Exploring biomarkers associated with deteriorating vascular health using a targeted proteomics chip: The SABPA study.

ABSTRACT: In this observational study, by the use of a multiplex proteomic platform, we aimed to explore associations between 92 targeted proteins involved in cardiovascular disease and/or inflammation, and phenotypes of deteriorating vascular health, with regards to ethnicity.Proteomic profiling (92 proteins) was carried out in 362 participants from the Sympathetic activity and Ambulatory Blood Pressure in Africans (SABPA) study of black and white African school teachers (mean age 44.7 ±â€Š9.9 years, 51.9% women, 44.5% Black Africans, 9.9% with known cardiovascular disease). Three proteins with <15% of samples below detectable limits were excluded from analyses. Associations between multiple proteins and prevalence of hypertension as well as vascular health [Carotid intima-media thickness (cIMT) and pulse wave velocity (PWV)] measures were explored using Bonferroni-corrected regression models.Bonferroni-corrected significant associations between 89 proteins and vascular health markers were further adjusted for clinically relevant co-variates. Hypertension was associated with growth differentiation factor 15 (GDF-15) and C-X-C motif chemokine 16 (CXCL16). cIMT was associated with carboxypeptidase A1 (CPA1), C-C motif chemokine 15 (CCL15), chitinase-3-like protein 1 (CHI3L1), scavenger receptor cysteine-rich type 1 protein M130 (CD163) and osteoprotegerin, whereas PWV was associated with GDF15, E-selectin, CPA1, fatty acid-binding protein 4 (FABP4), CXCL16, carboxypeptidase B (CPB1), and tissue-type plasminogen activator. Upon entering ethnicity into the models, the associations between PWV and CPA1, CPB1, GDF-15, FABP4, CXCL16, and between cIMT and CCL-15, remained significant.Using a multiplex proteomic approach, we linked phenotypes of vascular health with several proteins. Novel associations were found between hypertension, PWV or cIMT and proteins linked to inflammatory response, chemotaxis, coagulation or proteolysis. Further, we could reveal whether the associations were ethnicity-dependent or not.

Association Between Systemic Inflammation, Carotid Arteriosclerosis, and Autonomic Dysfunction.

Systemic inflammation is associated with arteriosclerotic disease progression and worse stroke outcome in patients with carotid arteriosclerotic disease. We hypothesize that systemic inflammation is mediated by impaired carotid baroreceptor and chemoreceptor function induced by carotid arteriosclerosis rather than by the generalized inflammatory arteriosclerotic process.Heart rate variability (HRV), serum levels of inflammatory markers, demographic and life style factors, and concomitant diseases with potential impact on systemic inflammation were determined in 105 patients with asymptomatic carotid stenosis of varying degree. Multivariate linear regression analyses were performed to ascertain independent determinants of carotid stenosis severity, autonomic function, and inflammation.Systemic inflammation (C-reactive protein, beta = .255; P = .014), age (beta = .232; P < .008), and arterial hypertension (beta = .206; P = .032) were associated with carotid stenosis severity. Only carotid stenosis severity and not generalized arteriosclerotic disease, concomitant diseases (arterial hypertension, diabetes mellitus, dyslipidemia, hypothyroidism), life style factors (smoking, obesity), or age was associated with a reduction in vagal tone (HRV HF band power beta = - .193; P < 0.049). Systemic inflammation was related to a reduction in vagal tone (HRV HF band power, beta = - .214; P = .031), and not to generalized arteriosclerotic disease, concomitant diseases (arterial hypertension, diabetes mellitus, dyslipidemia), life style factors (smoking, obesity), and age.In conclusion, systemic inflammation is associated with carotid rather than with generalized arteriosclerotic disease. The association between systemic inflammation and carotid arteriosclerosis is mediated by a reduction in vagal tone which indicates a major role of carotid arteriosclerosis-mediated autonomic dysfunction in the pathogenesis of systemic inflammation in arteriosclerotic disease.

Apolipoprotein E polymorphisms contribute to statin response in Chinese ASCVD patients with dyslipidemia.

