptor-Like Protein/metabolism , Heat Shock Transcription Factors/genetics , Heat Shock Transcription Factors/metabolism , Mechanotransduction, Cellular , Cells, Cultured , Gene Expression Regulation , Protein Binding , Genetic Predisposition to Disease , Binding Sites
7.
Sci Rep ; 14(1): 9477, 2024 04 25.
Article in English | MEDLINE | ID: mdl-38658599

ABSTRACT

To determine the association between complement C1q and vulnerable plaque morphology among coronary artery disease (CAD) patients. We conducted a retrospective observational study of 221 CAD patients admitted to The Second Affiliated Hospital of Xi'an Jiaotong University. Intravascular optical coherence tomography was utilized to describe the culprit plaques' morphology. Using logistic regression analysis to explore the correlation between C1q and vulnerable plaques, and receiver operator characteristic (ROC) analysis assess the predictive accuracy. As reported, the complement C1q level was lower in ACS patients than CCS patients (18.25 ± 3.88 vs. 19.18 ± 4.25, P = 0.045). The low complement-C1q-level group was more prone to develop vulnerable plaques. In lipid-rich plaques, the complement C1q level was positively correlated with the thickness of fibrous cap (r = 0.480, P = 0.041). Univariate and multivariate logistic regression analyses suggested that complement C1q could be an independent contributor to plaques' vulnerability. For plaque rupture, erosion, thrombus, and cholesterol crystals, the areas under the ROC curve of complement C1q level were 0.873, 0.816, 0.785, and 0.837, respectively (P < 0.05 for all). In CAD patients, the complement C1q could be a valuable indicator of plaque vulnerability.


Subject(s)
Complement C1q , Coronary Artery Disease , Plaque, Atherosclerotic , Tomography, Optical Coherence , Humans , Tomography, Optical Coherence/methods , Male , Female , Plaque, Atherosclerotic/diagnostic imaging , Plaque, Atherosclerotic/pathology , Middle Aged , Complement C1q/metabolism , Complement C1q/analysis , Coronary Artery Disease/diagnostic imaging , Coronary Artery Disease/pathology , Aged , Retrospective Studies , ROC Curve
8.
Clin Radiol ; 79(5): 386-392, 2024 May.
Article in English | MEDLINE | ID: mdl-38433042

ABSTRACT

AIM: To evaluate the prevalence, aetiology, and corresponding morbidity of coronary microvascular dysfunction (CMD) in patients with suspected myocardial ischaemia. MATERIALS AND METHODS: The present study included 115 patients with suspected myocardial ischaemia who underwent stress perfusion cardiac magnetic resonance imaging. CMD was assessed visually based on the myocardial perfusion results. The CMR-derived myocardial perfusion reserve index (MPRI) and left ventricular (LV) strain parameters obtained using the post-processing software CVI42 were employed to evaluate LV myocardial perfusion and deformation. LV strain parameters included global longitudinal, circumferential, and radial strain (GLS, GCS, and GRS), global systolic/diastolic longitudinal, circumferential, and radial strain rates (SLSR, SCSR, SRSR, DLSR, DCSR, and DRSR). RESULTS: Of the 115 patients, 12 patients were excluded and 103 patients were finally included in the study. CMD was observed in 79 % (81 patients, aged 53 ± 12 years) of patients. Regarding aetiology, 91 (88 %) patients had non-obstructive coronary artery disease (CAD), eight (8 %) had obstructive CAD, and four (4 %) had hypertrophic cardiomyopathy (HCM). The incidence of CMD was highest (100 %) in patients with HCM, followed by those with non-obstructive CAD (up to 79 %). There were no statistical differences between CMD and non-CMD groups in GCS, GRS, GLS, SRSR, SCSR, SLSR, DCSR, DRSR and DLSR. CONCLUSION: The incidence of CMD was higher in patients with signs and symptoms of ischaemia. CMD occurred with non-obstructive CAD, obstructive CAD, and HCM, with the highest prevalence of CMD in HCM.


