Circulating CD5L is associated with cardiovascular events and all-cause mortality in individuals with chronic kidney disease.

This study assessed the association of CD5L and soluble CD36 (sCD36) with the risk of a cardiovascular event (CVE), including CV death and all-cause mortality in CKD. We evaluated the association of CD5L and sCD36 with a predefined composite CV endpoint (unstable angina, myocardial infarction, transient ischemic attack, cerebrovascular accident, congestive heart failure, arrhythmia, peripheral arterial disease [PAD] or amputation by PAD, aortic aneurysm, or death from CV causes) and all-cause mortality using Cox proportional hazards regression, adjusted for CV risk factors. The analysis included 1,516 participants free from pre-existing CV disease followed up for 4 years. The median age was 62 years, 38.8% were female, and 26.8% had diabetes. There were 98 (6.5%) CVEs and 72 (4.8%) deaths, of which 26 (36.1%) were of CV origin. Higher baseline CD5L concentration was associated with increased risk of CVE (HR, 95% CI, 1.17, 1.0-1.36), and all-cause mortality (1.22, 1.01-1.48) after adjusting for age, sex, diabetes, systolic blood pressure, dyslipidemia, waist circumference, smoking, and CKD stage. sCD36 showed no association with adverse CV outcomes or mortality. Our study showed for the first time that higher concentrations of CD5L are associated with future CVE and all-cause mortality in individuals with CKD.

High Incidence of Adverse Outcomes in Haemodialysis Patients with Diabetes with or without Diabetic Foot Syndrome: A 5-Year Observational Study in Lleida, Spain.

BACKGROUND: We evaluated whether, in subjects receiving haemodialysis (HD), the presence of diabetic foot syndrome (DFS) was associated with increased mortality compared with subjects with diabetes mellitus (DM) without DFS and with non-diabetic subjects. METHODS: Retrospective, observational study in 220 subjects followed for six years. We calculated and compared the frequency and 5-year cumulative incidence of all-cause mortality, cardiovascular (CV) mortality, CV events, major adverse CV events (MACE), and new foot ulcer (FU) or amputation. We also examined prognostic factors of all-cause and CV mortality based on baseline characteristics. RESULTS: DM patients had a 1.98 times higher probability of all-cause mortality than those without DM (p = 0.001) and 2.42 times higher likelihood of CV mortality and new FU or amputation (p = 0.002 and p = 0.008, respectively). In the DM cohort, only the risk of a new FU or amputation was 2.69 times higher among those with previous DFS (p = 0.021). In patients with DM, older age was the only predictor of all-cause and CV mortality (p = 0.001 and p = 0.014, respectively). CONCLUSIONS: Although all-cause and CV mortality were increased on HD subjects with DM, the presence of DFS did not modify the excess risk. Additional studies are warranted to further explore the impact of DFS in subjects with DM undergoing HD.

Risk factors associated with valvular calcification in patients with chronic kidney disease. Analysis of NEFRONA study.

INTRODUCTION: Patients with chronic kidney disease (CKD) are at high risk of cardiovascular morbidity and mortality. Subclinical cardiac structural alterations have prognostic value in these patients. The aim was to analyse the prevalence of valvular calcification, the evolution and the relationship with different risk factors. MATERIAL AND METHODS: Part of the sample of the NEFRONA study was randomly selected. Aortic and mitral valve calcification were analysed in echocardiograms performed at the baseline visit and at 24 months. RESULTS: We included 397 patients, the estimated basal glomerular filtrate (eGFR) was 33 ml/min with significant decrease to 30.9 ml/min. There was an increase in the area of carotid and femoral plaque, as well as an increase in patients with aortic and mitral calcification at 24 months. A positive association of mitral calcification at 24 months with age, ankle-brachial index (ABI) and calcium-phosphorus product (CaxP) at baseline visit was observed, without association with eGFR. Aortic calcification at 24 months was positively associated with age, phosphorous and total carotid plaque area at baseline, with no relationship to eGFR. CONCLUSIONS: A significant prevalence of valvular calcification was observed in patients with CKD without known cardiovascular disease.Two-year progression was observed independently of the eGFR. Patients with higher risk of mitral valve calcification were those with older age, higher ABI and CaxP product. Patients with a higher risk of aortic calcification were those with older age, higher phosphorous levels and larger area of carotid plaque. Identifying these higher risk patients would help to avoid future cardiovascular events intensifying follow-ups.

