Progression Of Coronary Atherosclerosis Research Articles

Assessment of the Level of Matrix Metalloproteinases, VEGF and MicroRNA-34a in Patients With Non-obstructive and Obstructive Lesions of the Coronary Arteries.

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. 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. 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. 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.

Long-term outcomes of myocardial revascularization in patients with multivessel coronary artery disease and comorbid pathology

<b>Objective:</b> To assess the long-term outcomes of myocardial revascularization in patients with multivessel coronary artery disease and varying degrees of comorbidity.<br /> <b>Materials and methods:</b> 406 patients with low and moderate Syntax scores (SS) (<33) underwent primary percutaneous coronary intervention (PCI) (n=200) with a drug-eluting stent, and coronary artery bypass grafting (CABG) (n=206). Patients were stratified by the Charlson Comorbidity Index (CCI) into 2 groups: 1) CCI ≤ 3(n=108/26.6%); 2) CCI ≥ 4(n=298/73.4%). The mean follow-up period was 9±1.9 years. The endpoints of the study were as follows: major adverse cardiac and cerebrovascular events (МАССЕ), a repeat revascularization, decreased left ventricular ejection fraction, and high SS in dynamics.<br /> <b>Results:</b> An increase in CCI of more than 4 points was significantly associated with the risk of developing a combination of MACCE (HR 1.3, CI 1.2 – 1.4, p<0.001), all-cause mortality (HR 1.3, CI 1.2 – 1.4, p<0.001), and cerebrovascular accidents (CVA) (HR 2.2, CI 1.4 – 3.4, p=0.001). Patients with CCI ≥4 required repeat revascularization more frequently after PCI than after CABG (HR 2.6, CI 1.8 – 3.7, p<0.001). Among patients with varying degrees of comorbidity, the risk of progression of coronary atherosclerosis (SS≥33) was higher after CABG compared with PCI.<br /> <b>Conclusion:</b> A CCI score of more than 4 points was associated with an increased risk of developing of MACCE, all-cause mortality, and CVA. Among patients with varying degrees of comorbidity, PCI and CABG did not demonstrate significant advantages in terms of MACCE.

Steatotic liver disease and its newly proposed sub-classifications correlate with progression of the coronary artery calcium score.

A new nomenclature, Steatotic Liver Disease (SLD), has been proposed by consensus with sub-classifications and requires evidence-based validation. We assessed whether the presence and severity of SLD, as well as its sub-classifications, are associated with the progression of coronary atherosclerosis. This longitudinal cohort study included 13,811 adults who participated in repeated regular health screening examinations between January 1, 2004 and December 31, 2021 that included assessments of their coronary artery calcium (CAC) scores. SLD was defined using abdominal ultrasonography and classified as metabolic dysfunction associated steatotic liver disease (MASLD), MASLD with increased alcohol intake (MetALD), and cryptogenic SLD. SLD severity was assessed using fibrosis-4 (FIB-4) scores. The progression of CAC scores was measured using multidetector CT scans. The average duration of follow-up was 5.8 years. During follow-up, the annual rate of CAC progression in participants with and without SLD was 18% (95% CI 17%-19%) and 14% (95% CI 13%-14%) (p < 0.01), respectively. The multivariable ratios of progression rates when we compared participants with cryptogenic SLD, MASLD, or MetALD with those without SLD were 0.98 (95% CI 0.95-1.01), 1.03 (95% CI 1.03-1.04), and 1.07 (95% CI 1.04-1.09), respectively. The multivariable ratios of progression rates when we compared participants with SLD with FIB-4 score <1.3 and SLD with FIB-4 score ≥1.3 with those without SLD were 1.03 (95% CI 1.02-1.04), and 1.05 (95% CI 1.04-1.06), respectively. SLD was associated with a higher risk of coronary atherosclerosis, and the risk differed by sub-classifications and severity. These findings suggest that the newly proposed definition has clinical relevance in terms of stratifying cardiovascular disease risk.

Significance of the Wnt signaling pathway in coronary artery atherosclerosis.