Subject(s)
Cardiomyopathy, Hypertrophic , Coronary Artery Disease , Myocardial Ischemia , Humans , Coronary Artery Disease/diagnostic imaging , Coronary Artery Disease/epidemiology , Coronary Artery Disease/pathology , Prevalence , Myocardial Ischemia/diagnostic imaging , Myocardial Ischemia/epidemiology , Myocardium/pathology , Cardiomyopathy, Hypertrophic/pathology
9.
Int J Cardiovasc Imaging ; 40(4): 699-708, 2024 Apr.
Article in English | MEDLINE | ID: mdl-38416297

ABSTRACT

The morphological characteristics of in-stent restenosis (ISR) in relation to varying degrees of area stenosis have not been comprehensively examined. This study aimed to explore the tissue characteristics of patients experiencing ISR with different degrees of area stenosis through the utilization of optical coherence tomography (OCT). In total, 230 patients with ISR who underwent OCT were divided into the following three groups: area stenosis (AS) < 70% (n = 26); 70-80% (n = 119) and AS ≥ 80% (n = 85). Among the 230 patients, the clinical presentation as stable angina was 61.5% in AS < 70%, followed by 47.2% in 70% < AS ≤ 80%, and 31.8% in AS ≥ 80% (P = 0.010). The OCT findings showed that heterogeneous neointima, ISNA, LRP, neointima rupture, TCFA-like pattern, macrophage infiltration, red and white thrombus was more common with AS increased. Ordinal logistic regression analysis showed that higher AS was associated with previous dyslipidemia (odds ratio [OR], 4.754; 95% confidence interval [CI], 1.419-15.927, P = 0.011), neointimal rupture (OR: 3.640; 95% CI, 1.169-11.325, P = 0.026), red thrombus (OR: 4.482; 95% CI, 1.269-15.816, P = 0.020) and white thrombus (OR: 5.259; 95% CI, 1.660-16.659, P = 0.005). Patients with higher degrees of area stenosis in the context of ISR exhibited a greater number of discernible morphological characteristics as identified through OCT analysis. Furthermore, previous dyslipidemia, neointimal rupture, white thrombus and red thrombus were highly associated with and the progression of ISR lesions.


Subject(s)
Coronary Restenosis , Coronary Vessels , Neointima , Percutaneous Coronary Intervention , Predictive Value of Tests , Severity of Illness Index , Stents , Tomography, Optical Coherence , Humans , Male , Female , Coronary Restenosis/diagnostic imaging , Coronary Restenosis/etiology , Coronary Restenosis/pathology , Middle Aged , Aged , Coronary Vessels/diagnostic imaging , Coronary Vessels/pathology , Percutaneous Coronary Intervention/instrumentation , Percutaneous Coronary Intervention/adverse effects , Risk Factors , Treatment Outcome , Retrospective Studies , Coronary Artery Disease/diagnostic imaging , Coronary Artery Disease/therapy , Coronary Artery Disease/pathology , Coronary Stenosis/diagnostic imaging , Coronary Stenosis/pathology , Coronary Stenosis/therapy , Rupture, Spontaneous
10.
Sci Rep ; 14(1): 4412, 2024 02 22.
Article in English | MEDLINE | ID: mdl-38388639

ABSTRACT

Drug-coated balloon (DCB) angioplasty is one of the potential approaches to alleviating in-stent restenosis and treating peripheral artery disease. An in-silico model has been developed for sirolimus drug eluted from an inflated balloon in a patient-specific arterial cross-section consisting of fibrous tissue, fibrofatty tissue, dense calcium, necrotic core, and healthy tissue. The convection-diffusion-reaction equation represents the transport of drug, while drug binding, both specific and non-specific, can be modelled as a reaction process. The Brinkman equations describe the interstitial flow in porous tissue. An image processing technique is leveraged for reconstructing the computational domain. The Marker and Cell, and Immersed Boundary Methods are used to solve the set of governing equations. The no-flux interface condition and convection do amplify the tissue content, and the regions of dense calcium and necrotic core limited to or extremely close to the interface pose a clinical threat to DCB therapy. Simulations predict the effects of the positioning and clustering of plaque components in the domain. This study demands extensive intravascular ultrasound-derived virtual histology (VH-IVUS) imaging to understand the plaque morphology and determine the relative positions of different plaque compositions about the lumen-tissue interface, which have a significant impact on arterial pharmacokinetics.


