Clinical Atherosclerotic Disease Research Articles

#2009 FGF23 in patients with diabetic kidney disease and atherosclerosis

Abstract Background and Aims Diabetes mellitus (DM) and chronic kidney disease (CKD) are risk factors for vascular atherosclerosis, a pathological process with an important inflammatory component. The coexistence of these conditions in patients with diabetic kidney disease (DKD) has additive effects with worst cardiovascular mortality and morbidity rates when compared to non-diabetic CKD patient on cardiovascular outcomes. Accumulating research has shown that increased levels of bone-derived fibroblast growth factor 23 (FGF23), the major phosphate-regulating hormone, constitute a novel predictor of cardiovascular and all-cause mortality in CKD patients, with potential effects on disorders of glucose metabolism as well. The objective of this comparative study is to determine the differences in FGF23 levels in two groups of patients with CKD, with and without DM, matched by age, sex and renal function, all of them with clinical atherosclerotic disease. We also evaluated the relationships of FGF23 with several inflammatory markers and parameters of glucose metabolism. Method Sixty-six patients with CKD stages 3-4 (33 of them with DM) and diagnosed with peripheral vascular disease were included in the study. Whole blood and serum samples were obtained from all participants. CRP values, neutrophil/lymphocyte (N/L) ratio, HbA1c (%), fasting glucose, and Triglycerides and glucose (TyG) index, among other parameters, were obtained using standardized routine methods. Circulating levels of the intact form of FGF23, tumor necrosis factor (TNF) α, interleukin (IL) 6, and IL10 were determined by ELISA immunoassays in both groups. We also performed gene expression analysis for these three cytokines in peripheral blood cells (PBCs) using qPCR. Results The mean values of eGFR, ACR and phosphate were 37.6 ± 11.2 ml/min/1.73 m2; 294.1 ± 271.2 mg/g; 3.8 ± 0.82 mg/dL; respectively without differences between patients with and without DM The median circulating FGF23 values were higher in the DM group (51.59 [37.73-89.68] vs. 38.1 [33-54.14] pg/mL; p<0.001). Likewise, patients with DM presented higher levels of TNFα both in serum concentration (1.78 [0.72-2.47] vs. 1.28 [1.01-1.88] pg/mL; p<0.01) as in the expression of mRNA in PBCs (2.1 ± 1.26 vs. 1.87 ± 1.16 a.u.; p<0.05). No differences were observed for IL6 and IL10 levels, nor for CRP concentration or N/L ratio. As expected, fasting glucose, HbA1c and TyG index were higher in the group of subjects with DM. FGF23 was inversely correlated with eGFR (r=−0.435, p<0.0001), while it showed a positive association with ACR (r=0.416, p<0.001) and, interestingly, with proinflammatory cytokines including circulating TNFα (r=0.44, p<0.001), circulating IL6 (r=0.27, p=0.04), and TNF mRNA expression in PBCs (r=0.245, p=0.047). Furthermore, circulating FGF23 was also direct and significantly correlated with HbA1c (r=0.34, p<0.01). Conclusion These results suggest that FGF23 levels are higher in DKD than in non-DM CKD patients with similar renal function. DKD patients also had higher levels of the proinflammatory cytokine TNFα. Our results also show positive correlations of FGF23 with the inflammatory cytokines TNFα and IL6, as well as with HbA1c. Previous studies, shown that elevated TNFα and glucose promote FGF23 production, which may help to explain the higher levels of FGF23 in patients with DM Future studies should clarify whether FGF23 is simply a marker of atherosclerosis disease severity or a contributing factor to this complication in CKD.

USE OF ATHEROGENIC INDICES AS ASSESSMENT METHODS FOR CLINICAL ATHEROSCLEROTIC DISEASES

Accurate assessment of clinical atherosclerotic diseases is essential to guide effective therapeutic interventions, and atherogenic indices have emerged as valuable methods in this setting. The complexity of these pathologies demands approaches that go beyond the simple measurement of total cholesterol, requiring tools that consider the interaction between different lipoproteins and other risk factors. In this context, the use of atherogenic indices appears as a promising approach, providing a more comprehensive and refined assessment of atherosclerotic conditions. Objective: To comprehensively analyze scientific studies published in the last 10 years that investigated the use of atherogenic indices as methods of evaluating clinical atherosclerotic diseases. The review seeks to consolidate the available evidence by examining the effectiveness of these indices in early identification, risk stratification and monitoring the progress of atherosclerotic diseases. Methodology: The systematic review was conducted following the PRISMA guidelines. The PubMed, Scielo and Web of Science databases were consulted to identify relevant studies published in the last 10 years. The descriptors used were "atherogenic indices", "atherosclerotic diseases", "clinical assessment", "lipoproteins" and "cardiovascular risk factors". Inclusion criteria considered original studies that investigated the use of atherogenic indices in clinical populations, while exclusion criteria involved studies with unrepresentative samples and inadequate atherosclerotic assessment methods. Results: The results of the review highlight the diversity of available atherogenic indices and their usefulness in evaluating different aspects of atherosclerotic diseases, including prediction of cardiovascular events, risk stratification and treatment monitoring. The analysis identified indices that proved to be particularly sensitive and specific in different clinical contexts. Conclusion: In summary, the systematic review highlights the relevance of atherogenic indices as valuable tools in the assessment of clinical atherosclerotic diseases. The diversity of these indices and their ability to provide comprehensive information highlights their importance in clinical practice, contributing to a more refined and personalized approach to the management of these conditions.