The progression of coronary atherosclerosis is an active and regulated process. The Wnt signaling pathway is thought to play an active role in the pathogenesis of several cardiovascular diseases; however, a better understanding of this system in atherosclerosis is yet to be unraveled. In this study, real-time quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) and Western blotting were used to quantify the expression of Wnt3a, Wnt5a, and Wnt5b in the human coronary plaque, and immunohistochemistry was used to identify sites of local expression. To determine the pathologic significance of increased Wnt, human vascular smooth muscle cells (vSMCs) were treated with Wnt3a, Wnt5a, and Wnt5b recombinant proteins and assessed for changes in cell differentiation and function. RT-PCR and Western blotting showed a significant increase in the expression of Wnt3a, Wnt5a, Wnt5b, and their receptors in diseased coronary arteries compared with that in non-diseased coronary arteries. Immunohistochemistry revealed an abundant expression of Wnt3a and Wnt5b in diseased coronary arteries, which contrasted with little or no signals in normal coronary arteries. Immunostaining of Wnt3a and Wnt5b was found largely in inflammatory cells and myointimal cells. The treatment of vSMCs with Wnt3a, Wnt5a, and Wnt5b resulted in increased vSMC differentiation, migration, calcification, oxidative stress, and impaired cholesterol handling. This study demonstrates the upregulation of three important members of canonical and non-canonical Wnt signaling pathways and their receptors in coronary atherosclerosis and shows an important role for these molecules in plaque development through increased cellular remodeling and impaired cholesterol handling.

Association of cardiovascular health with subclinical coronary atherosclerosis progression among five racial and ethnic groups: The MASALA and MESA studies

Background and aimsSouth Asian adults (SA) are at higher risk for atherosclerotic cardiovascular disease (ASCVD) compared with other racial/ethnic groups. Life's Simple 7 (LS7) is a guideline-recommended, cardiovascular health (CVH) construct to guide optimization of cardiovascular risk factors. We sought to assess if the LS7 metrics predict coronary artery calcium (CAC) incidence and progression in asymptomatic SA compared with four other racial/ethnic groups. MethodsWe assessed the distribution of CVH metrics (inadequate: score 0–8, average: 9–10, optimal: 11–14, and per 1-unit higher score) and its association with incidence and progression of CAC among South Asians in the Mediators of Atherosclerosis in South Asians Living in America (MASALA) study compared with other race/ethnic groups from the Multiethnic Study of Atherosclerosis (MESA). ResultsWe included 810 SA, 2622 Non-Hispanic White (NHW), and 4192 Other adults (collectively 1893 Black, 1496 Hispanic and 803 Chinese American participants, respectively). SA and White participants compared to Other race/ethnicity groups were more likely to have optimal CVH metrics (26% SA vs 28% White participants vs 21% Other, respectively, p < 0.001). Similar to NHW and the Other race/ethnic group, SA participants with optimal baseline CVH were less likely to develop incident CAC on follow-up evaluation compared to participants with inadequate CVH metrics, optimal CVH/CAC = 0: 24% SA, 28% NHW, and 15% Other (p < 0.01). In multivariable linear and logistic regression models, there was no difference in annualized CAC incidence or progression between each race/ethnic group (pinteraction = 0.85 and pinteraction = 0.17, respectively). Optimal blood pressure control was associated with lower CAC incidence among SA participants [OR (95% CI): 0.30 (0.14–0.63), p < 0.01] and Other race and ethnicity participants [0.32 (0.19–0.53), p < 0.01]. ConclusionsOptimal CVH metrics are associated with lower incident CAC and CAC progression among South Asians, similar to other racial groups/ethnicities. These findings underscore the importance of optimizing and maintaining CVH to mitigate the future risk of subclinical atherosclerosis in this higher risk population.

Rewiring Endothelial Sphingolipid Metabolism to Favor S1P Over Ceramide Protects From Coronary Atherosclerosis.