Subject(s)
Angioplasty, Balloon, Coronary , Angioplasty, Balloon , Coronary Artery Disease , Plaque, Atherosclerotic , Humans , Calcium , Plaque, Atherosclerotic/therapy , Arteries/pathology , Necrosis , Ultrasonography, Interventional/methods , Coronary Artery Disease/pathology
11.
Nature ; 626(8000): 799-807, 2024 Feb.
Article in English | MEDLINE | ID: mdl-38326615

ABSTRACT

Linking variants from genome-wide association studies (GWAS) to underlying mechanisms of disease remains a challenge1-3. For some diseases, a successful strategy has been to look for cases in which multiple GWAS loci contain genes that act in the same biological pathway1-6. However, our knowledge of which genes act in which pathways is incomplete, particularly for cell-type-specific pathways or understudied genes. Here we introduce a method to connect GWAS variants to functions. This method links variants to genes using epigenomics data, links genes to pathways de novo using Perturb-seq and integrates these data to identify convergence of GWAS loci onto pathways. We apply this approach to study the role of endothelial cells in genetic risk for coronary artery disease (CAD), and discover 43 CAD GWAS signals that converge on the cerebral cavernous malformation (CCM) signalling pathway. Two regulators of this pathway, CCM2 and TLNRD1, are each linked to a CAD risk variant, regulate other CAD risk genes and affect atheroprotective processes in endothelial cells. These results suggest a model whereby CAD risk is driven in part by the convergence of causal genes onto a particular transcriptional pathway in endothelial cells. They highlight shared genes between common and rare vascular diseases (CAD and CCM), and identify TLNRD1 as a new, previously uncharacterized member of the CCM signalling pathway. This approach will be widely useful for linking variants to functions for other common polygenic diseases.


Subject(s)
Coronary Artery Disease , Endothelial Cells , Genome-Wide Association Study , Hemangioma, Cavernous, Central Nervous System , Humans , Coronary Artery Disease/genetics , Coronary Artery Disease/pathology , Endothelial Cells/metabolism , Endothelial Cells/pathology , Genetic Predisposition to Disease/genetics , Hemangioma, Cavernous, Central Nervous System/genetics , Hemangioma, Cavernous, Central Nervous System/pathology , Polymorphism, Single Nucleotide , Epigenomics , Signal Transduction/genetics , Multifactorial Inheritance
12.
Adv Med Sci ; 69(1): 56-60, 2024 Mar.
Article in English | MEDLINE | ID: mdl-38368744

ABSTRACT

PURPOSE: Growth differentiation factor 15 (GDF-15) is a member of the transforming growth factor beta superfamily and is faintly expressed under healthy conditions. GDF-15 is markedly elevated in a variety of diseases, including coronary artery disease (CAD), atrial fibrillation and heart failure. Here, we aimed to investigate the association of GDF-15 with the extent and severity of CAD in patients with stable CAD. METHODS: We enrolled 129 patients undergoing coronary angiography for the evaluation of stable CAD in the study. SYNTAX and SYNTAX II PCI/CABG scores were calculated. The CAD (+) study group was also stratified into two groups (high and low GDF-15) with respect to the mean GDF-15 value. Correlation and regression analyses were performed for further evaluation. RESULTS: Of the 129 patients, 75 had CAD. GDF-15 values were higher in the CAD (+) group (p â€‹< â€‹0.001). The two groups were compared according to a cut-off value of 2451.77. SYNTAX and SYNTAX II PCI/CABG scores were significantly associated with the high GDF-15 group (p â€‹< â€‹0.001). Additionally, correlation analysis showed a strong positive correlation between GDF-15 and SYNTAX (r: 0.859, p â€‹< â€‹0.001), SYNTAX II PCI (r: 0.921, p â€‹< â€‹0.001) and SYNTAX II CABG (r: 0.874, p â€‹< â€‹0.001) scores. Multivariate analysis identified GDF-15 as an independent predictor of CAD. CONCLUSION: GDF-15 is an independent predictor of CAD and is associated with CAD severity in terms of SYNTAX, SYNTAX II PCI and SYNTAX II CABG scores.