PCSK9 genetic variants and risk of vascular and non-vascular diseases in Chinese and UK populations.

Lowering low-density lipoprotein cholesterol (LDL-C) through PCSK9 inhibition represents a new therapeutic approach to preventing and treating cardiovascular disease (CVD). Phenome-wide analyses of PCSK9 genetic variants in large biobanks can help to identify unexpected effects of PCSK9 inhibition. In the prospective China Kadoorie Biobank, we constructed a genetic score using three variants at the PCSK9 locus associated with directly measured LDL-C [PCSK9 genetic score (PCSK9-GS)]. Logistic regression gave estimated odds ratios (ORs) for PCSK9-GS associations with CVD and non-CVD outcomes, scaled to 1 SD lower LDL-C. PCSK9-GS was associated with lower risks of carotid plaque [n = 8340 cases; OR = 0.61 (95% confidence interval: 0.45-0.83); P = 0.0015], major occlusive vascular events [n = 15 752; 0.80 (0.67-0.95); P = 0.011], and ischaemic stroke [n = 11 467; 0.80 (0.66-0.98); P = 0.029]. However, PCSK9-GS was also associated with higher risk of hospitalization with chronic obstructive pulmonary disease [COPD: n = 6836; 1.38 (1.08-1.76); P = 0.0089] and with even higher risk of fatal exacerbations amongst individuals with pre-existing COPD [n = 730; 3.61 (1.71-7.60); P = 7.3 × 10-4]. We also replicated associations for a PCSK9 variant, reported in UK Biobank, with increased risks of acute upper respiratory tract infection (URTI) [pooled OR after meta-analysis of 1.87 (1.38-2.54); P = 5.4 × 10-5] and self-reported asthma [pooled OR of 1.17 (1.04-1.30); P = 0.0071]. There was no association of a polygenic LDL-C score with COPD hospitalization, COPD exacerbation, or URTI. The LDL-C-lowering PCSK9 genetic variants are associated with lower risk of subclinical and clinical atherosclerotic vascular disease but higher risks of respiratory diseases. Pharmacovigilance studies may be required to monitor patients treated with therapeutic PCSK9 inhibitors for exacerbations of respiratory diseases or respiratory tract infections. Genetic analyses of over 100 000 participants of the China Kadoorie Biobank, mimicking the effect of new drugs intended to reduce cholesterol by targeting the PCSK9 protein, have identified potential severe effects of lower PCSK9 activity in patients with existing respiratory disease.PCSK9 genetic variants that are associated with lower cholesterol and reduced rates of cardiovascular disease are also associated with increased risk of a range of respiratory diseases, including asthma, upper respiratory tract infections, and hospitalization with chronic obstructive pulmonary disease (COPD).These genetic variants are not associated with whether or not individuals have COPD; instead, they are specifically associated with an increase in the chance of those who already have COPD being hospitalized and even dying, suggesting that careful monitoring of such patients should be considered during development of and treatment with anti-PCSK9 medication.

Use of Atherogenic Indices as Assessment Methods of Clinical Atherosclerotic Diseases.

Central illustration : Use of Atherogenic Indices as Assessment Methods of Clinical Atherosclerotic Diseases. The search for clinically useful methods to assess atherosclerotic diseases (ASCVD) with good accuracy, low cost, non-invasiveness, and easy handling has been stimulated for years. Thus, the atherogenic indices evaluated in this study may fit this growing demand. To assess the potential of atherogenic indices to evaluate patients with clinical atherosclerosis. Single-center cross-sectional study, through which the Castelli I and II indices, the atherogenic index of plasma (AIP), the lipoprotein combine index, and the variation in the peripheral perfusion index between 90 and 120 seconds after an endothelium-dependent (ΔPI90-120) vasodilator stimulus were evaluated in the prediction of atherosclerosis. Statistical significance was set at p < 0.05. The sample consisted of 298 individuals with an average age of 63.0±16.1 years, of which 57.4% were women. Paired comparisons of the ROC curve analysis of the indices that reached the area under the curve (AUC) > 0.6 show that ΔPI90-120 and AIP were superior to other indices, and no differences were observed between them (difference between AUC = 0.056; 95%CI -0.003-0.115). Furthermore, both the ΔPI90-120 [odds ratio (OR) 9.58; 95%CI 4.71-19.46)] and AIP (OR 5.35; 95%CI 2.30-12.45) were independent predictors of clinical atherosclerosis. The AIP and ΔPI90-120 represented better accuracy in discriminating clinical ASCVD. Moreover, they were independent predictors of clinical ASCVD, evidencing a promising possibility for developing preventive and control strategies for cardiovascular diseases. Therefore, they are markers for multicenter studies from the point of view of practicality, low cost, and external validity.