Growing evidence correlated changes in bioactive sphingolipids, particularly S1P (sphingosine-1-phosphate) and ceramides, with coronary artery diseases. Furthermore, specific plasma ceramide species can predict major cardiovascular events. Dysfunction of the endothelium lining lesion-prone areas plays a pivotal role in atherosclerosis. Yet, how sphingolipid metabolism and signaling change and contribute to endothelial dysfunction and atherosclerosis remain poorly understood. We used an established model of coronary atherosclerosis in mice, combined with sphingolipidomics, RNA-sequencing, flow cytometry, and immunostaining to investigate the contribution of sphingolipid metabolism and signaling to endothelial cell (EC) activation and dysfunction. We demonstrated that hemodynamic stress induced an early metabolic rewiring towards endothelial sphingolipid de novo biosynthesis, favoring S1P signaling over ceramides as a protective response. This finding is a paradigm shift from the current belief that ceramide accrual contributes to endothelial dysfunction. The enzyme SPT (serine palmitoyltransferase) commences de novo biosynthesis of sphingolipids and is inhibited by NOGO-B (reticulon-4B), an ER membrane protein. Here, we showed that NOGO-B is upregulated by hemodynamic stress in myocardial EC of ApoE-/- mice and is expressed in the endothelium lining coronary lesions in mice and humans. We demonstrated that mice lacking NOGO-B specifically in EC (Nogo-A/BECKOApoE-/-) were resistant to coronary atherosclerosis development and progression, and mortality. Fibrous cap thickness was significantly increased in Nogo-A/BECKOApoE-/- mice and correlated with reduced necrotic core and macrophage infiltration. Mechanistically, the deletion of NOGO-B in EC sustained the rewiring of sphingolipid metabolism towards S1P, imparting an atheroprotective endothelial transcriptional signature. These data demonstrated that hemodynamic stress induced a protective rewiring of sphingolipid metabolism, favoring S1P over ceramide. NOGO-B deletion sustained the rewiring of sphingolipid metabolism toward S1P protecting EC from activation under hemodynamic stress and refraining coronary atherosclerosis. These findings also set forth the foundation for sphingolipid-based therapeutics to limit atheroprogression.

1 - Insulin-like growth factor binding protein 7 is associated with development of cell senescence and progression of coronary atherosclerosis

1 - Insulin-like growth factor binding protein 7 is associated with development of cell senescence and progression of coronary atherosclerosis

Correlation of circulatory VEGF and miRNA 126 in angiographically proven coronary artery disease and its clinical importance

Background: Atherosclerotic ischemic coronary artery disease (CAD) is a major cause of morbidity and mortality in both developed and developing countries, indicating the need for the discovery of deeper molecular insights of CAD mechanisms, biomarkers, and innovative therapeutic targets. Vascular endothelial growth factor (VEGF) may have some role, in the progression of human coronary atherosclerosis. Circulating microRNAs (miR) have a potential as a diagnostic as well as a prognostic biomarker of cardiovascular disease and dysfunctions. Aims and Objectives: The aim of the study was to correlate the levels of miRNA-126 and VEGF in the serum of CAD patients. Materials and Methods: The study was conducted on 100 cases of freshly diagnosed CAD patients (angiographically proven) and 80 normal healthy patients. Various serum biomarkers were estimated. The level of serum VEGF and Mi-RNA was correlated for CAD patients. Results: Highly significantly difference was found in levels of hemoglobin A1C, low density lipoprotein, total cholesterol, and total homocysteine while high-density lipoproteins and triglycerides were less significantly different for controls and cases. VEGF levels of CAD cases were found to be very significantly higher as compared to controls. The miRNA-126 expression was found to be lower in the CAD subjects compared to non-CAD subjects. Conclusion: The study was suggested the role of VEGF in atherogenesis and plaque instability. No significant correlation was found among between miR-126 levels and VEGF levels among CAD cases. The study is limited by a smaller sample size and was single-centered; therefore, multicentric study with a larger patient cohort needs to be done and to validate our findings.

Spatial lipidomics of coronary atherosclerotic plaque development in a familial hypercholesterolemia swine model

Coronary atherosclerosis is caused by plaque build-up, with lipids playing a pivotal role in its progression. However, lipid composition and distribution within coronary atherosclerosis remain unknown. This study aims to characterize lipids and investigate differences in lipid composition across disease stages to aid in the understanding of disease progression. Matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) was used to visualize lipid distributions in coronary artery sections (n = 17) from hypercholesterolemic swine. We performed histology on consecutive sections to classify the artery segments and to investigate colocalization between lipids and histological regions of interest in advanced plaque, including necrotic core and inflammatory cells. Segments were classified as healthy (n = 6), mild (n = 6), and advanced disease (n = 5) artery segments. Multivariate data analysis was employed to find differences in lipid composition between the segment types, and the lipids' spatial distribution was investigated using non-negative matrix factorization (NMF). Through this process, MALDI-MSI detected 473 lipid-related features. NMF clustering described three components in positive ionization mode: triacylglycerides (TAG), phosphatidylcholines (PC), and cholesterol species. In negative ionization mode, two components were identified: one driven by phosphatidylinositol(PI)(38:4), and one driven by ceramide-phosphoethanolamine(36:1). Multivariate data analysis showed the association between advanced disease and specific lipid signatures like PC(O-40:5) and cholesterylester(CE)(18:2). Ether-linked phospholipids and LysoPC species were found to colocalize with necrotic core, and mostly CE, ceramide, and PI species colocalized with inflammatory cells. This study, therefore, uncovers distinct lipid signatures correlated with plaque development and their colocalization with necrotic core and inflammatory cells, enhancing our understanding of coronary atherosclerosis progression.