Subject(s)
Coronary Angiography , Coronary Artery Disease , Growth Differentiation Factor 15 , Severity of Illness Index , Humans , Growth Differentiation Factor 15/blood , Coronary Artery Disease/pathology , Coronary Artery Disease/blood , Female , Male , Middle Aged , Aged , Biomarkers/blood , Prognosis
13.
Circulation ; 149(22): 1752-1769, 2024 May 28.
Article in English | MEDLINE | ID: mdl-38348663

ABSTRACT

BACKGROUND: Vascular calcification, which is characterized by calcium deposition in arterial walls and the osteochondrogenic differentiation of vascular smooth muscle cells, is an actively regulated process that involves complex mechanisms. Vascular calcification is associated with increased cardiovascular adverse events. The role of 4-hydroxynonenal (4-HNE), which is the most abundant stable product of lipid peroxidation, in vascular calcification has been poorly investigated. METHODS: Serum was collected from patients with chronic kidney disease and controls, and the levels of 4-HNE and 8-iso-prostaglandin F2α were measured. Sections of coronary atherosclerotic plaques from donors were immunostained to analyze calcium deposition and 4-HNE. A total of 658 patients with coronary artery disease who received coronary computed tomography angiography were recruited to analyze the relationship between coronary calcification and the rs671 mutation in aldehyde dehydrogenase 2 (ALDH2). ALDH2 knockout (ALDH2-/-) mice, smooth muscle cell-specific ALDH2 knockout mice, ALDH2 transgenic mice, and their controls were used to establish vascular calcification models. Primary mouse aortic smooth muscle cells and human aortic smooth muscle cells were exposed to medium containing ß-glycerophosphate and CaCl2 to investigate cell calcification and the underlying molecular mechanisms. RESULTS: Elevated 4-HNE levels were observed in the serum of patients with chronic kidney disease and model mice and were detected in calcified artery sections by immunostaining. ALDH2 knockout or smooth muscle cell-specific ALDH2 knockout accelerated the development of vascular calcification in model mice, whereas overexpression or activation prevented mouse vascular calcification and the osteochondrogenic differentiation of vascular smooth muscle cells. In patients with coronary artery disease, patients with ALDH2 rs671 gene mutation developed more severe coronary calcification. 4-HNE promoted calcification of both mouse aortic smooth muscle cells and human aortic smooth muscle cells and their osteochondrogenic differentiation in vitro. 4-HNE increased the level of Runx2 (runt-related transcription factor-2), and the effect of 4-HNE on promoting vascular smooth muscle cell calcification was ablated when Runx2 was knocked down. Mutation of Runx2 at lysine 176 reduced its carbonylation and eliminated the 4-HNE-induced upregulation of Runx2. CONCLUSIONS: Our results suggest that 4-HNE increases Runx2 stabilization by directly carbonylating its K176 site and promotes vascular calcification. ALDH2 might be a potential target for the treatment of vascular calcification.