Subclinical atheromatosis localization and burden in a low-to-moderate cardiovascular risk population: the ILERVAS study.

INTRODUCTION AND OBJECTIVES: There is a discrepancy between risk assessment based on cardiovascular risk factors (CVRF) and atheromatosis burden. The objective was to identify the prevalence of subclinical diseases with common risk factors, such as atheromatosis, occult kidney disease, prediabetes, and diabetes in a middle-aged population with low-to-moderate cardiovascular risk; to assess the vascular distribution, and severity of subclinical atheromatosis. METHODS: Randomized, interventional, longitudinal clinical trial. The intervention consisted of vascular ultrasound examination in the carotid and femoral arteries assessing 12 territories, combined with clinical, anthropometric, lifestyle, and biochemical parameters. Inclusion criteria consisted of women (aged 50-70 years) and men (aged 45-65 years) with at least 1 CVRF. Exclusion criteria consisted of a clinical history of diabetes, chronic kidney disease, or a prior CV event. Here, baseline characteristics of the ILERVAS cohort are shown. RESULTS: A total of 8330 middle-aged asymptomatic participants, 50.7% women, were enrolled. The presence of 1-2 CVRF was found in 74.8% and adherence to the Mediterranean diet was low in 52.8%. Several previously unknown chronic diseases were diagnosed, such as dyslipidemia (21.1%), hypertension (15.3%), kidney disease (15.4%), obesity (10.6%), and diabetes (2.3%). Subclinical atheromatosis was found in 71.4% of participants, localized in common femoral (54.5%), carotid bifurcation (41.1%) and internal carotid (22%). Intermediate atheromatosis (2-3 territories with atheroma plaque) was found in 32.6%, and generalized atheromatosis (>3 territories) in 19.7. Total plaque area was higher in men (0.97 cm2 vs 0.58 cm2, P<.001). Total plaque area was also higher in the femoral artery, and increased with the number of CVRF. CONCLUSIONS: Subclinical atheromatosis was highly prevalent in a middle-aged population with low-to moderate cardiovascular risk, with 1 in 5 participants having generalized atheromatosis. ClinicalTrials.gov Identifier: NCT03228459.

[Risk factors associated with valvular calcification in patients with chronic kidney disease. Analysis of NEFRONA Study]. / Factores de riesgo asociados a la calcificación valvular en pacientes con enfermedad renal crónica. Análisis del Estudio Nefrona.

INTRODUCTION: Patients with chronic kidney disease (CKD) are at high risk of cardiovascular morbidity and mortality. Subclinical cardiac structural alterations have prognostic value in these patients. The aim was to analyse the prevalence of valvular calcification, the evolution and the relationship with different risk factors. MATERIAL AND METHODS: Part of the sample of the NEFRONA study was randomly selected. Aortic and mitral valve calcification were analysed in echocardiograms performed at the baseline visit and at 24 months. RESULTS: We included 397 patients, the estimated basal glomerular filtrate (eGFR) was 33ml/min with significant decrease to 30.9ml/min. There was an increase in the area of carotid and femoral plaque, as well as an increase in patients with aortic and mitral calcification at 24 months. A positive association of mitral calcification at 24 months with age, ankle-brachial index (ABI) and calcium-phosphorus product (CaxP) at baseline visit was observed, without association with eGFR. Aortic calcification at 24 months was positively associated with age, phosphorous and total carotid plaque area at baseline, with no relationship to eGFR. CONCLUSIONS: A significant prevalence of valvular calcification was observed in patients with CKD without known cardiovascular disease.Two-year progression was observed independently of the eGFR. Patients with higher risk of mitral valve calcification were those with older age, higher ABI and CaxP product. Patients with a higher risk of aortic calcification were those with older age, higher phosphorous levels and larger area of carotid plaque. Identifying these higher risk patients would help to avoid future cardiovascular events intensifying follow-ups.