Prediction of Progression of Coronary Atherosclerosis Using Molecular and Imaging Biomarkers

Prediction of Progression of Coronary Atherosclerosis Using Molecular and Imaging Biomarkers

Quercetin relieves coronary atherosclerosis via regulating fibroblast growth factor 2.

This study aims to investigate the role of quercetin in coronary atherosclerosis and explore its possible mechanisms. Hematoxylin-eosin (H&E), immunohistochemical (IHC), and aniline blue staining were used to analyze the pathological changes in the cross-section of the aorta. Traditional Chinese Medicine Systems Pharmacology Database (TCMSP), Swiss Target Prediction, and PubChem were utilized to predict and screen the bioactive ingredients of traditional Chinese medicine (Huanglian, Yuxingcao, and Jinyinhua) for coronary atherosclerosis. Inflammatory factors and vascular protection parameters were quantitatively detected using ELISA and western blot. The proliferation and migration of vascular smooth muscle cells (VSMC) were evaluated using the Cell Counting Kit-8 (CCK-8), 5-ethynyl-2-deoxyuridine (EdU), and wound healing assays. The targets of quercetin were predicted using DisGeNET, Matascape, SWISSMODEL, cellular thermal shift assay (CETSA), and fluorescence titrimetric methods. Based on our findings, quercetin was identified as the active component of Huanglian, Yuxingcao, and Jinyinhua that exerted a positive effect on coronary atherosclerosis. In vivo and in vitro data demonstrated that quercetin improved the pathological changes in model mice and inhibited the proliferation, migration, and inflammatory response of VSMC cells. Specifically, we found that fibroblast growth factor 2 (FGF2) is a direct target of quercetin, and overexpression of FGF2 attenuated the anti-atherosclerosis function of quercetin. Overall, our study confirms the functional role of the quercetin-FGF2 axis in the progression of coronary atherosclerosis, providing a potential target for its treatment.

Long-Term Results of Stenting in Patients with Hemodynamically Significant Lesions of the Left Main Coronary Artery

The aim. To study the long-term results of stenting in patients with coronary artery disease with hemodynamically significant left main coronary artery (LMCA) stenoses.&#x0D; Materials and methods. The study included 67 patients (56 men, 11 women) with a mean age of 63 ± 2.1 years.&#x0D; Results. Among the 67 patients included in the study, 29 patients (43.3%) underwent percutaneous coronary inter-vention using a single-stent technique. These were patients with ostial LMCA lesions, lesions of the middle third of the LMCA and some patients with Medina 1.1.0; 1.0.1; 1.0.0; 0.1.0; 0.0.1 lesions of the distal part of the LMCA. The median follow-up was 2 years. Using a questionnaire, we managed to establish contact with 25 patients (86.2%). Among these, 1 patient (3.4%) died of non-cardiac causes and 7 patients (24.1%) had a recurrence of angina within 2 years. The causes of angina recurrence in 2 cases (6.9%) were restenosis in the stent with transition to the mouth of the side branch, which required repeated stenting of the LMCA with transition to the left circumflex artery. In 5 patients (17.2%), angina recur-rence was associated with progression of coronary atherosclerosis of another localization.&#x0D; Among 67 patients with LMCA stenting, the two-stent technique was used in 38 patients (56.7%). These were pa-tients with Medina 1.1.0; 1.0.1; 1.0.0; 0.1.0; 0.0.1 lesions of the distal part of the LMCA. The median follow-up was 2 years. Using a questionnaire, we managed to contact 35 patients (92.1%). Among these, 4 patients (10.5%) died, but only one of them due to cardiac causes (2.6%), and 3 patients (7.9%) had recurrent angina within 2 years, two of whom underwent stenting by the T and protrusion (TAP) technique and one by culotte. The first two patients underwent angioplasty of restenosis in stents using balloons with a therapeutic coating. In the last patient, stent recoil in the left circumflex artery mouth was observed due to severe calcification, so this patient underwent re-implantation of the stent system in the recoil zone.&#x0D; Conclusions. The problem of choosing a method of revascularization for patients with hemodynamically significant LMCA lesions remains controversial to this day, despite the wide range of evidence. Doctors should jointly decide on the choice of treatment methodology solely in the interests of the patient, taking into account all the factors that may affect the patient’s quality of life in the long term.