BACKGROUND: Apolipoprotein E (ApoE) plays an important role in lipid metabolism and clearance. Statins are the most common drugs used to modulate the lipid profile in the clinic therapy; the associations between ApoE polymorphisms and statin response to lipids were inconsistent in previous studies among different ethnicities. Our study aimed to demonstrate the relationships among the statins response and the ApoE gene common polymorphisms and lifestyle risk factors in Chinese arteriosclerotic cardiovascular disease (ASCVD) patients with dyslipidemia. METHODS: A total of 1002 dyslipidemia ASCVD patients were recruited in this study, including 311 patients with a history of type 2 diabetes mellitus (T2DM). These patients were all treated with drugs atorvastatin (10 mg/d) or rosuvastatin (5 mg/d) for at least 4 weeks and genotyped for ApoE e2/e3/e4 alleles, using Kompetitive Allele Specific PCR (KASP) and Sanger sequencing. The plasma lipids levels were determined before and after statins treatment. RESULTS: The results of ApoE genotyping with KASP method were consistent with the sequencing analysis. In the total 1002 patients, the E2 phenotypes (e2/e3, e2/e2) had significant lower low-density lipoprotein cholesterol (LDL-C) baseline levels than subjects with E3 (e3/e3, e2/e4) and E4 (e3/e4, e4/e4) phenotypes (P = 0.007, 0.005, respectively), and E2 phenotypes had the highest triglyceride (TG) baseline levels. To statins treatment, E2 phenotypes had a better response in TG, Total cholesterol (TC) and LDL-C reduction percentage compared with other phenotypes, and smoking/alcohol drinking status also had a significant influence on statins response of LDL-C lowering. No significant difference was found in the effects of lipids decreasing between atorvastatin and rosuvastatin drugs in all patients. CONCLUSIONS: We developed the KASP technique for the ApoE genotyping, and demonstrated ApoE polymorphisms interacted with smoking/drinking to influence the declining extent of TG, TC and LDL-C levels after statins therapy in Chinese dyslipidemia ASCVD patients. These discoveries developed our cognition with the genetic polymorphisms effects on statin response, which should be taken more seriously in smoking/drinking E4 amino acid isoform carriers.

Increased ApoB/ApoA1 ratio is associated with excess weight, body adiposity, and altered lipid profile in children / A razão ApoB/ApoA1 aumentada está associada ao excesso de peso, de adiposidade corporal e ao perfil lipídico alterado em crianças

Abstract Objective: To investigate ApoB/ApoA1 ratio and its association with cardiovascular risk factors in children. Methods: Cross-sectional study with 258 children aged 8 and 9 years old, enrolled in all urban schools in the city of Viçosa-MG. Anthropometric and body composition assessment, as well as biochemical profile of the children was performed. Socioeconomic variables and sedentary lifestyle were evaluated through a semi-structured questionnaire. Results: Many children had excess weight (35.2%), abdominal adiposity (10.5%), and body fat (15.6%), as well as increased ApoB/ApoA1 ratio (14.7%), total cholesterol (51.8%), and triglycerides (19.8%). Children with excess weight and total and central fat had a higher prevalence of having a higher ApoB/ApoA1 ratio, as well as those with atherogenic lipid profile (increased LDL-c and triglycerides and low HDL-c). A direct association was found between the number of cardiovascular risk factors and the ApoB/ApoA1 ratio (p = 0.001), regardless of age and income. Conclusion: The increased ApoB/ApoA1 ratio was associated with excess weight, body adiposity (total and central), and altered lipid profile in children. Children with a higher number of cardiovascular risk factors had higher ApoB/ApoA1 ratio, in both genders.

Resumo Objetivo: Investigar a razão ApoB/ApoA1 e sua relação com fatores de risco cardiovascular em crianças. Métodos: Estudo transversal com 258 crianças de 8 e 9 anos, matriculadas em todas as escolas urbanas de Viçosa-MG. Foi feita avaliação antropométrica, da composição corporal e bioquímica das crianças. As variáveis socioeconômicas e o sedentarismo foram avaliados por questionário semiestruturado. Resultados: Muitas crianças apresentaram excesso de peso (35,2%), de adiposidade abdominal (10,5%) e de gordura corporal (15,6%), bem como a razão ApoB/ApoA1 (14,7%), colesterol-total (51,8%) e triglicerídeos (19,8%) aumentados. Crianças com excesso de peso e de gordura total e central apresentaram maiores prevalências de maior razão ApoB/ApoA1, bem como as com perfil lipídico aterogênico (LDL-c e triglicerídeos aumentados e baixo HDL-c). Foi encontrada associação direta entre o número de fatores de risco cardiovascular e a razão ApoB/ApoA1 (p = 0,001), independente da idade e renda. Conclusão: A razão ApoB/ApoA1 aumentada esteve associada ao excesso de peso, de adiposidade corporal (total e central) e ao perfil lipídico alterado nas crianças. As crianças com maior número de fatores de risco cardiovascular apresentaram maior razão ApoB/ApoA1, em ambos os sexos.