Leukotrienes in the atherosclerotic cardiovascular diseases — a systematic review

Introduction: The role of inflammation in the pathogenesis of atherosclerotic diseases is strongly suggested. There are multiple studies indicating the possibility of a pathophysiological connection between atherosclerotic changes and leukotrienes (LTs) — the products of arachidonic acid metabolism. The goal of this systematic review, performed in line with the PRISMA statement, was to investigate the potential role of LTs in the pathophysiology of atherosclerotic cardiovascular diseases (CVD). Material and methods: The MEDLINE, EMBASE, and Cochrane Database of Systematic Reviews were searched to identify the potentially eligible studies. Publications that contained information on any type of LTs identified in blood or urine were included in the review. A database search identified 2082 records. Reliable LTs identification in patients with CVD was used in 30 publications. Results: Stable and acute forms of coronary artery disease are characterized by the overproduction of different types of LTs. The level of LTB4 and LTC4 in the blood is elevated in patients with cerebral ischemia. Patients with acute and chronic peripheral artery disease have elevated levels of LTE4 in urine. Conclusions: The findings of this systematic review show that there is a clear tendency to indicate the association of cardiovascular atherosclerotic diseases with increased production of LTs. This dependency detailed characteristic remains unclear and the question on the impact of elevated leukotrienes on clinical atherosclerotic disease manifestations is still open.

Obesity is associated with coronary artery stenosis independently of metabolic risk factors: The population-based SCAPIS study

Background and aimsPrevious studies reported divergent results on whether metabolically healthy obesity is associated with increased coronary artery calcium and carotid plaques. We investigated this in a cross-sectional fashion in a large, well-defined, middle-aged population using coronary CT angiography (CCTA) and carotid ultrasound. MethodsIn the SCAPIS study (50–65 years, 51% female), CCTA and carotid artery ultrasound were performed in 23,674 individuals without clinical atherosclerotic disease. These subjects were divided into six groups according to BMI (normal weight, overweight, obese) and the presence of metabolic syndrome (MetS) according to the NCEP consensus criteria. ResultsThe severity of coronary artery stenosis was increased in individuals with obesity without MetS compared to normal-weight individuals without MetS (OR 1.47, 95%CI 1.34–1.62; p < 0.0001), even after adjusting for non-HDL-cholesterol and several lifestyle factors. Such difference was not observed for the presence of carotid artery plaques (OR 0.94, 95%CI 0.87–1.02; p = 0.11). Obese or overweight individuals without any MetS criteria (except the waist criterion) showed significantly more pronounced stenosis in the coronary arteries as compared to the normal-weight individuals, while one criterion was needed to show increased plaque prevalence in the carotid arteries. High blood pressure was the most important single criterion for increased atherosclerosis in this respect. ConclusionsIndividuals with obesity without MetS showed increased severity of coronary artery stenosis, but no increased occurrence of carotid artery plaques compared to normal-weight individuals without MetS, further emphasizing that obesity is not a benign condition even in the absence of MetS.

Alirocumab reduces total coronary plaque burden in patients with familial hypercholesterolaemia and no previous clinical atherosclerotic disease

Abstract Background It is well known that statins, ezetimibe and other lipid lowering treatments such as Evolocumab (PCSK9-Inhibitor) reduce cardiovascular events by decreasing LDL-cholesterol (LDL-C) levels and slowing the progression of coronary atherosclerosis. Nevertheless, cardiovascular (CV) risk remains. Alirocumab, a PCSK9 inhibitor has demonstrated a reduction in cardiovascular events but its relationship with coronary atherosclerosis reduction has not been adequately demonstrated. Purpose The ARCHITECT trial sought to determine whether Alirocumab 150 mg/2 weeks is able to stop or reverse coronary atherosclerosis progression, by assessing coronary plaque burden (CPB) by serial multidetector computed tomography (MDCT). Methods A total of 104 patients with molecularly characterized heterozygous familial hypercholesterolaemia (FH) without clinical cardiovascular disease were enrolled in this trial. Patients had to have CPB &amp;gt;30% as documented by MDCT, be on maximum tolerated statin therapy with or without ezetimibe and LDL-C &amp;gt;100 mg/dL. Patients underwent a MDCT at enrollment and after 18-month treatment with alirocumab and they were analyzed by means of QAngio CT (Medis medical imaging system, the Netherlans). The pre-specified primary endpoint was change in CPB. Results Median age was 53.3 (46.2–59.4) years (54, 51.9% woman). Median LDL-cholesterol was 138.9 mg/dL. There was a significant reduction in the primary endpoint as Alirocumab reduced CPB from 34.6 (32.9–36.8)% to 30.4 (27.4–33.4)%. Significant reductions in LDL-C (67%) and atherosclerotic plaque volume were also found. Plaque regression as estimated by CPB was found in 91 (87.5%) patients. Main resuts may be found in figure 1. Conclusions Alirocumab demonstrated significant regression of CPB on MDCT over 18 months. ARCHITECT provides crucial mechanistic clues on coronary plaque behavior under the use of Alirocumab and its results could link and explain ODYSSEY-OUTCOMES results. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Sanofi

Functional Impairment of Endothelial Colony Forming Cells (ECFC) in Patients with Severe Atherosclerotic Cardiovascular Disease (ASCVD).