The Impact of Semaglutide on Liver Fat Assessed by Serial Cardiac CT scans in Patients with Type 2 Diabetes: Results from STOP Trial

IntroductionThere is increasing prevalence of hepatic steatosis. Hepatic steatosis is increasingly recognized as the independent risk factor for cardiovascular mortality. However, there are limited options for the treatment of fatty liver. In this study we evaluated the effect of semaglutide on liver fat as measured by non-contrast cardiac CT scans. MethodsSTOP is a randomized controlled trial that evaluated semaglutide treatment effect on coronary atherosclerosis progression (STOP) in type 2 diabetes. We utilized unenhanced cardiac CT scans to quantify liver fat based on CT Hounsfield attenuation method. A total of 114 subjects qualified for this study of the 140 subjects randomized, 59 in semaglutide group and 55 in the placebo group and were followed for 12 months. Multivariate regression models were used to evaluate the change in liver fat content overtime. Results114 subjects were included in the study, 61% male, mean age of 57.8±8.1 years and mean BMI of 32.0±6.7. The average of the three liver measures showed an improvement in the semaglutide group 1.4±9.0 versus worsening in the placebo group of 1.9±9.5 mean HU. The multivariable linear regression models including age, gender, BMI, hypertension, hyperlipidemia, past smoking and baseline liver attenuation, showed that the semaglutide group average liver attenuation measures improved by 4.4 HU versus placebo across the trial, p=0.002 indicating improvement in the liver fat content in treatment group. ConclusionIn type 2 diabetes patients with hepatic steatosis, treatment with semaglutide resulted in a significant improvement in fatty liver resolution compared to placebo.

Premature coronary artery disease and severe hypertriglyceridemia in a patient with monogenic diabetes: a case report

Aim. Maturity- onset diabetes of the young (MODY) is a group of monogenic diseases with an autosomal dominant inheritance. This is a rarely diagnosed disease, occurring in 1 of 10 thousand adults and in 1 of 23 thousand children. Brief description. We present a case report of a patient with a monogenic diabetes HNF4A-MODY, severe hypertriglyceridemia, progressive premature coronary artery disease and a HNF4A gene pathogenic variant (ENST00000316099.8:c.1145dup).Discussion. This case demonstrates the effectiveness of triple hypoglycemic therapy, including empagliflozin for the treatment of monogenic diabetes. Despite the fact that the patient with diabetes reached the target glycated hemoglobin level, the combination of the disease with other cardiovascular risk factors (hypertension, hypertriglyceridemia, obesity, smoking, male sex) led to the progression of coronary and peripheral atherosclerosis. Considering the data of genetic testing, returning to sulfonylurea therapy should be considered. It is important for patient to follow a strict lipid-lowering diet and taking combination lipid-lowering therapy (rosuvastatin, fenofibrate and omega-3 polyunsaturated fatty acids) in order to achieve the target level of low-density lipoprotein cholesterol &lt;1,4 mmol/l and triglycerides &lt;1,7 mmol/l.

Pathophysiological role of epicardial adipose tissue and its phenotypes in patients with diabetes and cardiovascular comorbidities

Abstract Introduction Epicardial adipose tissue (EAT) is an active endocrine organ that regulates multiple aspects of cardiac biology including myocardial redox state, intracellular Ca2+ cycling, the electrophysiological and contractile properties of cardiomyocytes, cardiac fibrosis, and coronary atherosclerosis progression. Purpose We evaluated associations of CMR-measured EAT area (EATa) with myocardial structure, function and 31P-MRS assessed energetics (phosphocreatine to ATP ratio) in patients with type 2 diabetes (T2D) with and without comorbidities of coronary artery disease (CAD) requiring coronary artery bypass grafting (CABG) and aortic stenosis requiring aortic valve replacement (AVR). We also examined the EAT phenotypes in patients with T2D with and without CAD, CAD patients without T2D and compared them to controls with severe AS without T2D. Methods 145 participants were recruited including CAD patients undergoing CABG with (30) and without T2D (25); severe AS patients with (20) and without T2D (20) undergoing AVR; T2D patients without cardiovascular disease (30) and healthy controls (20). A month prior to surgery cardiac PCr/ATP; EATa; LV volumes, mass, ejection fraction, mitral inflow E/A ratio, global longitudinal strain (GLS) and myocardial tissue characteristics were assessed. EAT samples were obtained from patients undergoing cardiac surgery for histological assessments. Results Participants were matched in age, sex distribution, and body mass index. Across all groups, patients with T2D showed higher EATa compared to those without T2D (138±50 vs 101±51cm2; p&amp;lt;0.0001). EATa was significantly higher in AS patients with T2D versus AS patients without T2D, while there was no significant difference in EATa between the CAD patients with and without T2D. Among the structural parameters, there were significant correlations between the EATa and myocardial pre-contrast T1 (p=0.02; r=0.20). Among the functional parameters there were inverse correlations of EATa with mitral inflow E/A (r=-0.34, p=0.002) and with GLS (r=-0.23, p=0.009). Among the metabolic biomarkers, there were no correlations between the EATa and PCr/ATP ratio. Histologically, compared to the control group of AS patients without T2D, patients with CAD with and without T2D showed larger adipocyte size and higher tissue fibrosis. There were no significant differences in EAT phenotype in adipocyte size, tissue fibrosis or inflammation between CAD patients with and without T2D. Conclusions This comprehensive EAT phenotyping study combined invasive and non-invasive methodologies and showed similar magnitudes of changes in EATa, adipocyte size and EAT fibrosis in CAD patients with and without T2D. While we have detected significant relationship of the EATa with the myocardial fibrosis, diastolic function and GLS, there were no correlations of myocardial PCr/ATP with the EATa suggesting other key mechanisms involved in the energetic deficit in patients with T2D.