Correlations Between Serum Cholesterol and Vascular Lesions in Fabry Disease Patients.

BACKGROUND: Fabry disease is an X-linked lysosomal storage disorder and shows globotriosylceramide (Gb3) accumulation in multiple organs, resulting from a deficiency of α-galactosidase. In patients with Fabry disease, cardiovascular disease occurs at an early age. Previous studies have shown that serum levels of high-density lipoprotein-cholesterol (HDL-C) increase in this disease, yet its clinical significance for cardiovascular disease remains unclear. Methods and Results: In order to determine why the serum HDL-cholesterol is high in various cardiovascular diseases of Fabry disease patients, we evaluated the serum lipid profiles, ocular vascular lesions, and levels of serum vascular endothelial growth factor (VEGF) and intercellular adhesion molecule-1 in 69 patients with Fabry disease diagnosed by genetic examination. The serum HDL-C/total cholesterol (T-Chol) ratio was significantly high, especially in male patients (41.5±1.7%) regardless of body mass index. Ocular vascular lesions were more likely to occur in female patients with a high HDL-C/T-Chol ratio compared with most male patients. Female patients with a high HDL-C/T-Chol ratio also presented a high serum VEGF level, suggesting that vascular endothelium dysfunction and arteriosclerotic changes progress more severely than in patients with a normal HDL-C/T-Chol ratio. In most patients, enzyme replacement therapy improved serum Gb3 and lyso-Gb3 levels, but these Gb3 and lyso-Gb3 still remained higher than in healthy controls, which appears to result in continuous vascular arteriosclerotic changes. CONCLUSIONS: We concluded that increased low-density lipoprotein-cholesterol uptake to the vascular wall caused by endothelial dysfunction is likely to contribute to the high HDL-C/T-Chol ratio observed in Fabry disease patients.

Correlation between serum low-density lipoprotein cholesterol concentration and arterial wall stiffness.

BACKGROUND: Elevated serum low-density lipoprotein cholesterol (LDL-C) concentration is a risk factor for atherosclerosis, which involves remodelling of the arterial walls with their subsequent stiffening. AIM: We sought to evaluate the relationship between serum lipid levels and the elastic properties of the arterial wall. METHODS: The study group comprised 315 men and women aged 55.84 ± 9.44 years. Serum glucose and lipid concentrations were determited. All subjects underwent blood pressure (BP) measurement, transthoracic echocardiography, and assessment of vascular compliance of large (C1) and small arteries (C2) using the HDI/Pulse Wave™ CR-2000 Research CardioVascular Profiling System (Hypertension Diagnostics Inc., Eagan, MN, USA). The subjects were divided into three groups: group I - LDL-C < 2.6 mmol/L, group II - LDL-C ≥ 2.6 mmol/L and < 4.0 mmol/L, and group III - LDL-C ≥ 4.0 mmol/L. RESULTS: There were no intergroup differences with regard to smoking status (p = 0.56), serum glucose concentration (p = 0.13), body mass index (p = 0.96), systolic (p = 0.17) and diastolic BP (p = 0.29), or C1 (p = 0.09). However, C2 was higher in groups I and II than in group III (5.12 ± 2.57 vs. 5.18 ± 2.75 vs. 4.20 ± 1.58 mL/mmHg × 100, respectively, p < 0.01). Multivariate regression analysis negated the independent associations between C1 and serum lipid levels. In contrast, C2 was independently inversely associated with serum LDL-C concentration (r = -0.15, p < 0.01). CONCLUSIONS: Higher serum LDL-C concentration seems to contribute independently to stiffening of small arterial vasculature in otherwise healthy adults. Screening for dyslipidaemia in the general population and its prompt treatment are highly recom-mended.

Association between serum uric acid level and renal arteriolar hyalinization in individuals without chronic kidney disease.