Endothelial dysfunction is a key factor in atherosclerosis. However, the link between endothelial repair and severity of atherosclerotic cardiovascular disease (ASCVD) is unclear. This study investigates the relationship between ASCVD, markers of inflammation, and circulating endothelial progenitor cells, namely hematopoietic cells with paracrine angiogenic activity and endothelial colony forming cells (ECFC). Two hundred and forty-three subjects from the TELARTA study were classified according to the presence of clinical atherosclerotic disease. ASCVD severity was assessed by the number of involved vascular territories. Flow cytometry was used to numerate circulating progenitor cells (PC) expressing CD34 and those co-expressing CD45, CD34, and KDR. Peripheral blood mononuclear cells ex vivo culture methods were used to determine ECFC and Colony Forming Unit- endothelial cells (CFU-EC). The ECFC subpopulation was analyzed for proliferation, senescence, and vasculogenic properties. Plasma levels of IL-6 and VEGF-A were measured using Cytokine Array. Despite an increased number of circulating precursors in ASCVD patients, ASCVD impaired the colony forming capacity and the angiogenic properties of ECFC in a severity-dependent manner. Alteration of ECFC was associated with increased senescent phenotype and IL-6 levels. Our study demonstrates a decrease in ECFC repair capacity according to ASCVD severity in an inflammatory and senescence-associated secretory phenotype context.

Statin treatment and serum low-density lipoprotein (LDL) level in the Birjand elderly dwellers: Birjand Longitudinal Aging Study (BLAS) Wave3.

Elderly people have a greater risk than others to develop atherosclerotic disorders. Statins are the most efficient treatments against atherosclerosis; however, the pros and cons of the treatment should be put in balance in regard to the target level of low-density lipoprotein cholesterol (LDL-C). This study evaluates the level of LDL in the Birjand elderly population and determines the achievement of target LDL-C level, according to the American College of Cardiology (ACC) guidelines. A retrospective observational study of statin therapy was performed from October 2018 using Birjand community health assessment data of the BLAS project. We used the 2018 ACC/AHA guidelines to determine the achievement of target LDL level in statin treated patients with clinical atherosclerotic cardiovascular diseases (ASCVD), or elderly high risk diabetic patients and dyslipidemia ones, in the Birjand elderly dwellers, stratified by statin treatment intensity. Statin and non-statin users were also compared in terms of demographic and laboratory findings. Mann-Whitney U test and Chi-Square test were used for data analysis. Out of 1418 elderly residents in this study, 683 individuals (48.2%) were male with a mean age of 69.73±7.56 years. The total mean level of LDL-C in elderly participants was 122.83±36.21mg/dL. The mean level of LDL-C in statin use and none statin use group was 104.97±36.01 and 129.09±34.14, respectively. Only 304 (29.2%) of participants who were eligible for statin administration used the statin. While 69 (18.3%) individuals from 378 (26.7%) were using statin though they were not eligible for it. In the clinical ASCVD group, 39 (28.3%) of elderly participants achieved target LDL-C based on the ACC/AHA guideline. This was 58 (37.4%) for other participants with LDL-C ≥190mg/dL, diabetic or participants with Framingham Risk Score (FRS) ≥10%. The majority of patients who were eligible for high or moderate-intensity statin treatment had not received statin. Only one third of clinical ASCVD patients and almost half of high risk patients achieved LDL-C target values. Findings illustrate current treatment may need to be reconsidered in Birjand elderly dwellers treated with statin and physicians, should be updated on the use of statins.