Incidence of flow-limiting coronary artery stenoses in patients with diabetes - a coronary angiography natural history study

Abstract Background Diabetes is an established risk factor for the development of coronary atherosclerosis. We sought to assess the association between diabetes and the incidence of coronary artery atherosclerosis progression on coronary angiography. Methods Using the Swedish Coronary Angiography and Angioplasty Registry (SCAAR), we included all coronary artery segments with mild to no atherosclerosis defined as &amp;lt;50% luminal obstruction in patients undergoing a first-time coronary angiography in Sweden between 1989 and 2017. Patients with two or more vessel disease were excluded as were patients with a previous history of coronary artery disease. In patients with one vessel disease, the diseased vessel including all its branches were excluded. Patients were followed for 15 years until a clinically indicated re-angiography was done, death occurred or end of follow-up (April 2018). The primary outcome was plaque progression to flow-limiting coronary artery stenosis defined as ≥50% luminal obstruction on repeat angiography assessed using epidemiological tables, Kaplan Meier event rates, and Cox proportional hazard models. The importance of selected risk factors (smoking, hypertension, hyperlipidemia, and established coronary artery disease) was assessed. Results A total of 2 661 245 coronary segments in 248 736 patients were included in the study. Diabetes was present in 30 533 patients and 320 815 coronary artery segments. Kaplan-Meier event rates and incidence rates (IR) per 1000 segment-years were higher in patients with diabetes (5.5%, IR 2.78 [95% CI 2.70–2.85] vs. 3.0%, 1.44 [1.42–1.46]) resulting in an almost two-folded hazard ratio (HR) of plaque progression (HR 1.93 [95% CI 1.87– 2.00]). The anatomical distribution of plaque progression was similar between the two cohorts on all levels of analysis (coronary artery level, main artery and branches level, and coronary segment level artery). Diabetic patients with established coronary artery disease had a significantly higher risk of future events compared to those without clinically significant coronary artery disease. Conclusions Diabetes was associated with an almost twofold higher incidence rate of plaque progression but did not appear to alter the anatomical location of plaque development compared to the absence of diabetes. Once coronary artery disease is established, the rate of atherosclerotic events accelerates. Therefore, adopting aggressive primary prevention strategies is crucial to reduce the risk of adverse outcomes in diabetic patients.Event rates and anatomical distributionProgression of stenoses by risk factor

The concentration of small-diameter HDL particles (HDLp1) predicts the incidence of coronary calcium score in diabetic subjects without established cardiovascular disease