Subject(s)
Aldehyde Dehydrogenase, Mitochondrial , Aldehydes , Core Binding Factor Alpha 1 Subunit , Mice, Knockout , Myocytes, Smooth Muscle , Vascular Calcification , Animals , Aldehydes/metabolism , Vascular Calcification/metabolism , Vascular Calcification/genetics , Vascular Calcification/pathology , Humans , Core Binding Factor Alpha 1 Subunit/metabolism , Core Binding Factor Alpha 1 Subunit/genetics , Aldehyde Dehydrogenase, Mitochondrial/genetics , Aldehyde Dehydrogenase, Mitochondrial/metabolism , Mice , Myocytes, Smooth Muscle/metabolism , Myocytes, Smooth Muscle/pathology , Myocytes, Smooth Muscle/drug effects , Male , Muscle, Smooth, Vascular/metabolism , Muscle, Smooth, Vascular/pathology , Female , Middle Aged , Coronary Artery Disease/metabolism , Coronary Artery Disease/genetics , Coronary Artery Disease/pathology , Cells, Cultured , Renal Insufficiency, Chronic/metabolism , Renal Insufficiency, Chronic/genetics , Renal Insufficiency, Chronic/pathology , Aged
14.
J Cardiovasc Pharmacol ; 83(6): 547-556, 2024 Jun 01.
Article in English | MEDLINE | ID: mdl-38421206

ABSTRACT

ABSTRACT: Atherosclerosis is an insidious and progressive inflammatory disease characterized by the formation of lipid-laden plaques within the intima of arterial walls with potentially devastating consequences. While rupture of vulnerable plaques has been extensively studied, a distinct mechanism known as plaque erosion (PE) has gained recognition and attention in recent years. PE, characterized by the loss of endothelial cell lining in the presence of intact fibrous cap, contributes to a significant and growing proportion of acute coronary events. However, despite a heterogeneous substrate underlying coronary thrombosis, treatment remains identical. This article provides an overview of atherosclerotic PE characteristics and its underlying mechanisms, highlights its clinical implications, and discusses potential therapeutic strategies.


Subject(s)
Plaque, Atherosclerotic , Humans , Animals , Rupture, Spontaneous , Coronary Artery Disease/therapy , Coronary Artery Disease/pathology , Atherosclerosis/pathology , Atherosclerosis/metabolism , Endothelial Cells/pathology , Endothelial Cells/metabolism
15.
Theranostics ; 14(3): 1241-1259, 2024.
Article in English | MEDLINE | ID: mdl-38323308

ABSTRACT

Rationale: The transition from acute inflammation to fibrosis following myocardial ischemia‒reperfusion (MIR) significantly affects prognosis. Macrophages play a pivotal role in inflammatory damage and repair after MIR. However, the heterogeneity and transformation mechanisms of macrophages during this transition are not well understood. Methods: In this study, we used single-cell RNA sequencing (scRNA-seq) and mass cytometry to examine murine monocyte-derived macrophages after MIR to investigate macrophage subtypes and their roles in the MIR process. S100a9-/- mice were used to establish MIR model to clarify the mechanism of alleviating inflammation and fibrosis after MIR. Reinfusion of bone marrow-derived macrophages (BMDMs) after macrophage depletion (MD) in mice subjected to MIR were performed to further examine the role of S100a9hi macrophages in MIR. Results: We identified a unique subtype of S100a9hi macrophages that originate from monocytes and are involved in acute inflammation and fibrosis. These S100a9hi macrophages infiltrate the heart as early as 2 h post-reperfusion and activate the Myd88/NFκB/NLRP3 signaling pathway, amplifying inflammatory responses. As the tissue environment shifts from proinflammatory to reparative, S100a9 activates transforming growth factor-ß (Tgf-ß)/p-smad3 signaling. This activation not only induces the transformation of myocardial fibroblasts to myofibroblasts but also promotes fibrosis via the macrophage-to-myofibroblast transition (MMT). Targeting S100a9 with a specific inhibitor could effectively mitigate acute inflammatory damage and halt the progression of fibrosis, including MMT. Conclusion: S100a9hi macrophages are a promising therapeutic target for managing the transition from inflammation to fibrosis after MIR.


