The Prothrombotic Predominance in Metabolic Syndrome: A Complex Pathomechanism

Patients with metabolic syndrome (MS) have many cardiovascular complications related to atherothrombotic complications. MS contributes premature atherosclerosis, increases platelet activation, promotes coagulation factors, and reduces fibrinolytic activity. The last step in the atherothrombotic cascade is blood clot formation, and altered clot structure is a key role to determine cardiovascular complications. The MS, caused in part by an excess of atherosclerosis and in part by fibrinolytic dysfunction, is profoundly related to an excess of CVD. These combinations of factors involved in MS parameters contribute the increased propensity of people with MS to develop atherothrombosis and fibrinolysis. Awareness and preventive measures are important to improve outcomes in patients with MS.

Premature atherosclerosis and acute coronary syndrome in a child with end-stage renal disease

Background Although acute coronary syndrome is rare in children, it is the most important cause of mortality in children with end-stage renal disease. Case presentation Here, a 16-year-old pediatric patient, who has been on dialysis since the age of 3, and who was diagnosed with acute coronary syndrome and placed an emergency percutaneous transcatheter stent in the left anterior descending branch of the left coronary artery is presented. It is important that the present patient does not have any electrocardiography findings in favor of cardiovascular disease and that he cannot fully explain the complaint of chest pain due to his mental retardation. Conclusions Early detection of acute coronary syndrome is life-saving, especially in children with chronic kidney disease.

Premature atherosclerotic cardiovascular disease: association of clinical factors with form of atherosclerosis onset

Background The cardiovascular death rate significantly declined last decades. But premature atherosclerosis burden remains an unresolved problem. Purpose The study aimed to assess the association of clinical factors with types of premature atherosclerosis onset. Methods Date of 702 patients (pts) (523 men and 179 women) with premature atherosclerosis (men ≤55 (48.6±6.2), women ≤60 (52.7±7.0) years of age) were analyzed with decision tree method using SPSS 23.0 program with the Python GUI module. Clinical and instrumental variables (n=109) were used. The test sample was formed by the cross-validation method. Results Myocardial infarction at the onset of atherosclerosis (n=542, 77.2%) was associated with the presence of peripheral atherosclerosis (1st order node, p<0.0001, F=93.174). The 2nd order node was a uric acid level (p<0.0001, F=26.493) in pts without peripheral atherosclerosis. In pts with uric acid level, less than 225 mmol/L-the left ventricle posterior wall thickness more than 10 mm was a 3d order node (p<0.0001, F=30.143). Area under the ROC-curve 0.916, p=0.011. Multivessel lesion according to coronary angiography data (102 patients) was associated with family history of cardiovascular disease (p=0.001, F=13.238), the area under the ROC-curve was 0.667, p=0.041. For pts. with peripheral atherosclerosis (n=66, 9,4%) the aortic root diameter obtained by an echo was the 1st order node (p<0.0001, F=36.057). In pts with aortic root diameter over 27 mm, a 2nd order node was creatinine level above 90 mmol/L (p=0.036, F=9.945) and in pts with a smaller diameter of aortic root was the history of hypertension emergency (p=0.001, F=13.897). Area under the ROC-curve 0.676, p=0.02. For pts. with ischemic stroke (n=26, 3,7%) as atherosclerosis onset 1st order node was brachiocephalic atherosclerosis lesion (p<0.0001, F=30.259). Among them, untarget BP level was 2nd order node (p=0.033, F=4.958). For pts without atherosclerosis age over 46.7 yrs was a 2nd order node (p<0.0001, F=24.515), and for pts younger than 46.7 yrs admission glucose higher than 11.06 mmol/L was a 3rd order node (p=0.026, F=12.382). This model had high predictive accuracy (area under the ROC-curve 0.963, p<0.0001). Conclusion Thus multiple clinical variants of premature atherosclerotic cardiovascular disease onset appeal to develop an individualized approach to early diagnosis and management of this kind of patient. FUNDunding Acknowledgement Type of funding sources: None.

Variable Changes of Circulating ANGPTL3 and ANGPTL4 in Different Obese Phenotypes: Relationship with Vasodilator Dysfunction

Obesity associates with premature atherosclerosis and an increased burden of cardiovascular disease, especially when accompanied by abnormalities of lipid and glucose metabolism. Angiopoietin-like (ANGPTL)3 and ANGPTL4 are metabolic regulators, whose upregulation is associated with dyslipidemia, insulin resistance and atherosclerosis. We analyzed, therefore, changes in circulating ANGPTL3 and ANGPTL4 in obese patients with different metabolic phenotypes and their relation with impaired vasodilator reactivity, an early abnormality in atherosclerosis. Compared to the lean subjects (n = 42), circulating ANGPTL3 was elevated (both p > 0.001) in the patients with metabolically unhealthy obesity (MUO; n = 87) and type 2 diabetes (T2D; n = 31), but not in those with metabolically healthy obesity (MHO; n = 48, p > 0.05). Circulating ANGPTL4, by contrast, was increased in all obese subgroups (all p < 0.001 vs. lean subjects). Vasodilator responses to both acetylcholine and sodium nitroprusside were reduced in the three obese subgroups vs. lean subjects (all p < 0.001), with greater impairment in the patients with T2D than in those with MHO and MUO (all p < 0.05). In the whole population, an inverse relationship (r = 0.27; p = 0.003) was observed between circulating ANGPTL4 and endothelium-dependent vasorelaxation. Circulating ANGPTL3 and ANGPTL4 undergo variable changes in obese patients with different metabolic phenotypes; changes in ANGPTL4 relate to endothelial dysfunction, making this protein a possible target for vascular prevention in these patients.