BACKGROUND AND AIMS: Recent studies have reported an association between serum uric acid (SUA) and renal arteriolar changes in patients with chronic kidney disease (CKD). However, the association in individuals without CKD remains unclear. In this study, we investigated the relationship between SUA and renal arteriolar lesions in individuals without CKD from our living kidney donor cohort. METHODS: Between January 2006 and May 2016, 393 living kidney donors underwent "time-zero" biopsy at Kyushu University Hospital. Patients were divided into sex-specific quartiles of SUA before donation: Q1, Q2, Q3, and Q4 (male: <5.2,5.2-5.8,5.9-6.4, and ≥6.5 mg/dL, female: <3.8,3.8-4.3,4.4-5.0, and ≥5.1 mg/dL). Renal arteriolar hyalinization and wall thickening were assessed using a semiquantitative grading system. Predictive performance was compared between models with and without SUA by calculating the net reclassification improvement (NRI). RESULTS: In total, 158 (40.2%) patients had arteriolar hyalinization, and 148 (37.6%) had wall thickening. High SUA was significantly associated with arteriolar hyalinization in multivariable logistic analysis (odds ratio [OR] per 1-mg/dL increase in SUA, 1.24; 95% confidence interval [CI], 1.00-1.53; p = 0.048. OR for Q4 vs. Q2, 2.22; 95% CI, 1.17-4.21; p = 0.01). We found no association between SUA and wall thickening. When SUA was incorporated into a predictive model with conventional atherosclerotic factors, the NRI was 0.21 (p = 0.04). CONCLUSIONS: High SUA was an independent risk factor for arteriolar hyalinization in individuals without CKD. SUA provided additional predictive value beyond conventional atherosclerotic factors in predicting arteriolar hyalinization.

Proteomic analysis and comparison of intra­ and extracranial cerebral atherosclerosis responses to hyperlipidemia in rabbits.

The present study aimed to investigate protein expression levels of intra­ and extracranial atherosclerosis in rabbits following administration of a high­fat diet. Rabbits were randomly divided into control (group A; n=9) and high­fat diet (group B; n=9) groups. At week 12, tissues were sectioned from the common carotid artery (CCA) and middle cerebral artery (MCA). Pathological analysis was performed. Differential protein expression levels were examined by 2­D gel electrophoresis (2­DE) and mass spectrometry (MS) analysis and validated by western blotting. Serum lipid levels, the intima­media thickness (IMT) and degree of atherosclerosis of the CCA and MCA were increased at week 12 in the high­fat diet group compared with rabbits that received a normal diet. 2­DE and MS analysis of the protein extracted from CCA and MCA detected >439 different proteins; the expression of 25 proteins was altered, and 8 proteins [albumin A chain, tropomyosin α­1 chain (TPM1), heat shock protein 70 (HSP70), α­smooth muscle actin, ß­galactose binding agglutinin, TPM4 isoform 2, cell keratin 9, single octylic acid glyceride ß­2) demonstrated significant alterations in expression levels. Due to limited antibody sources, only three differentially expressed proteins (TPM1, HSP70 and α­smooth muscle actin) were examined by western blotting. The results of our previous study demonstrated that hyperlipidemia affected the IMT of intracranial and extracranial cerebral arteries. In the present study, protein expression levels of TPM1 and α­smooth muscle actin from extracranial cerebral arteries were significantly increased compared with intracranial cerebral arteries; however, protein expression levels of HSP70 from intracranial cerebral arteries was increased compared with extracranial cerebral arteries. The differences may be closely associated with cell proliferation and metastasis, and oxidoreduction, in intra­ and extracranial cerebral atherosclerosis. HSP70 may have protective properties against atherosclerosis via underlying anti­inflammatory mechanisms, furthermore, differential protein expression levels (TPM1, HSP70 and α­smooth muscle actin) between intra­ and extracranial cerebral arteries may facilitate the identification of novel biological markers for the diagnosis and treatment of cerebral arteriosclerosis.

Anthocyanin Rich-Black Soybean Testa Improved Visceral Fat and Plasma Lipid Profiles in Overweight/Obese Korean Adults: A Randomized Controlled Trial.