Subject(s)
Coronary Artery Disease , Myocardial Reperfusion Injury , Mice , Animals , Macrophages/metabolism , Myocardial Reperfusion Injury/pathology , Fibrosis , Inflammation/metabolism , Coronary Artery Disease/pathology , Ischemia/pathology , Reperfusion , Sequence Analysis, RNA , Mice, Inbred C57BL
16.
Zhonghua Xin Xue Guan Bing Za Zhi ; 52(2): 144-149, 2024 Feb 24.
Article in Chinese | MEDLINE | ID: mdl-38326065

ABSTRACT

Objective: To explore the effects and safety of saline mixed 1∶1 with contrast medium (mixed medium) and pure heparinized saline as alternative media for optimal Optical Coherence Tomography (OCT) guided percutaneous coronary intervention (PCI). Methods: This single-center, prospective cohort study enrolled patients who underwent PCI with OCT guidance for chronic stable angina or acute coronary syndrome at the Department of Cardiology, the Second Hospital of Jilin University from October 2021 to August 2022. The target vessels were examined using OCT with three different flushing media at the same anatomical positions: contrast agent, mixed medium, and pure heparinized saline. An independent observer analyzed all imaging results and evaluated the lumen imaging quality, using the proportion of the clear imaging field (CIF%) as a quantitative measure for analysis. The average luminal diameter was compared among different flushing media. The study also assessed the image quality of the luminal anatomical structures, lesion pathologies, and stents. Results: A total of 105 patients were enrolled in the study, including 110 target vessels. The age of the enrolled patients was (60.5±8.4) years, with 60 male patients (57.1%). OCT examinations were successfully completed using all three media, and no related complications were observed in any groups. The three flushing media presented with the same image quality in terms of depicting the lumen anatomical structures, lesion characteristics, and stent-related features. The mixed medium group achieved a comparable CIF% to the contrast group with both right and left coronary arteries (right coronary 100.0% (100.0%, 100.0%) vs. 100.0% (100.0%, 100.0%), P>0.05; left coronary 100.0% (95.9%, 100.0%) vs. 100.0% (100.0%, 100.0%), P>0.05). While the saline group reached a comparable CIF% to the contrast group with right coronary arteries (100.0% (97.6%, 100.0%) vs. 100.0% (95.9%, 100.0%), P>0.05) but showed a significantly lower CIF% with left coronary arteries (84.9% (75.9%, 93.4%) vs. 100.0% (100.0%, 100.0%), P<0.05). For the average diameter of the coronary lumen, there was no statistically significant difference between the mixed medium group and the saline group compared to the contrast group with both right and left coronary arteries (P>0.05). Conclusions: A 1∶1 heparinized saline and contrast mixture can serve as a substitute flushing medium for OCT examination during PCI procedure. Pure saline can also yield good results in OCT examination of the right coronary artery, and both alternatives are safe for use as flushing medium in OCT imaging.


Subject(s)
Coronary Artery Disease , Percutaneous Coronary Intervention , Humans , Male , Middle Aged , Aged , Tomography, Optical Coherence/methods , Percutaneous Coronary Intervention/methods , Coronary Angiography , Prospective Studies , Stents , Coronary Vessels/diagnostic imaging , Coronary Vessels/pathology , Treatment Outcome , Coronary Artery Disease/pathology , Predictive Value of Tests
17.
Int J Mol Sci ; 25(3)2024 Jan 30.
Article in English | MEDLINE | ID: mdl-38338972

ABSTRACT

Computed tomography angiography (CTA) has validated the use of pericoronary adipose tissue (PCAT) attenuation as a credible indicator of coronary inflammation, playing a crucial role in coronary artery disease (CAD). This study aimed to evaluate the long-term effects of high-dose statins on PCAT attenuation at coronary lesion sites and changes in plaque distribution. Our prospective observational study included 52 patients (mean age 60.43) with chest pain, a low-to-intermediate likelihood of CAD, who had documented atheromatous plaque through CTA, performed approximately 1 year and 3 years after inclusion. We utilized the advanced features of the CaRi-Heart® and syngo.via Frontier® systems to assess coronary plaques and changes in PCAT attenuation. The investigation of changes in plaque morphology revealed significant alterations. Notably, in mixed plaques, calcified portions increased (p < 0.0001), while non-calcified plaque volume (NCPV) decreased (p = 0.0209). PCAT attenuation generally decreased after one year and remained low, indicating reduced inflammation in the following arteries: left anterior descending artery (LAD) (p = 0.0142), left circumflex artery (LCX) (p = 0.0513), and right coronary artery (RCA) (p = 0.1249). The CaRi-Heart® risk also decreased significantly (p = 0.0041). Linear regression analysis demonstrated a correlation between increased PCAT attenuation and higher volumes of NCPV (p < 0.0001, r = 0.3032) and lipid-rich plaque volume (p < 0.0001, r = 0.3281). Our study provides evidence that high-dose statin therapy significantly reduces CAD risk factors, inflammation, and plaque vulnerability, as evidenced by the notable decrease in PCAT attenuation, a critical indicator of plaque progression.