Abstract Introduction Type 2 diabetes (DM2) decisively influences the evolution of coronary atherosclerosis. However, this is a heterogeneous and poorly understood process. While in 50% of diabetics the chance of incident Coronary Calcium Score (CAC) in 5 years exceeds 40%, in 10% of diabetics the chance of incident CAC is less than 10%. To better understand the progression of coronary atherosclerosis measured by CAC in diabetics without cardiovascular disease, we studied the impact of the concentration of the small-diameter subfraction of HDL (HDLp1, 7 to 8nm). HDLp1 has been implicated as a central mediator of the anti-inflammatory effect of the HDL pool and could play a specific role in CAC incidence among diabetics. Methods From 2370 individual with two CAC evaluations and hydrogen spectroscopy/magnetic resonance (H1-NMR) plasma profile available, we found 461 diabetic individuals, non-users of statins, without previous cardiovascular disease, with CAC=0 in the first measurement and a second CAC measurement after an average period of 5 years. [HDLp1] concentration was measured by H1-NMR and divided into tertiles. The incidence of CAC was defined as an initial CAC of 0 followed by CAC&amp;gt;0 in the second measurement. Stepwise forward logistic regressions were used to identify risk factors for CAC incidence. Discrimination analysis was performed by calculating the area under the ROC curve (AUROC). Results A total of 143 (31.0%) patients had incident CAC. In stepwise logistic regression, alongside factors such as age, gender, systolic blood pressure, smoking, LDL-C, C-reactive protein and HbA1c, the 3rd tertile of [HDLp1] was associated with 55.2% (95% CI 15-110%, p =0.0039) and 140% (95% CI 32-341%, p&amp;lt;0.001) higher risk of CAC incidence compared to the 2nd tertile and 1st tertile, respectively. When compared to a model composed of 10 confounding variables (age, gender, systolic blood pressure, BMI, smoking, Lp(a), LDL-C,triglycerides, C-reactive protein and HbA1c) for predicting the incidence of CAC, the diameter of HDLp1 substantially increased the AUROC from 0.651 (95% CI 0.597-0.705) to 0.684 (95% CI 0.631–0.736), p=0.027 for the DeLong test comparing AUROCs. A restricted cubic spline demonstrated a strong association between [HDLp1] and CAC incidence. Conclusion The concentration of HDLp1 improves the predictive capacity for the incidence of CAC in diabetic individuals, non-users of statins, without cardiovascular disease.Spline HDLp1 concentration vs CAC incideROC for incident CAC

Abstract 13977: Insulin-Like Growth Factor Binding Protein 7 is Associated With Development of Cell Senescence and Progression of Coronary Atherosclerosis

Introduction: Cellular senescence, an irreversible cell cycle arrest, has been associated with atherosclerosis. Senescent cells (SC) secrete proinflammatory molecules contributing to disease progression. Insulin-like growth factor binding protein 7 (IGFBP7) binds IGF-1 and also interacts with IGF-1 receptor, suppressing intracellular IGF-1 signaling. IGFBP7 has been linked to heart failure-associated cell senescence. Hypothesis: We hypothesize that SC secrete IGFBP7, and IGFBP7 contributes to atherogenesis. Methods: Premature cell senescence was induced by treatment of smooth muscle cells (SMC) with H2O2. IGFBP7 levels were measured by immunoblotting of cell lysates and conditioned media (CM) and by immunohistochemistry in Apoe-null mice and in Rapacz hypercholesterolemic pigs. Binding of IGFBP7 with IGF-1 receptor was quantified by proximity ligation assay. Results: H2O2-treated SMC have marked increase in expression of the senescence markers beta-galactosidase (SA-βGal) and γH2A.X, and 3-fold (P&lt;0.05) increase in IGFBP7 in cell CM. Abundant senescent SMC (αSMA + /SA-βGal + ) were detected in fibrous cap’s plaque in murine innominate artery and these cells had increased IGFBP7 compared to SMC in the vascular media. Increased IGFBP7 levels (1.8-fold increase, P&lt;0.05) were also detected in porcine coronary plaque and IGFBP7 upregulation correlated with elevated IGFBP7/IGF-1 receptor binding. These data suggest a mechanistic link between senescence, IGFBP7 upregulation and atherogenesis. SMC were incubated with CM from senescent SMC (or non-senescent controls) to determine if SC-secreted IGFBP7 inhibits IGF-1 signaling. Preincubation with CM from SC inhibited IGF-1-induced Akt phosphorylation, however co-incubation with anti-IGFBP7 antibody reversed this effect, indicating that IGFBP7 in the CM mediates the inhibitory effect on IGF-1 signaling. Conclusions: We have shown that SMC senescence induced IGFBP7 and that high IGFBP7 levels were associated with senescent SMC in the atherosclerotic plaque. IGFBP7 inhibits IGF-1 signaling in vitro and binds IGF-1 receptor in plaque SMC. Our results suggest a novel role of IGFBP7 in senescence and in atherogenesis and identify IGFBP7 as a potential target for anti-atherogenic therapy.