Statin Intolerance and Noncompliance: An Empiric Approach

Statin Intolerance and Noncompliance: An Empiric Approach

MO031KLOTHO GENE PROMOTER METHYLATION IN THE VASCULATURE IS RELATED TO INFLAMMATION IN HUMAN ATHEROSCLEROSIS

Abstract Background and Aims Atherosclerosis, a vascular pathological process with an important inflammatory component, underlies most of the cardiovascular diseases (CVD). Deficiencies in the antiaging factor α-Klotho (KL) have been related to the appearance and progression of atherosclerotic damage associated with CVD. In addition, some studies have demonstrated that KL gene is expressed in human arteries and that low vascular KL expression levels are related with clinical atherosclerotic disease. Among the epigenetic mechanisms that regulate the expression of the KL gene, methylation of the CpG islands in the promoter region is one of the most studied. In this pilot study, we propose that this mechanism participates in the regulation of vascular KL expression and contributes to the deficiency in vascular KL levels observed in CVD. Moreover, we determined the influence of different inflammatory components in the methylation status of KL promoter. Method We developed a case-control study that included 25 patients with diagnosis of clinical atherosclerotic vascular disease undergoing elective vascular surgery and 15 cadaveric organ donors with no medical history of CVD, respectively. Vascular fragments were retrieved from all subjects, and the degree of methylation of the KL gene promoter was assessed by bisulfite sequencing. Additionally, vascular gene expression in both groups was assessed by qPCR for KL, two DNA methyltransferases (DNMT1 and DNMT3A), and three inflammatory-related loci (TNF, IL10 and NFKB1). Serum concentrations of TNFα and IL10 were measured by ELISA immunoassay, and complementary inflammatory parameters (CRP and neutrophil/lymphocyte ratio) by standardized routine methods. Results The vascular tissue of patients in the case group presented a higher percent level of methylated positions in the KL promoter region (71.4±8.3% vs. 39.4±12.3%, P&amp;lt;0.05), as well as a significant decrease in the expression of KL gene (a 40% reduction as compared to controls, P&amp;lt;0.05). Considering the whole study population, the methylation degree was inversely related to the endogenous transcript levels of KL gene (r=-0.66, P&amp;lt;0.0001). Moreover, the expression of DNMT1 was significantly increased in the case group (P&amp;lt;0.05), as well as those of the proinflammatory genes TNF and NFKB1 (P&amp;lt;0.0001 and P&amp;lt;0.05, respectively), being all of them directly associated with the vascular methylation levels of KL gene (r=0.51, P&amp;lt;0.0001 for DNMT1; r=0.45, P&amp;lt;0.001 for TNF; r= 0.37, P&amp;lt;0.05 for NFKB1). Furthermore, vascular expression of DNMT1 and DNMT3A directly correlated with both inflammatory markers in this tissue (P&amp;lt;0.0001, for all). Systemic levels of IL10 presented a direct association with vascular KL gene expression (r=0.28, P&amp;lt;0.05), while inverse associations were observed with the methylation degree of KL gene (r=-0.38, P&amp;lt;0.05) and DNMT1 expression (r=-0,29, P&amp;lt;0.05). Conclusion These results suggest that the methylation of KL gene promoter in the vasculature is a mechanism associated with the inflammatory response that would partly explain its reduction during atherosclerotic injury.

MO037EPIGENETIC REGULATION OF KLOTHO IN PERIPHERAL BLOOD CIRCULATING CELLS IS ASSOCIATED CELLS IS ASSOCIATED WITH SOLUBLE PROTEIN SERUM IN CARDIOVASCULAR DISEASE

Abstract Background and Aims The antiaging factor α-Klotho (KL) has been related to cardiovascular diseases (CVD), including coronary artery disease, heart failure and peripheral arterial disease. The soluble form of this protein (sKL), which is mainly produced by the kidneys, have demonstrated to display different protective effects on the cardiovascular system, e.g., prevention of vascular calcification, oxidative stress, or cardiac fibrosis. Likewise, different clinical studies have pointed out that CVD is a state of sKL deficiency, even when the renal function is still preserved. It has been demonstrated that peripheral blood circulating cells (PBCCs) also express KL, but little is known about its expression profile during CVD. The aim of this work is to determinate if the expression of KL gene and its promoter methylation in PBCCs are correlated with serum levels of the soluble protein, and if there exist any association with the underlying inflammatory process that occurs during CVD. Method Forty-four patients diagnosed with clinical atherosclerotic vascular disease (case group) and 15 subjects without CVD background (control group) were included in the study. Whole blood and serum samples were obtained from all participants. We performed gene expression analysis for KL expression in PBCCs by qPCR, as well as for DNMT1 and DNMT3A (members of the DNA-methyltransferases family), TNF, IL10 and NFKB1 (inflammatory parameters). We assessed the degree of methylation of the KL gene promoter in these cells by bisulfite sequencing. Furthermore, we determined circulating levels of sKL, TNFα and IL10 by ELISA immunoassay in serum samples of both groups. Results Results showed a lower expression of KL gene in PBCCs of patients with CVD compared to controls (45% reduction, P&amp;lt;0.001), which was accompanied by a higher degree of methylation of its promoter (36.7±6.3% vs. 15.9±4.8%, P&amp;lt;0.05). The case group also presented significantly higher levels of DNMT1 and DNMT3A transcripts in these cells (P&amp;lt;0.0001 for both), as well as higher values of proinflammatory parameters (gene expression of TNF and NFKB1, and TNF/IL10 ratio; P&amp;lt;0.001 for all of them). Serum levels of sKL were decreased in the CVD group compared to controls (a reduction of 57.5%, P&amp;lt;0.0001). KL expression in PBCCs correlated directly with systemic levels of sKL (r=0.20, P&amp;lt;0.05), but inversely with expression of DNMT1 (r=-0.33, P&amp;lt;0.01) and inflammatory parameters (r=-0.37, P&amp;lt;0.01 for NFKB1 expression; r=-0.38, P&amp;lt;0.01 for TNF/IL10 expression ratio; and r=-0.39, P&amp;lt;0.01 for serum TNFα/IL10 ratio). No significant associations were found between inflammatory markers and methylation degree of KL gene promoter. Conclusion These results indicate an association between epigenetic regulation of KL gene in PBCC and systemic levels of the soluble protein in CVD, which could be influenced by the proinflammatory state present in these disorders.