Anthocyanin-rich black soybeans have been used in traditional East Asian medicine to cure diseases related to oxidative stress and carcinogens, but not obesity. Our objective was to investigate the effects of anthocyanin-rich black soybean testa extracts (BBT), Glycine max (Chongja No. 3), on obesity. In total, 63 participants defined as overweight or obese by their body mass index (BMI >23) or waist circumference (WC >90 cm for males, >85 cm for females) were sorted into two groups: 32 receiving the trial medication (BBT, 2.5 g/d) and 31 receiving the placebo (starch, 2.5 g/d). Participants completed an 8-week, randomized, double-blinded, and placebo-controlled clinical trial. There were no significant differences between the two groups at the beginning of the trial, and both required the same safety assessments. Significant decreases in abdominal fat, described according to WC and hip circumference, and lipid profiles such as triacylglycerols (TG), low density lipoprotein cholesterol (LDLc), and non-high density lipoprotein cholesterol (non-HDLc) were observed in the BBT group at the conclusion of the clinical trial. The indicators for arteriosclerosis such as total cholesterol (TC)/HDLc and LDLc/HDLc were significantly decreased in the BBT group, but had not changed in the placebo group. With no difference between the two groups in energy-adjusted dietary intakes and physical activity, BBT was shown to strongly improve plasma lipid profiles, related to the reduction of WC (an indicator of abdominal fat) as long as high dietary fiber and low cholesterol diets were maintained. In conclusion, BBT can potentially be developed as a functional food for preventing abdominal obesity with high fiber and low cholesterol diets.

Advice on lifestyle changes (diet, red wine and physical activity) does not affect internal carotid and middle cerebral artery blood flow velocity in patients with carotid arteriosclerosis in a randomized controlled trial.

BACKGROUND: A Mediterranean diet, with and without small daily amounts of red wine, and physical activity reduce the risk of cerebrovascular disease and improve cognition. An increase in cerebral blood flow may be the underlying mechanism. Under normal conditions, cerebral blood flow velocity changes in the internal carotid arteries and in large basal cerebral arteries correlate closely with cerebral blood flow changes, as the diameter of these vessels hardly changes and only the smaller vessels downstream change their diameter. METHODS: A prospective randomized controlled trial was performed in 108 patients with carotid atherosclerosis (mean age 64 years, 67% men, 66% on statin therapy). Half of them were advised to follow a polyphenol-rich modified Mediterranean diet including 1-2 tomatoes, 3-5 walnuts and a bar of dark chocolate (25 g) a day and to perform moderate physical exercise for 30 min/day (lifestyle changes). Within these two groups, half of the patients were randomized either to avoid any alcohol or to drink 100 ml of red wine (women) or 200 ml of red wine (men) daily. Bilateral middle cerebral and internal carotid blood flow velocity (peak systolic, peak end-diastolic and mean) was measured at baseline and after 4 and 20 weeks using colour-coded duplex ultrasound. Insonation depth and insonation angle were used to identically place the sample volume during follow-up investigations. A general linear model with Tukey-Kramer adjustment for multiple comparisons was used to assess the primary end points. For the analysis we used the mean values of the right and left artery. RESULTS: Neither lifestyle changes nor red wine had an effect on peak systolic, peak end-diastolic or mean cerebral blood flow velocity. CONCLUSIONS: Advice on lifestyle changes, including a modified polyphenol-rich Mediterranean diet, a glass of red wine daily and physical exercise, did not affect middle cerebral and internal carotid blood flow velocity in our patient group with carotid atherosclerosis. An increase in cerebral blood flow is thus unlikely to be the cause of the reduced risk of cerebrovascular disease and improved cognitive functioning described in the literature. One possible explanation for the fact that blood flow velocity was not affected by red wine, diet and physical activity advice is that two thirds of our patients were already on statin therapy. Statins increase cerebral blood flow and vasomotor reactivity via nitric oxide.

A study on the effect of resveratrol on lipid metabolism in hyperlipidemic mice.

BACKGROUND: The content of resveratrol is relatively high in Polygonum cuspidatum Sieb. et Zucc., and the resveratrol has the effect of blood vessel dilating, microcirculation improving, platelet aggregation inhibiting and anti-cancer. The objective of this paper was to study the effect of resveratrol on lipid metabolism in hyperlipidemia mice. MATERIALS AND METHODS: Through the establishment of an experimental mouse model of hyperlipidemia, the effect of resveratrol on change in total cholesterol (TC), triglyceride (TG), high density lipoprotein cholesterol (HDL-c), and low-density lipoprotein cholesterol (LDL-c) levels in mouse serum were determined. RESULTS: Resveratrol group can apparently reduce TC, TG, LDL-c and AI of hyperlipidemic mice in a dose effect manner. CONCLUSION: We concluded that resveratrol can effectively reduce blood lipid levels of hyperlipidemic mice.