Impact of bariatric surgery on subclinical atherosclerosis in patients with morbid obesity.

BACKGROUND: The main cause of death in obese individuals is cardiovascular disease precipitated by atherosclerosis. Endothelial dysfunction and inflammation are considered early events in the development of the disease. OBJECTIVES: The aim of this study was to identify biomarkers of subclinical atherosclerosis in patients with morbid obesity by comparing clinical, vascular, and biochemical parameters indicative of endothelial dysfunction in patients with and without atheromatous plaque and monitoring changes after bariatric surgery. SETTINGS: Multicenter collaboration between Biochemistry and Biomedicine Department in Barcelona University and University Hospital Arnau de Vilanova in Lleida. METHODS: Plasma samples from 66 patients with morbid obesity were obtained before bariatric surgery and at 6 and 12 months after. Patients were divided into 2 groups based on the presence of atheromatous plaque. We used contrast-enhanced carotid ultrasound, enzyme-linked immunosorbent assay, Griess, and EndoPAT-2000 methods. RESULTS: Patients with plaque showed the worst profile of cardiovascular risk factors. Carotid intima-media thickness and plasminogen activator inhibitor-1 were higher in plaque group (P < .0001). After bariatric surgery, vasa vasorum, oxidized low-density lipoprotein, and plasminogen activator inhibitor-1 decreased (P < .0001 in all cases). CONCLUSIONS: Obesity promotes atherogenesis, leading to vascular endothelial damage. Bariatric surgery reduces cardiovascular risk and the prognosis is better for patients without plaque. The increase in plasminogen activator inhibitor-1, carotid intima-media thickness, and vasa vasorum proliferation might be the first alterations in the atheromatous process in obesity and could serve as good biomarkers of subclinical atherosclerosis.

Semantic segmentation with DenseNets for carotid artery ultrasound plaque segmentation and CIMT estimation.

BACKGROUND AND OBJECTIVE: The measurement of carotid intima media thickness (CIMT) in ultrasound images can be used to detect the presence of atherosclerotic plaques. Usually, the CIMT estimation strategy is semi-automatic, since it requires: (1) a manual examination of the ultrasound image for the localization of a region of interest (ROI), a fast and useful operation when only a small number of images need to be measured; and (2) an automatic delineation of the CIM region within the ROI. The existing efforts for automating the process have replicated the same two-step structure, resulting in two consecutive independent approaches. In this work, we propose a fully automatic single-step approach based on semantic segmentation that allows us to segment the plaque and to estimate the CIMT in a fast and useful manner for large data sets of images. METHODS: Our single-step approach is based on densely connected convolutional neural networks (DenseNets) for semantic segmentation of the whole image. It has two remarkable characteristics: (1) it avoids ROI definition, and (2) it captures multi-scale contextual information in the complete image interpretation, due to the concatenation of feature maps carried out in DenseNets. Once the input image is segmented, a straightforward method for CIMT estimation and plaque detection is applied. RESULTS: The proposed method has been validated with a large data set (REGICOR) of more than 8000 images, corresponding to two territories of the carotid artery: common carotid artery (CCA) and bulb. Among them, a subset of 331 images has been used to evaluate the performance of semantic segmentation (≈90% for train, ≈10% for test). The experimental results demonstrated that our method outperforms other deep models and shallow approaches found in the literature. In particular, our CIMT estimation reaches a correlation coefficient of 0.81, and a CIMT mean error of 0.02 and 0.06 mm in CCA and Bulb images, respectively. Furthermore, the accuracy for plaque detection is 96.45% and 78.09% in CCA and Bulb, respectively. To test the generalization power, the method has also been tested with another data set (NEFRONA) that includes images acquired with different equipment. CONCLUSIONS: The validation carried out demonstrates that the proposed method is accurate and objective for both plaque detection and CIMT measurement. Moreover, the robustness and generalization capacity of the method have been proven with two different data sets.