MO453SERUM AND VASCULAR FIBROBLAST GROWTH FACTOR 23 (FGF23) ARE ASSOCIATED WITH VASCULAR CALCIFICATION

Abstract Background and Aims Mineral metabolism imbalances and inflammation are related to the development of vascular calcification (VC). Fibroblast growth factor-23 (FGF23) is the main regulator of phosphate homeostasis and various studies have shown the existence of an association between elevated levels of FGF23 and the appearance of cardiovascular disease (CVD). We conducted a case-control study to test the hypothesis that serum and vascular levels of FGF23 are associated with the presence of VC. In addition, we determined the influence of inflammation in these levels. Method One hundred and thirty-three patients diagnosed with clinical atherosclerotic disease undergoing elective vascular surgery, and 20 cadaveric organ donors with no medical history of CVD, were included in this study. Serum levels of intact FGF23 (iFGF23), together with tumor necrosis factor-alpha (TNFα), interleukin (IL)10, were determined by ELISA. Vascular fragments of aorta, carotid and femoral arteries were obtained for assaying the gene expression of FGF23, TNF, IL10 and RUNX2 by qPCR. Immunohistochemical procedures were employed to determine vascular protein levels of FGF23, TNFα and IL10. VC was diagnosed by imaging techniques and confirmed by histological procedures including von Kossa staining. Results Case group presented a higher prevalence of hypertension, hypercholesterolemia and reduced estimated glomerular filtration rate, with no differences regarding other parameters. Serum iFGF23 and TNFα/IL10 ratio were higher in the case group (P&amp;lt;0.01 and P&amp;lt;0.001, respectively). Vascular expression of FGF23 was detected in 58.6% of CVD patients vs 35% of donors, with mean expression levels significantly higher in the first group (P&amp;lt;0.01). Vascular expression of TNF/IL10 was also increased (P&amp;lt;0.001) in CVD patients. FGF23 immunoreactivity was detected in 84% of CVD patients and only in 35% of controls. Immunoreactivity for FGF23 and TNFα/IL10 ratio were significantly higher in CVD patients (P&amp;lt;0.001 and P&amp;lt;0.0001, respectively). Stratified analysis according to serum iFGF23 levels showed a higher prevalence of VC in the upper tertiles. Patients with VC presented increased levels of all the FGF23 variables including serum [1.5 (1.2-1.6) vs. 1.4 (0.9-1.5) pg/mL, P&amp;lt;0.01], vascular mRNA [26.1 (14.3-67.4) vs. 18.8 (8.8-312.9) log AU, P&amp;lt;0.01] and vascular immunoreactivity [4.6 (3.8-4.9) vs. 3.7 (3.1-4.1) log µm2, P&amp;lt;0.05]. Moreover, FGF23 immunoreactivity was detected in 92.3% of fragments with VC and only in 53.6% of those without VC. Serum TNFα/IL10 and RUNX2 mRNA levels were also higher in this group (P&amp;lt;0.01 for both). Correlation analysis showed associations of serum iFGF23 with serum TNFα (r=0.375, P&amp;lt;0.001), neutrophil/lymphocyte (r=0.142, P&amp;lt;0.05), vascular RUNX2 mRNA (r=0.55, P&amp;lt;0.05), and vascular FGF23 immunoreactivity (r=0.281, P&amp;lt;0.05) in the CVD group. Vascular FGF23 expression correlated with RUNX2 mRNA (r=0.315, P&amp;lt;0.05) and FGF23 immunoreactivity (r=0.254, P&amp;lt;0.05). Multiple regression analysis showed that iFGF23 levels were determined by UAE, HDL, FGe, calcium and TNFα levels (adjusted R2= 0.473, P&amp;lt;0.0001) and that vascular FGF23 mRNA expression was determined by TNFα, PCR, glucose and age (adjusted R2= 0.795, P&amp;lt;0.0001). Multivariate logistic regression, with VC as dependent variable, showed that both iFGF23 and vascular mRNA constitute independent risk factors for the existence of VC [OR (95% CI): 1.05 and 1.12, P&amp;lt;0.05 for both]. Conclusion Patients with atherosclerosis and VC present significantly higher serum concentrations of FGF23, as well as higher immunoreactivity and gene expression levels in the vascular wall compared to patients without VC. Moreover, both serum and vascular mRNA levels of FGF23 are associated with the inflammatory status. Whether the increase in systemic and vascular FGF23 can directly promote or favor the calcifying process in the vascular bed is currently an issue under discussion.

Association Between LOX-1, LAL, and ACAT1 Gene Single Nucleotide Polymorphisms and Carotid Plaque in a Northern Chinese Population.

Objective: Carotid atherosclerosis is one of the major risk factors for ischemic stroke. The presence of carotid plaque has been widely used to assess the risk of clinical atherosclerotic disease. Lectin-type oxidized LDL (low-density lipoprotein) receptor 1 (LOX-1), lysosomal acid lipase (LAL), and acyl-CoA:cholesterol acyltransferase 1 (ACAT1) are important for lipid accumulation in atherosclerosis. The objective of this study was to investigate the relationship between single nucleotide polymorphisms (SNPs) in the LOX-1, LAL, and ACAT1 genes and the presence of carotid plaque in a Northern Chinese population. Methods: Three polymorphisms in LOX-1 (rs1050286), LAL (rs11203042), and ACAT1 (rs11576517) were identified and genotyped in 215 patients with carotid plaque and 252 controls using the polymerase chain reaction with high-resolution melting analysis. Results: The LOX-1 (rs1050286) AA and LAL (rs11203042) TT genotypes were significantly associated with increased risk of carotid plaque, whereas a ACAT1 (rs11576517) TT genotype was shown to be protective against carotid plaque in a Northern Chinese population (p < 0.05). Even after the Bonferroni correction, the LAL (rs11203042) TT genotype (odds ratio = 3.838, 95% confidence interval = 1.748-8.426, p < 0.001) was still associated with an increased risk for carotid plaque. Conclusions: These results suggest that the LAL (rs11203042) TT genotype is associated with increased risk for carotid plaque in a Northern Chinese population, and that the LOX-1 (rs1050286) AA genotype shows a nonstatistically significant trend towards association. However, no association was found between the ACAT1 (rs11576517) polymorphisms and carotid plaque presence.