Abstract 14816: PCSK9 Inhibitors Modify Plaque and Reduce Plaque Progression: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Introduction: Elevated coronary plaque burden and high-risk plaque characteristics, such as thin fibrous cap, are associated with an increased risk of adverse cardiovascular events. However, there is limited evidence on the effect of PCSK9 inhibitors (PCSK9i) on changes to plaque burden and composition. Hypothesis: We aimed to conduct a systematic review and meta-analysis of randomized controlled trials (RCTs) to evaluate the effects of standard lipid-lowering therapy with vs. without PCSK9i on plaque burden and phenotype. Methods: We searched PubMed, Embase and Cochrane Central for studies that performed serial intravascular imaging comparing patients with vs. without PCKS9i therapy. Two reviewers independently performed study selection, data extraction and assessment of bias. All outcomes were continuous; thus, we computed pooled mean difference (MD) or standardized mean difference (SMD) with 95% confidence intervals (CI). Random-effects models were used. Statistical analysis was performed using Review Manager 5.4.1. Results: We included 1,696 patients from 6 RCTs. The mean follow-up ranged from 36 to 76 weeks. Mean age ranged from 58.4 to 61.8 years; 1,246 (65%) were male; and 368 (21.6%) had previous myocardial infarction. Percent atheroma volume (MD -1.05%; 95% CI -1.32, -0.77%; p&lt;0.001), total atheroma volume (MD -6.33 mm 3 ; 95% CI -10.01,-2.66 mm 3 ; p&lt;0.001), and total lipid index (SMD -0.58; 95% CI -0.90,-0.26; p&lt;0.001) were significantly reduced in patients treated with PCSK9i. The minimum fibrous cap thickness (SMD 0.59; 95% CI 0.26,0.93; p&lt;0.001) was also significantly improved in patients randomized to PCSK9i. Conclusions: Our findings suggests that PCSK9i reduce progression of coronary atherosclerosis and stabilizes plaque, as evidence by favorable changes in percent atheroma volume, total atheroma volume, lipid index of the plaque, and minimal fibrous cap thickness.

Single-Cell RNA Sequencing of Coronary Perivascular Adipose Tissue From End-Stage Heart Failure Patients Identifies SPP1+ Macrophage Subpopulation as a Target for Alleviating Fibrosis.

Perivascular adipose tissue (PVAT) is vital for vascular homeostasis, and PVAT dysfunction is associated with increased atherosclerotic plaque burden. But the mechanisms underlining coronary PVAT dysfunction in coronary atherosclerosis remain elusive. We performed single-cell RNA sequencing of the stromal vascular fraction of coronary PVAT from 3 groups of heart transplant recipients with end-stage heart failure, including 3 patients with nonobstructive coronary atherosclerosis, 3 patients with obstructive coronary artery atherosclerosis, and 4 nonatherosclerosis control subjects. Bioinformatics was used to annotate the cellular populations, depict the cellular developmental trajectories and interactions, and explore the differences among 3 groups of coronary PVAT at the cellular and molecular levels. Pathological staining, quantitative real-time polymerase chain reaction, and in vitro studies were performed to validate the key findings. Ten cell types were identified among 67 936 cells from human coronary PVAT. Several cellular subpopulations, including SPP1+ (secreted phosphoprotein 1) macrophages and profibrotic fibroadipogenic progenitor cells, were accumulated in PVAT surrounding atherosclerotic coronary arteries compared with nonatherosclerosis coronary arteries. The fibrosis percentage was increased in PVAT surrounding atherosclerotic coronary arteries, and it was positively associated with the grade of coronary artery stenosis. Cellular interaction analysis suggested OPN (osteopontin) secreted by SPP1+ macrophages interacted with CD44 (cluster of differentiation 44)/integrin on fibroadipogenic progenitor cells. Strikingly, correlation analyses uncovered that higher level of SPP1 in PVAT correlates with a more severe fibrosis degree and a higher coronary stenosis grade. In vitro studies showed that conditioned medium from atherosclerotic coronary PVAT promoted the migration and proliferation of fibroadipogenic progenitor cells, while such effect was prevented by blocking CD44 or integrin. SPP1+ macrophages accumulated in the PVAT surrounding atherosclerotic coronary arteries, and they promoted the migration and proliferation of fibroadipogenic progenitor cells via OPN-CD44/integrin interaction and thus aggravated the fibrosis of coronary PVAT, which was positively correlated to the coronary stenosis burden. Therefore, SPP1+ macrophages in coronary PVAT may participate in the progression of coronary atherosclerosis.