Are Obesity Indices Useful for Detecting Subclinical Atheromatosis in a Middle-Aged Population?

OBJECTIVE: There is a close relationship between excess adiposity and cardiovascular disease. Although body mass index (BMI) is the most used approach to estimate excess weight, other anthropometric indices have been developed to measure total body and abdominal adiposity. Here, our objective was to assess the usefulness of these anthropometric indices to detect subclinical atheromatous disease. METHODS: A cross-sectional study with 6,809 middle-aged subjects (mean age, 57 [53-63] years) with low to moderate cardiovascular risk from the ILERVAS project. Measures of total body fat (BMI, Clínica Universidad de Navarra - Body Adiposity Estimator [CUN-BAE], and Deurenberg's formula) and central adiposity (waist and neck circumferences, conicity index, waist-to-height ratio, Bonora's equation, the A body adiposity index, and body roundness index) were performed in all participants. Bilateral carotid and femoral ultrasound vascular studies allowed the identification of subjects with plaque. -Results: All measured indices were significantly higher in males with subclinical carotid or femoral plaques (p ≤ 0.021 for all). Also, a positive and significant correlation between all indices and the number of affected territories was found (p ≤ 0.013 for all). From the ROC analysis, all measurements identified patients with asymptomatic atheromatosis but none of them helped make clinical decisions. Regarding females, the results were less conclusive. CONCLUSION: Obesity indices are related to subclinical atheromatosis, especially in men, in a large cohort of middle-aged subjects. However, the indices could not detect the presence of arterial plaque, so, when used in isolation, are unlikely to be decisive.

Mediterranean diet, physical activity and subcutaneous advanced glycation end-products' accumulation: a cross-sectional analysis in the ILERVAS project.

PURPOSE: Adherence to Mediterranean diet (MedDiet) and physical activity have been associated to lower cardiovascular risk and mortality. Our purpose was to test the modification of advanced glycation end-products (AGEs) as one of the underlying mechanisms explaining this relationship. METHODS: Cross-sectional study assessing the adherence to MedDiet (14-item Mediterranean Diet Adherence Screener) and physical activity (International Physical Activity Questionnaire short form) in 2646 middle-aged subjects without known cardiovascular disease and type 2 diabetes from the ILERVAS study. Skin autofluorescence (SAF), a non-invasive assessment of subcutaneous AGEs, was measured. Multivariable logistic regression models were done to study interactions and independent associations with a likelihood ratio test. RESULTS: Participants with a high adherence to MedDiet had lower SAF than those with low adherence (1.8 [IR 1.6; 2.1] vs. 2.0 [IR 1.7; 2.3] arbitrary units, p < 0.001), without differences according to categories of physical activity. There was an independent association between high adherence to MedDiet and the SAF values [OR 0.59 (0.37-0.94), p = 0.026]. When adherence to MedDiet was substituted by its individual food components, high intake of vegetables, fruits and nuts, and low intake of sugar-sweetened soft beverages were independently associated with a decreased SAF (p ≤ 0.045). No interaction between MedDiet and physical activity on SAF values was observed except for nuts consumption (p = 0.047). CONCLUSIONS: Adherence to the MedDiet, but not physical activity, was negatively associated to SAF measurements. This association can be explained by some typical food components of the MedDiet. The present study offers a better understanding of the plausible biological conditions underlying the prevention of cardiovascular disease with MedDiet. ClinTrials.gov identifier: NCT03228459.

Circulating ADAMs are associated with renal and cardiovascular outcomes in chronic kidney disease patients.