Effect of Statin Therapy on Outcomes of Patients With Acute Ischemic Stroke and Atrial Fibrillation.

BackgroundThere is insufficient evidence on the effect of statins, particularly high‐intensity statins, in patients with acute ischemic stroke and atrial fibrillation. We investigated the impact of statins on the outcomes in these patients, including those who might be vulnerable to statin therapy and those without clinical atherosclerotic cardiovascular diseases.Methods and ResultsA total of 2153 patients with acute ischemic stroke and atrial fibrillation were enrolled in the present nationwide, multicenter, cohort study. The primary composite end point was the occurrence of net adverse clinical and cerebral events (NACCE; death from any cause, stroke, acute coronary syndrome, or major bleeding) over a 3‐year period based on statin intensity. NACCE rates were lower in patients receiving low‐ to moderate‐intensity (adjusted hazard ratio 0.64; 95% CI: 0.52‐0.78) and high‐intensity statins (hazard ratio 0.51; 95% CI 0.40‐0.66) than in those not receiving statin therapy. High‐intensity statins were associated with a lower risk for NACCE than low‐ to moderate‐intensity statins (hazard ratio 0.76; 95% CI 0.59‐0.96). Subgroup analyses showed that the differences in hazard ratio for 3‐year NACCE favored statin use across all subgroups, including older patients, those with low cholesterol levels, patients receiving anticoagulants, and patients without clinical atherosclerotic cardiovascular diseases. Magnified benefits of high‐intensity statins compared with low‐ to moderate‐intensity statins were observed in patients who underwent revascularization therapy and those under 75 years of age.ConclusionsStatins, particularly high‐intensity statins, could reduce the risk for NACCE in patients with acute ischemic stroke and atrial fibrillation; this needs to be further explored in randomized controlled trials.

Statin Naïve Patients with Myocardial Infarction have more Echolucent Plaques Compared to Long-term Statin Treated Chronic Atherosclerotic Patients – A 3D Ultrasound Study

Introduction: Size and morphology of carotid atherosclerotic plaques can be quantified by ultrasound (US) imaging. Carotid artery plaque size and gray-scale median (GSM) have been identified as risk markers for both cardiovascular events and stroke ADDIN EN.CITE ADDIN EN.CITE.DATA (1, 2). Unstable plaques have a thin fibrotic cap and a lipid or hemorrhagic core ADDIN EN.CITE ADDIN EN.CITE.DATA (3-6). A higher amount of lipid and hemorrhage have been observed in echolucent carotid plaques presenting as lower GSM compared to echogenic carotid plaques containing fibrotic tissue and calcification ADDIN EN.CITE ADDIN EN.CITE.DATA (7-10). Classic cardiovascular risk scores such as Framingham score lack precision ADDIN EN.CITE ADDIN EN.CITE.DATA (11, 12). Information about atherosclerotic plaque characteristics and development can potentially improve risk stratification. Methods: : Two patient populations were included prospectively; a group admitted with first-time myocardial infraction and naive to statin treatment and a group followed for peripheral arterial disease on stable statin treatment for more than six months, all being ≤65 years old. Both carotid arteries were scanned with 3D ultrasound by the same sonographer. All plaques were analyzed using a semiautomated software. Gray-scale readings were normalized with adventitia as reference and GSM recorded. In patients with bilateral carotid artery plaques the thickest plaque was used for data analyses. Results: In the statin treated patients (n=70 , 64% male, mean age 60 (range 40-65)) compared to the statin naive patients (n= 70, 79% male, mean age 57 (range 38-65)) we found an increased plaque thickness (difference 0.65 mm, P=0.001), a larger plaque volume (difference 31.98 mm3, P=0.001) as well as a higher GSM (difference 9.46, 95% confidence interval: 1.59 - 17.33, P=0.019) (figure 1). The differences in thickness and volume disappeared after adjustment for age, gender, smoking, hypertension and diabetes mellitus (P= 0.066 and 0.050, respectively). The differences in GSM persisted after adjusting for volume (difference of 9.05, CI95%: 0.90 - 17.21, P=0.030). There was no correlation between volume and GSM (P=0.16). Conclusion: .By 3D US we detected differences in carotid plaque thickness, volume and morphology between two different atherosclerotic populations. The statin treated group with known clinical atherosclerotic disease, had larger plaques indicating a more advanced stage of disease as the difference diminished when adjusting for atherosclerotic risk factors. Also, this group had more echogenic plaques (higher GSM) which indicate less vulnerability, or a more stable stage of disease as compared to the statin naive group. Carotid 3D US imaging may prove clinically useful for identification and assessment of treatment response in high-risk patients with vulnerable plaques Disclosure: Co-author H. Sillesen has received research grants from Philips Ultrasound.