Serum calcification propensity predicts all-cause mortality in predialysis CKD.

Medial arterial calcification is accelerated in patients with CKD and strongly associated with increased arterial rigidity and cardiovascular mortality. Recently, a novel in vitro blood test that provides an overall measure of calcification propensity by monitoring the maturation time (T50) of calciprotein particles in serum was described. We used this test to measure serum T50 in a prospective cohort of 184 patients with stages 3 and 4 CKD, with a median of 5.3 years of follow-up. At baseline, the major determinants of serum calcification propensity included higher serum phosphate, ionized calcium, increased bone osteoclastic activity, and lower free fetuin-A, plasma pyrophosphate, and albumin concentrations, which accounted for 49% of the variation in this parameter. Increased serum calcification propensity at baseline independently associated with aortic pulse wave velocity in the complete cohort and progressive aortic stiffening over 30 months in a subgroup of 93 patients. After adjustment for demographic, renal, cardiovascular, and biochemical covariates, including serum phosphate, risk of death among patients in the lowest T50 tertile was more than two times the risk among patients in the highest T50 tertile (adjusted hazard ratio, 2.2; 95% confidence interval, 1.1 to 5.4; P=0.04). This effect was lost, however, after additional adjustment for aortic stiffness, suggesting a shared causal pathway. Longitudinally, serum calcification propensity measurements remained temporally stable (intraclass correlation=0.81). These results suggest that serum T50 may be helpful as a biomarker in designing methods to improve defenses against vascular calcification.

A case of cutaneous polyarteritis nodosa with elevated serum interleukin-6 levels complicated by leg arterial stenosis and destructive arthropathy of the left ankle.

We report a case of a 60-year-old female with cutaneous polyarteritis nodosa (CPN) of the left ankle, accompanied by elevated serum interleukin (IL)-6 levels. Computed tomographic angiography revealed severe narrowing of medium-sized arteries in her left leg. Destructive arthropathy in the left ankle was identified by X-ray and magnetic resonance imaging. This is the first Japanese case of severe CPN complicated by destructive arthropathy. Quantification of serum IL-6 might be useful in diagnosis and evaluation of CPN.

A daily glass of red wine associated with lifestyle changes independently improves blood lipids in patients with carotid arteriosclerosis: results from a randomized controlled trial.

BACKGROUND: Physical exercise and a Mediterranean diet improve serum lipid profile. The present work studied whether red wine has an effect on top of a lipid-lowering lifestyle in patients with carotid atherosclerosis. METHODS: A prospective randomised unblinded trial was performed from 2009 to 2011 in 108 patients with carotid atherosclerosis, 65% of whom were already on statin therapy with a low mean LDL of 104.9 mg/dl. Half of them were advised to follow a modified Mediterranean diet and to perform moderate physical exercise during 30 min/day (lifestyle changes) for 20 weeks. Within these two groups half of the patients were randomised either to avoid any alcohol or to drink 100 ml of red wine (women) or 200 ml of red wine (men) daily. RESULTS: LDL was significantly lowered by 7% in the lifestyle-changes group compared to the no-lifestyle-changes group (p = 0.0296) after 20 weeks. Lifestyle changes lowered the LDL/HDL ratio after 20 weeks by 8% (p = 0.0242) and red wine independently by 13% (p = 0.0049). The effect on LDL/HDL ratio after 20 weeks was, however, more pronounced in the non-LC group. Total cholesterol (-6%; p = 0.0238) and triglycerides (-13%; p = 0.0361) were lowered significantly by lifestyle changes after 20 weeks compared to the no-lifestyle-changes group. Lipoprotein (a) was not significantly affected by any intervention. The given results are per ITT analysis. CONCLUSIONS: Lifestyle changes including a modified Mediterranean diet and physical exercise as well as a glass of red wine daily improve independently the LDL/HDL ratio in patients with carotid arteriosclerosis even though the vast majority of them was already on statin therapy.

[Assessment of osteopontin and osteoprotegerin levels in abdominal aortic aneurysm patients]. / Ocena stezenia osteopontyny i osteoprotegryny u chorych z tetniakiem aorty brzusznej.