Subject(s)
Coronary Artery Disease , Hydroxymethylglutaryl-CoA Reductase Inhibitors , Plaque, Atherosclerotic , Humans , Middle Aged , Plaque, Atherosclerotic/diagnostic imaging , Plaque, Atherosclerotic/drug therapy , Plaque, Atherosclerotic/pathology , Computed Tomography Angiography/methods , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Follow-Up Studies , Coronary Angiography/methods , Coronary Artery Disease/diagnostic imaging , Coronary Artery Disease/drug therapy , Coronary Artery Disease/pathology , Inflammation/drug therapy , Inflammation/pathology , Coronary Vessels/diagnostic imaging , Coronary Vessels/pathology , Adipose Tissue
18.
J Cardiovasc Comput Tomogr ; 18(2): 154-161, 2024.
Article in English | MEDLINE | ID: mdl-38238196

ABSTRACT

BACKGROUND: To identify anatomical and morphological plaque features predictors of PCI and create a multiparametric score to increase the predictive yield. Moreover, we assessed the incremental predictive value of FFRCT (Fractional Flow Reserve derived from CCTA) trans-lesion gradient (ΔFFRCT) when integrated into the score. METHODS: Observational cohort study including patients undergoing CCTA for suspected coronary artery disease, with FFRCT available, referred to invasive coronary angiogram and assessment of fractional flow reserve. Plaque analysis was performed using validated semi-automated software. Logistic regression was performed to identify anatomical and morphological plaque features predictive of PCI. Optimal thresholds were defined by area under the receiver-operating characteristics curve (AUC) analysis. A scoring system was developed in a derivation cohort (70 â€‹% of the study population) and tested in a validation cohort (30 â€‹% of patients). RESULTS: The overall study population included 340 patients (455 vessels), among which 238 patients (320 vessels) were included in the derivation cohort. At multivariate logistic regression analysis, absence of left main disease, diameter stenosis (DS), non-calcified plaque (NCP) volume, and percent atheroma volume (PAV) were independent predictors of PCI. Optimal thresholds were: DS â€‹≥ â€‹50 â€‹%, volume of NCP>113 â€‹mm3 and PAV>17 â€‹%. A weighted score (CT-PCI Score) ranging from 0 to 11 was obtained. The AUC of the score was 0.80 (95%CI 0.74-0.86). The integration of ΔFFRCT in the CT-PCI score led to a mild albeit not significant increase in the AUC (0.82, 95%CI 0.77-0.87, p â€‹= â€‹0.328). CONCLUSIONS: Plaque anatomy and morphology derived from CCTA could aid in identifying patients amenable to PCI.


Subject(s)
Coronary Artery Disease , Coronary Stenosis , Fractional Flow Reserve, Myocardial , Percutaneous Coronary Intervention , Plaque, Atherosclerotic , Humans , Computed Tomography Angiography , Constriction, Pathologic/pathology , Coronary Angiography , Coronary Artery Disease/diagnostic imaging , Coronary Artery Disease/therapy , Coronary Artery Disease/pathology , Coronary Stenosis/diagnostic imaging , Coronary Stenosis/therapy , Coronary Stenosis/pathology , Coronary Vessels/diagnostic imaging , Coronary Vessels/pathology , Plaque, Atherosclerotic/pathology , Predictive Value of Tests , Syndrome
19.
IUBMB Life ; 76(6): 300-312, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38251784