Abstract P175: Predicting Healthy Arterial Aging Versus Premature Atherosclerosis In Young Adults: The Bogalusa Heart Study

Introduction: Early differentiation of healthy arterial aging versus premature atherosclerosis is important for optimal atherosclerotic cardiovascular disease (ASCVD) risk stratification and prevention. We sought to identify predictors for the long-term absence of carotid plaque in young adults. Hypothesis: Calcium and phosphate are found in excess in atherosclerotic lesions, therefore we hypothesized that mineral markers may help to explain residual heterogeneity in arterial aging phenotypes beyond traditional ASCVD risk factors. Methods: We included 508 participants from the Bogalusa Heart Study without clinical ASCVD who were free of carotid plaque at baseline (2001-02) and underwent ultrasound at follow-up (2013-16). Modified Poisson regression estimated the persistent absence of carotid plaque over 12.8 years. Results: Participants were on average 36.2 years old at baseline, 64% were women, and 29% were African American. Although a majority (97%) of participants had a 10-year ASCVD risk <7.5%, only 68% remained free of plaque ( Figure ). Beyond younger age (RR=1.20, 95% CI: 1.07-1.36, per 10 years) and a total cholesterol-HDL-cholesterol ratio <3.5 (RR=1.15, 95% CI: 1.01-1.30), normal values of traditional risk factors did not predict long-term absence of plaque. Independent from traditional markers, including glomerular filtration rate, serum calcium-phosphate product (RR=1.08, 95% CI: 1.01-1.14, per 1-SD lower), phosphate (RR=1.15, 95% CI: 1.03-1.29, per 1 mg/dL lower), and dietary sodium <2300 mg/day (RR=1.20, 95% CI: 1.03-1.41) significantly associated with non-development of plaque. Conclusions: Lower calcium-phosphate homeostasis and low sodium intake independently associated with long-term absence of carotid plaque. However, nearly one-third of young adults with a relatively low burden of traditional risk factors developed premature atherosclerosis. These results suggest that dietary and intrinsic minerals are early contributors to the development of arterial aging phenotypes.

Mitochondrial protein CMPK2 regulates IFN alpha-enhanced foam cell formation, potentially contributing to premature atherosclerosis in SLE

Background Premature atherosclerosis occurs in patients with SLE; however, the mechanisms remain unclear. Both mitochondrial machinery and proinflammatory cytokine interferon alpha (IFN-α) potentially contribute to atherogenic processes in SLE. Here, we explore the roles of the mitochondrial protein cytidine/uridine monophosphate kinase 2 (CMPK2) in IFN-α-mediated pro-atherogenic events. Methods Foam cell measurements were performed by oil red O staining, Dil-oxLDL uptake and the BODIPY approach. The mRNA and protein levels were measured by qPCR and Western blotting, respectively. Isolation of CD4+ T cells and monocytes was performed with monoclonal antibodies conjugated with microbeads. Manipulation of protein expression was conducted by either small interference RNA (siRNA) knockdown or CRISPR/Cas9 knockout. The expression of mitochondrial reactive oxygen species (mtROS) was determined by flow cytometry and confocal microscopy. Results IFN-α enhanced oxLDL-induced foam cell formation and Dil-oxLDL uptake by macrophages. In addition to IFN-α, several triggers of atherosclerosis, including thrombin and IFN-γ, can induce CMPK2 expression, which was elevated in CD4+ T cells and CD14+ monocytes isolated from SLE patients compared to those isolated from controls. The analysis of cellular subfractions revealed that CMPK2 was present in both mitochondrial and cytosolic fractions. IFN-α-induced CMPK2 expression was inhibited by Janus kinase (JAK)1/2 and tyrosine kinase 2 (Tyk2) inhibitors. Both the knockdown and knockout of CMPK2 attenuated IFN-α-mediated foam cell formation, which involved the reduction of scavenger receptor class A (SR-A) expression. CMPK2 also regulated IFN-α-enhanced mtROS production and inflammasome activation. Conclusions The study suggests that CMPK2 plays contributing roles in the pro-atherogenic effects of IFN-α.

Wnt signaling enhances macrophage responses to IL-4 and promotes resolution of atherosclerosis

Atherosclerosis is a disease of chronic inflammation. We investigated the roles of the cytokines IL-4 and IL-13, the classical activators of STAT6, in the resolution of atherosclerosis inflammation. Using Il4-/-Il13-/- mice, resolution was impaired, and in control mice, in both progressing and resolving plaques, levels of IL-4 were stably low, and IL-13 was undetectable. This suggested that IL-4 is required for atherosclerosis resolution, but collaborates with other factors. We had observed increased Wnt signaling in macrophages in resolving plaques, and human genetic data from others showed that a loss-of-function Wnt mutation was associated with premature atherosclerosis. We now find an inverse association between activation of Wnt signaling and disease severity in mice and humans. Wnt enhanced the expression of inflammation resolving factors after treatment with plaque-relevant low concentrations of IL-4. Mechanistically, activation of the Wnt pathway following lipid lowering potentiates IL-4 responsiveness in macrophages via a PGE2/STAT3 axis.