Abdominal Aortic Aneurysm (AAA) is multifactorial disease with unknown ethiology. Among the theories on the pathogenesis of AAA are some ge. netic factors, infections, disorders in connective tissue (collagenosis), arteriosclerosis, inflammation, incorrect immune response (autoimmunity). It was discovered that crucial for AAA development is intense inflammatory reaction combined with high proteolytic activity. Recent evidence confirmed the association between osteopontin (OPN) and osteoprotegerin (OPG) levels and cardiovascular diseases and arterio. sclerosis. The aim of this work was assessment of plasma levels of OPN and OPG in the group of the patients with AAA and correlation of results with clinical parameters, "classical" risk factors for development of AAA, arteriosclerosis and morbidity. The reference group consist of the patients with Leriche Syndrome (LS). The OPG level was assessed in plasma and OPN levels were assessed in plasma and urine. Plasma OPG levels were higher in AAA group than in LS group (difference not statistically significant, p = 0.0549). It was statistically significant positive correlation between plasma OPN levels and CRP levels in the groups of AAA and LS patients. It was not any association between plasma OPG and OPN levels and abdominal aortic diameter. Plasma OPG levels correlated positively with the existence of coronary artery disease in AAA patients. Insignificant, but higher levels of this protein were found also in a group of AAA patient with myocardial infarction. In LS group we found statistically significant positive association between plasma OPG levels and patient with stroke. However, in AAA patients with incidence of stroke, we found higher plasma levels of OPN. Interestingly, there was not any association between OPN levels in the urine and clinical parameters, risk factors and morbidity, including kidney diseases. inflammatory role of OPN and depicts better reflection of inflammatory reaction of OPN than OPG in both group of patients. Plasma OPG levels in AAA patients are more associated with coronary artery disease than with peripheral artery disease, what is characteristic for LS patients. Lack of association of urine OPN levels with above mentioned parameters suggest minor importance of this urine protein in clinical condition evaluation of patients with AAA and advanced arteriosclerosis.

PTH: a new target in arteriosclerosis?

CONTEXT: Growing evidence demonstrates that hyperparathyroidism is associated with an increased risk of cardiovascular morbidity and mortality. However, little is known about the relation between serum PTH levels within the normal range and cardiovascular diseases (CVD). OBJECTIVE: In this study the relationship of serum PTH levels within the normal range with CVD and abdominal aortic calcifications was investigated. DESIGN: A cross-sectional, population-based study was performed using data of the Longitudinal Aging Study Amsterdam, including 558 men and 537 women, aged 65-88 years. Models were controlled for sex, age, body mass index, hypertension, diabetes mellitus, high-density lipoprotein cholesterol, total cholesterol, smoking, physical activity, alcohol consumption, glomerular filtration rate, season of blood collection, calcium or diuretic use, and serum 25-hydroxyvitamin D and osteocalcin levels when these variables were found to be relevant confounders. RESULTS: Multivariate models showed that subjects in the highest quintile of serum PTH had a significantly higher risk of CVD as compared with subjects in the lowest quintile (odds ratio 2.22, confidence interval 1.39-3.56). The relationship between PTH and abdominal aortic calcifications was observed only in men, which remained significant after adjusting for confounders (odds ratio 4.03, confidence interval 1.50-10.83). CONCLUSIONS: This study demonstrated that in older persons the presence of serum PTH levels within the upper normal range is highly related to CVD. In men, this association may partly be explained by calcifications of the abdominal aorta. Because CVD poses an important health risk, further elucidation of the role of serum PTH in CVD and arteriosclerosis is relevant.

Decreased APOE-containing HDL subfractions and cholesterol efflux capacity of serum in mice lacking Pcsk9.