Potential Statin Overuse in Older Patients: A Retrospective Cross-Sectional Study Using French Health Insurance Databases.

Although compelling evidence exists supporting statins (HMG-CoA reductase inhibitors) for secondary prevention in older patients with clinical atherosclerotic diseases, the same cannot be said for primary prevention. The objectives of this study were to estimate the frequency of potential statin overuse in older patients, the potential drug cost savings if corrected, and the associated factors. A retrospective cross-sectional study was conducted in Alsace and Lorraine (France) from 1 January to 30 April 2017. All statin users aged 80years or over living in the community (including nursing homes) and identified from the French health insurance database were analyzed. Potential statin overuse was defined according to the STOPP/START (Screening Tool of Older People's Prescriptions/Screening Tool to Alert to Right Treatment) criteria. Among the 38,268 aged insured, 23,228 (60.7%) had potential statin overuse. Of those living in the community, 22,132 (60.0%) patients had potential statin overuse: 12,352 (55.8%) for primary and 9780 (44.2%) for secondary prevention. Among nursing home residents, 1096 (79.0%) had potential statin overuse: 394 (35.9%) for primary and 702 (64.1%) for secondary prevention. The potential drug cost savings associated with the adjustment of potential statin overuse were €924,100 for the study period. Living in nursing home [adjusted odds ratio (ORadjusted) 3.91, 95% confidence interval (CI) 2.82-5.41] and being a female (ORadjusted 2.84, 95% CI 2.54-3.17) were the main risk factors associated with potential statin overuse. The frequency of potential statin overuse is very high among older people aged 80years or over, highlighting the need to re-evaluate statin therapy and consider deprescribing, particularly for primary prevention and in nursing homes.

2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines.

2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines.

A3153 Metabolic risk factors in patients with arterial hypertension

Objectives: The objectives of this study were to identify and compare the prevalence of metabolic risk factors among hypertensive individuals and people with normal blood pressure measurements. Methods: The present work was a hospital based, analytical cross sectional study conducted over the period of one year from November 2016 to December 2017. The study included 217 hypertensive patients and 184 non-hypertensive subjects aged 35–70 years, who were free of clinical atherosclerotic cardiovascular diseases. Arterial hypertension is defined as blood pressure of ≥140/90 mm Hg or more. International Diabetes Federation criteria were used for diagnosis of metabolic syndrome. The data referring to the clinical and biochemical profiles were processed using the SPSS software to obtain absolute frequencies and percentages. The Student's t-test was used to compare the means, with values of p < 0.05 considered statistically significant. Results: The study sample consisted of 159 men (39.6%) and 241 women (60.4%). The mean age of participants was 47.2 ± 12.1 years. It was found that 54.4% (118) of the individuals with hypertension had metabolic syndrome, versus 21.4% (18) of those with normal blood pressure levels. Individuals with hypertension showed a significant difference in blood pressure levels (p < 0.001), abdominal circumference (p < 0.001), and plasma triglycerides (p < 0.001). Conclusion: Metabolic syndrome was more common in patients with arterial hypertension than for those in subjects without hypertension. Statistically significant difference was observed in abdominal obesity and serum triglyceride level between hypertensive patients and non-hypertensive subjects. The frequency of metabolic risks associated with metabolic syndrome is greater when hypertension is present.

New Possibilities of Antithrombotic Therapy of Patients with Peripheral and Widespread Atherosclerotic Lesion

Atherosclerotic peripheral artery disease (PAD) is well-known thrombotic risk factor in different cohorts of patients. This current review analyzes epidemiological data of trials and registries about influence both clinical and asymptomatic peripheral atherosclerotic disease on adverse ischemic events. Individual assessment of the atherothrombotic prevalence, which is directly related to vascular thrombotic risk, remains an important problem. Issue of PAD routine screening using traditional methods of ultrasound duplex scanning, measurement of ankle-brachial index is discussed in details. Comparative efficiency of present antiplatelet and anticoagulant drugs is shown in the key of preventing PAD thrombotic complications. PAD detection can be the reason for intensification of antithrombotic treatment, the only one option of which until recently was an additional treatment with P2Y12 platelet receptors blockers. However, the routine treatment with dual antiplatelet therapy in stable manifestations of atherothrombosis is not supported by the current guidelines. In this regard, it seems relevant to intensify therapy by simultaneously affecting on the platelet and plasma components of hemostasis in patients with PAD, that was demonstrated in a recently published study COMPASS. Treatment with rivaroxaban small doses in addition to acetylsalicylic acid allowed to improve significantly outcomes in a wide range of patients with stable manifestations of atherothrombosis without high risk of bleeding and severe renal impairment. However, use of this multicomponent therapy has not been approved by relevant clinical recommendations yet, which causes certain difficulties in choosing optimal scheme of antithrombotic treatment among patients with PAD.