BACKGROUND: A disintegrin and metalloproteinase (ADAM) 17, also known as tumour necrosis factor α-converting enzyme (TACE), is a metalloproteinase that releases the ectodomains of most growth factors, cytokines, receptors and enzymes and has been associated with the presence of chronic kidney disease (CKD) and cardiovascular (CV) disease. The role of circulating ADAMs in the progression of renal function and CV events in CKD patients is unknown. METHODS: A total of 2570 subjects from an observational and multicentre study with CKD Stages 3-5, CKD Stage 5D and controls without any history of CV disease were studied. Circulating ADAM activity was assessed using a fluorometric technique. Progression of renal disease was defined as a 30% increase in serum creatinine or dialysis requirement after 24 months of follow-up. CV outcomes were assessed after 48 months of follow-up. RESULTS: Patients with advanced CKD had higher ADAM activity as compared with patients with moderate CKD or controls. Male patients with progression of CKD had higher ADAM levels at baseline compared with patients with stable renal function {22.19 relative fluorescence units/µL/h [95% confidence interval (CI) 11.22-37.32] versus 12.15 (7.02-21.50)}. After multivariate adjustment, higher ADAM activity was identified as a risk factor for progression of CKD in male patients [30% increase in the creatinine odds ratio (OR) 2.72 (95% CI 1.58-4.68), P < 0.001; dialysis requirement OR 3.00 (95% CI 1.65-5.46), P < 0.001; dialysis requirement or 30% increase in the creatinine OR 3.15 (95% CI 2.06-4.81), P < 0.001]. ADAM activity was also identified as an independent risk factor for CV events [hazard ratio (HR) 1.68 (95% CI 1.20-2.36), P = 0.003]. CONCLUSIONS: High ADAMs activity levels are independently associated with CKD progression in males and with CV events in CKD patients.

Characteristics of atheromatosis in the prediabetes stage: a cross-sectional investigation of the ILERVAS project.

BACKGROUND: Prediabetes has recently been associated with subclinical atheromatous disease in the middle-aged population. Our aim was to characterize atheromatous plaque burden by the number of affected territories and the total plaque area in the prediabetes stage. METHODS: Atheromatous plaque burden (quantity of plaques and total plaque area) was assessed in 12 territories from the carotid and femoral regions using ultrasonography in 6688 non-diabetic middle-aged subjects without cardiovascular disease. Prediabetes was defined by glycosylated hemoglobin (HbA1c) between 5.7 and 6.4% according to the American Diabetes Association guidelines. RESULTS: Prediabetes was diagnosed in 33.9% (n = 2269) of the ILERVAS participants. Subjects with prediabetes presented a higher prevalence of subclinical atheromatous disease than participants with HbA1c < 5.7% (70.4 vs. 67.5%, p = 0.017). In the population with prediabetes this was observed at the level of the carotid territory (p < 0.001), but not in the femoral arteries. Participants in the prediabetes stage also presented a significantly higher number of affected territories (2 [1;3] vs. 1 [0;3], p = 0.002), with a positive correlation between HbA1c levels and the number of affected territories (r = 0.068, p < 0.001). However, atheromatosis was only significantly (p = 0.016) magnified by prediabetes in those subjects with 3 or more cardiovascular risk factors. The multivariable logistic regression model showed that the well-established cardiovascular risk factors together with HbA1c were independently associated with the presence of atheromatous disease in participants with prediabetes. When males and females were analyzed separately, we found that only men with prediabetes presented both carotid and femoral atherosclerosis, as well as an increase of total plaque area in comparison with non-prediabetic subjects. CONCLUSIONS: The prediabetes stage is accompanied by an increased subclinical atheromatous disease only in the presence of other cardiovascular risk factors. Prediabetes modulates the atherogenic effect of cardiovascular risk factors in terms of distribution and total plaque area in a sex-dependent manner. Trial registration NCT03228459 (clinicaltrials.gov).

Subclinical atherosclerosis burden predicts cardiovascular events in individuals with diabetes and chronic kidney disease.