BACKGROUND: Studies in animals showed that PCSK9 is involved in HDL metabolism. We investigated the molecular mechanism by which PCSK9 regulates HDL cholesterol concentration and also whether Pcsk9 inactivation might affect cholesterol efflux capacity of serum and atherosclerotic fatty streak volume. METHODS: Mass spectrometry and western blot were used to analyze the level of apolipoprotein E (APOE) and A1 (APOA1). A mouse model overexpressing human LDLR was used to test the effect of high levels of liver LDLR on the concentration of HDL cholesterol and APOE-containing HDL subfractions. Pcsk9 knockout males lacking LDLR and APOE were used to test whether LDLR and APOE are necessary for PCSK9-mediated HDL cholesterol regulation. We also investigated the effects of Pcsk9 inactivation on cholesterol efflux capacity of serum using THP-1 and J774.A1 macrophage foam cells and atherosclerotic fatty streak volume in the aortic sinus of Pcsk9 knockout males fed an atherogenic diet. RESULTS: APOE and APOA1 were reduced in the same HDL subfractions of Pcsk9 knockout and human LDLR transgenic male mice. In Pcsk9/Ldlr double-knockout mice, HDL cholesterol concentration was lower than in Ldlr knockout mice and higher than in wild-type controls. In Pcsk9/Apoe double-knockout mice, HDL cholesterol concentration was similar to that of Apoe knockout males. In Pcsk9 knockout males, THP-1 macrophage cholesterol efflux capacity of serum was reduced and the fatty streak lesion volume was similar to wild-type controls. CONCLUSIONS: In mice, LDLR and APOE are important factors for PCSK9-mediated HDL regulation. Our data suggest that, although LDLR plays a major role in PCSK9-mediated regulation of HDL cholesterol concentration, it is not the only mechanism and that, regardless of mechanism, APOE is essential. Pcsk9 inactivation decreases the HDL cholesterol concentration and cholesterol efflux capacity in serum, but does not increase atherosclerotic fatty streak volume.

Significance of CAVI, hs-CRP and homocysteine in subclinical arteriosclerosis among a healthy population in China.

PURPOSE: The purpose of this study is to evaluate the ability of cardio-ankle vascular index (CAVI), high-sensitivity C-reactive protein (hs-CRP) levels and homocysteine (Hcy) levels to screen for subclinical arteriosclerosis (subAs) in an apparently healthy population, with the view to obtaining an optimal diagnostic marker or profile for subAs. METHODS: Subjects (152) undergoing routine health examinations were recruited and divided into two groups: carotid arteriosclerosis (CA) and non-carotid arteriosclerosis (NCA), according to carotid intima-media thickness (CMIT). CAVI was calculated based on blood pressure and pulse wave velocity. Serum hs-CRP and Hcy levels were also measured. A Receiver Operating Characteristic (ROC) curve was plotted to evaluate the efficacy of each in carotid arteriosclerosis screening. Ten parameter combinations, designated W1 to W10, were compared in terms of sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV). RESULTS: The levels of all three parameters were significantly higher in the CA group, compared with the NCA group. ROC curves showed that the area under the curve (AUC) for CAVI was 0.708 (95%CI: 0.615-0.800), which is significantly larger than that of either hs-CRP (0.622) or Hcy (0.630), respectively (P < 0.001). Maximum sensitivity (100%) and NPV (100%) were attained with W10, while maximum specificity (86.2%) and PPV (46.7%) were obtained with W7. With W9, the maximum Youden index (0.416) was obtained, with a sensitivity of 77.8% and specificity of 63.8%. CONCLUSIONS: CAVI is more effective than hs-CRP or Hcy for subAs screening. The optimal profile was obtained with a combination of CAVI and other parameters.

Association between cystatin C and arteriosclerosis in the absence of chronic kidney disease.

AIM: Chronic kidney disease (CKD) is a known risk factor for cardiovascular disease (CVD). Cystatin C was recently reported to be an endogenous surrogate of kidney function, and a high level of cystatin C is reported to be a strong predictor of CVD; however, the association between cystatin C and arteriosclerosis in a non-CKD population is unclear. This study aimed to clarify the association between cystatin C and arteriosclerosis in a non-CKD population. METHODS: Of the 637 Japanese adults (264 men, 373 women) enrolled, we analyzed 446 participants with an estimated glomerular filtration rate (eGFR) >60 mL/min and no proteinuria (177 men, 269 women) without a history of CVD. Kidney function was evaluated according to serum cystatin C levels and eGFR. Arteriosclerosis was evaluated on the basis of the cardio-ankle vascular index (CAVI) and carotid intima-media thickness (CIMT). RESULTS: The mean age of our subjects was 67.0±10.0 years. No variables showed any significant differences according to gender. The results of multiple linear regression analysis showed a significant correlation between serum cystatin C and CAVI only in women, but not CIMT. CONCLUSION: We observed a significant correlation between cystatin C and CAVI, which is a marker of early-stage arteriosclerosis, in women in a non-CKD population with no proteinuria and eGFR>60 mL/min.