ABSTRACT

Genome-wide association studies (GWAS) have identified coronary artery disease (CAD) susceptibility locus on chromosome 3q22.3. This locus contains a cluster of several genes that includes muscle rat sarcoma virus (MRAS). Common MRAS variants are also associated with CAD causing risk factors such as hypertension, dyslipidemia, obesity, and type II diabetes. The MRAS gene is an oncogene that encodes a membrane-bound small GTPase. It is involved in a variety of signaling pathways, regulating cell differentiation and cell survival (mitogen-activated protein kinase [MAPK]/extracellular signal-regulated kinase and phosphatidylinositol 3-kinase) as well as acute phase response signaling (tumor necrosis factor [TNF] and interleukin 6 [IL6] signaling). In this review, we will summarize the role of genetic MRAS variants in the etiology of CAD and its comorbidities with the focus on tissue distribution of MRAS isoforms, cell type/tissue specificity, and mode of action of single nucleotide variants in MRAS associated complex traits. Finally, we postulate that CAD risk variants in the MRAS locus are specific to smooth muscle cells and lead to higher levels of MRAS, particularly in arterial and cardiac tissue, resulting in MAPK-dependent tissue hypertrophy or hyperplasia.


Subject(s)
Coronary Artery Disease , Genome-Wide Association Study , Humans , Coronary Artery Disease/genetics , Coronary Artery Disease/pathology , Genetic Predisposition to Disease , Polymorphism, Single Nucleotide , Animals , Signal Transduction , ras Proteins
20.
Am J Cardiol ; 214: 115-124, 2024 Mar 01.
Article in English | MEDLINE | ID: mdl-38232806

ABSTRACT

In-stent restenosis with neoatherosclerosis has been known as the predictor of target lesion revascularization (TLR) after percutaneous coronary intervention. However, the impact of in-stent calcification (ISC) alone on clinical outcomes remains unknown since neoatherosclerosis by optical coherence tomography includes in-stent lipid and calcification. We aimed to assess the effect of ISC on clinical outcomes and clinical differences among different types of ISC. We included 126 lesions that underwent optical coherence tomography-guided percutaneous coronary intervention and divided those into the ISC group (n = 38) and the non-ISC group (n = 88) according to the presence of ISC. The cumulative incidence of clinically driven TLR (CD-TLR) was compared between the ISC and non-ISC groups. The impact of in-stent calcified nodule and nodular calcification on CD-TLR was evaluated using the Cox hazard model. The incidence of CD-TLR was significantly higher in the ISC group than in the non-ISC group (p = 0.004). In the multivariate Cox hazard model, ISC was significantly associated with CD-TLR (hazard ratio [HR] 3.58, 95% confidence interval [CI] 1.33 to 9.65, p = 0.01). In-stent calcified nodule/nodular calcification and in-stent nodular calcification alone were also the factors significantly associated with CD-TLR (HR 3.34, 95%CI 1.15 to 9.65, p = 0.03 and HR 5.21, 95%CI 1.82 to 14.91, p = 0.002, respectively). ISC without in-stent calcified nodule/nodular calcification, which was defined as in-stent smooth calcification, was not associated with CD-TLR. In conclusion, ISC was associated with a higher rate of CD-TLR. The types of calcifications that led to a high rate of CD-TLR were in-stent calcified nodule/nodular calcification and in-stent nodular calcification alone but not in-stent smooth calcification. In-stent calcified nodule and nodular calcification should be paid more attention.


Subject(s)
Calcinosis , Coronary Artery Disease , Percutaneous Coronary Intervention , Humans , Coronary Vessels/diagnostic imaging , Coronary Vessels/pathology , Tomography, Optical Coherence , Treatment Outcome , Stents/adverse effects , Calcinosis/epidemiology , Calcinosis/pathology , Coronary Artery Disease/diagnosis , Coronary Artery Disease/surgery , Coronary Artery Disease/pathology , Coronary Angiography
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