BACKGROUND: Individuals with diabetes have remarkably high rates of cardiovascular morbidity and mortality. However, the incremental cardiovascular risk in diabetes is heterogeneous and has often been related to renal involvement. The purpose of this study was to analyse the prognostic value of subclinical atherosclerosis in determining the incidence of first cardiovascular events (CVEs) in individuals with diabetes and chronic kidney disease (CKD) compared to CKD individuals without diabetes. METHODS: We included data from individuals with CKD with and without diabetes, free from pre-existing cardiovascular disease, from the NEFRONA cohort. Participants underwent baseline carotid and femoral ultrasound and were followed up for 4 years. All CVEs during follow-up were registered. Bivariate analysis and Fine-Gray competing risk models were used to perform the statistical analysis. RESULTS: During the mean follow-up time of 48 months, a total of 203 CVE was registered. 107 CVE occurred among participants without diabetes (19.58 per 1000 person-years) and 96 CVE occurred among participants with diabetes (44.44 per 1000 person-years). Following the competing risk analysis, the variables predicting CVEs in CKD individuals without diabetes were the number of territories with plaque at baseline (HR 1.862, 95% CI [1.432;2.240]), age (HR 1.026, 95% CI [1.003;1.049]) and serum concentrations of 25-OH vitamin D (HR 0.963, 95% CI [0.933;0.094]). The only variable predicting CVEs among CKD participants with diabetes was the number of territories with plaque at baseline (HR 1.782, 95% CI [1.393, 2.278]). For both models, concordance (C) index yielded was over 0.7. CONCLUSIONS: The burden of subclinical atherosclerosis is the strongest predictor of future CVEs in diabetic individuals with CKD. Early detection of subclinical atherosclerotic burden by multiterritorial vascular ultrasound could improve CVE prediction in this population.

Lung function measurements in the prediabetes stage: data from the ILERVAS Project.

AIMS: Patients with type 2 diabetes have been considered a susceptible group for pulmonary dysfunction. Our aim was to assess pulmonary function on the prediabetes stage. METHODS: Pulmonary function was assessed in 4,459 non-diabetic subjects, aged between 45 and 70 years, without cardiovascular disease or chronic pulmonary obstructive disease from the ongoing study ILERVAS. A "restrictive spirometric pattern", an "abnormal FEV1" and an "obstructive ventilatory defect" were assessed. Prediabetes was defined by glycosylated hemoglobin (HbA1c) between 5.7 and 6.4% according to the American Diabetes Association criteria. RESULTS: Population was composed of 52.1% women, aged 57 [53;63] years, a BMI of 28.6 [25.8;31.8] kg/m2, and with a prevalence of prediabetes of 29.9% (n = 1392). Subjects with prediabetes had lower forced vital capacity (FVC: 93 [82;105] vs. 96 [84;106], p < 0.001) and lower forced expired volume in the first second (FEV1: 94 [82;107] vs. 96 [84;108], p = 0.011), as well as a higher percentage of the restrictive spirometric pattern (16.5% vs. 13.6%, p = 0.015) and FEV1 < 80% (20.3% vs. 17.2%, p = 0.017) compared to non-prediabetes group. In the prediabetes group, HbA1c was negatively correlated with both pulmonary parameters (FVC: r = - 0.113, p < 0.001; FEV1: r = - 0.079, p = 0.003). The multivariable logistic regression model in the whole population showed that there was a significant and independent association between HbA1c with both restrictive spirometric pattern [OR = 1.42 (1.10-1.83), p = 0.008] and FEV1 < 80% [OR = 1.50 (1.19-1.90), p = 0.001]. CONCLUSIONS: The deleterious effect of type 2 diabetes on pulmonary function appears to be initiated in prediabetes, and it is related to metabolic control. TRIAL REGISTRATION CLINICALTRIALS.GOV: NCT03228459.

Ultrasound Tissue Characterization of Carotid Plaques Differs Between Patients with Type 1 Diabetes and Subjects without Diabetes.

The aim of the study was to investigate ultrasound tissue characterization of carotid plaques in subjects with and without diabetes type 1 (T1D). B-mode carotid ultrasound was performed to assess the presence and type of plaque in a group of 340 subjects with and 304 without T1D, all of them without cardiovascular disease. One hundred and seven patients with T1D (49.5% women; age 54 ± 9.8 years) and 67 control subjects without diabetes who had at least one carotid plaque were included in the study. The proportion of subjects who had only echolucent plaques was reduced in the group of patients with T1D (48.6% vs. 73.1%). In contrast, the proportion with only echogenic (25.2% vs. 7.5%) and calcified plaques (9.4% vs. 1.5%) was increased compared with subjects without diabetes. Moreover, having at least one echogenic plaque was more frequent in T1D patients compared with subjects without diabetes (49.5% vs. 26.9% p = 0.005). In addition to diabetes (OR 2.28; p = 0.026), age (OR 1.06, p = 0.002) was the other variable associated with echogenic plaque existence in multiple regression analysis. Patients with T1D exhibit a differential pattern of carotid plaque type compared with subjects without diabetes, with an increased frequency of echogenic and extensively calcified plaques.

Association of Candidate Gene Polymorphisms With Chronic Kidney Disease: Results of a Case-Control Analysis in the Nefrona Cohort.

Chronic kidney disease (CKD) is a major risk factor for end-stage renal disease, cardiovascular disease and premature death. Despite classical clinical risk factors for CKD and some genetic risk factors have been identified, the residual risk observed in prediction models is still high. Therefore, new risk factors need to be identified in order to better predict the risk of CKD in the population. Here, we analyzed the genetic association of 79 SNPs of proteins associated with mineral metabolism disturbances with CKD in a cohort that includes 2,445 CKD cases and 559 controls. Genotyping was performed with matrix assisted laser desorption ionization-time of flight mass spectrometry. We used logistic regression models considering different genetic inheritance models to assess the association of the SNPs with the prevalence of CKD, adjusting for known risk factors. Eight SNPs (rs1126616, rs35068180, rs2238135, rs1800247, rs385564, rs4236, rs2248359, and rs1564858) were associated with CKD even after adjusting by sex, age and race. A model containing five of these SNPs (rs1126616, rs35068180, rs1800247, rs4236, and rs2248359), diabetes and hypertension showed better performance than models considering only clinical risk factors, significantly increasing the area under the curve of the model without polymorphisms. Furthermore, one of the SNPs (the rs2248359) showed an interaction with hypertension, being the risk genotype affecting only hypertensive patients. We conclude that 5 SNPs related to proteins implicated in mineral metabolism disturbances (Osteopontin, osteocalcin, matrix gla protein, matrix metalloprotease 3 and 24 hydroxylase) are associated to an increased risk of suffering CKD.

Skin Autofluorescence Measurement in Subclinical Atheromatous Disease: Results from the ILERVAS Project.

AIM: Advanced glycation end-products (AGEs) have been involved in the atherogenic process in the high-risk population. The goal of this study was to demonstrate that AGEs are related to subclinical atheromatous disease in subjects with low to moderate vascular risk. METHODS: A cross-sectional study in which 2,568 non-diabetic subjects of both sexes without cardiovascular disease were included. Subcutaneous content of AGEs was assessed by skin autofluorescence (SAF) and subclinical atheromatous disease was measured by assessing the atheromatous plaque burden in carotid and femoral regions using ultrasonography. In addition, serum pentosidine, carboxymethyl-lysine (CML) and AGE receptors (RAGE) were assessed in a nested case-control study with 41 subjects without plaque and 41 individuals subjects with generalized disease. RESULTS: Patients with atheromatous plaque had a higher SAF than those with no plaque (1.9 [1.7 to 2.3] vs. 1.8 [1.6 to 2.1] arbitrary units (AU), p＜0.001). The SAF correlated with the total number of affected regions (r= 0.171, p＜0.001), increasing progressively from 1.8 [1.6 to 2.1] AU in those without atheromatous disease to 2.3 [1.9 to 2.7] AU in patients with ≥ 8 plaques (p＜0.001). A correlation was also observed between SAF and the total plaque area (r=0.113, p＜0.001). The area under the Receiver Operating Characteristic curve was 0.65 (0.61 to 0.68) for identifying male subjects with atheromatous disease. The multivariable logistic regression model showed a significant and independent association between SAF and the presence of atheromatous disease. However, no significant differences in serum pentosidine, CML, and RAGE were observed. CONCLUSIONS: Increased subcutaneous content of AGEs is associated with augmented atheromatous plaque burden. Our results suggest that SAF may provide clinically relevant information to the current strategies for the evaluation of cardiovascular risk, especially among the male population.

Effects of Mediterranean Diet and Physical Activity on Pulmonary Function: A Cross-Sectional Analysis in the ILERVAS Project.

A few studies showed that both adherence to Mediterranean diet (MedDiet) and physical activity practice have a positive impact on pulmonary function in subjects with lung disease. These associations are not well studied in subjects free from lung disease. In a cross-sectional study conducted in 3020 middle-aged subjects free of lung disease, adherence to the MedDiet using the Mediterranean Diet Adherence Screener, and physical activity practice using the International Physical Activity Questionnaire short form were recorded. Respiratory function was assessed using forced spirometry and the results were evaluated according to the Global initiative for Chronic Obstructive Lung Disease. Logistic regression models were used to analyze the associations between adherence to the MedDiet and physical activity practice with the presence of ventilatory defects. Participants with a high adherence to MedDiet, in comparison to those with low adherence, had both higher forced vital capacity (FVC; 100 (87⁻109) vs. 94 (82⁻105) % of predicted, p = 0.003) and forced expired volume in the first second (FEV1; 100 (89⁻112) vs. 93 (80⁻107) % of predicted, p < 0.001). According to their degree of physical activity, those subjects with a high adherence also had both higher FVC (100 (88⁻107) vs. 94 (83⁻105) % of predicted, p = 0.027) and FEV1 (100 (89⁻110) vs. 95 (84⁻108) % of predicted, p = 0.047) in comparison with those with low adherence. The multivariable logistic regression models showed a significant and independent association between both low adherence to MedDiet and low physical activity practice, and the presence of altered pulmonary patterns, with differences between men and women. However, no joint effect between adherence to MedDiet and physical activity practice on respiratory function values was observed. Low adherence to MedDiet and low physical activity practice were independently associated with pulmonary impairment. Therefore, the lung mechanics seem to benefit from heart-healthy lifestyle behaviors.

The influence of sleep apnea syndrome and intermittent hypoxia in carotid adventitial vasa vasorum.

Subjects with sleep apnea-hypopnea syndrome (SAHS) show an increased carotid intima-media thickness. However, no data exist about earlier markers of atheromatous disease, such as the proliferation and expansion of the adventitial vasa vasorum (VV) to the avascular intima in this setting. Our aim was to assess carotid VV density and its relationship with sleep parameters in a cohort of obese patients without prior vascular events. A total of 55 subjects evaluated for bariatric surgery were prospectively recruited. A non-attended respiratory polygraphy was performed. The apnea-hypopnea index (AHI) and the cumulative percentage of time spent with oxygen saturation below 90% (CT90) were assessed. Serum concentrations of soluble intercellular adhesion molecule 1, P-selectin, lipocalin-2 and soluble vascular cell adhesion molecule 1 (sVCAM-1) were measured. Contrast-enhanced carotid ultrasound was used to assess the VV density. Patients with SAHS (80%) showed a higher adventitial VV density (0.801±0.125 vs. 0.697±0.082, p = 0.005) and higher levels of sVCAM-1 (745.2±137.8 vs. 643.3±122.7 ng/ml, p = 0.035) than subjects with an AHI lower than 10 events/hour. In addition, a positive association exist between mean VV density and AHI (r = 0.445, p = 0.001) and CT90 (r = 0.399, p = 0.005). Finally, in the multiple linear regression analysis, female sex, fasting plasma glucose and AHI (but not CT90) were the only variables independently associated with the mean adventitial VV density (R2 = 0.327). In conclusion, a high VV density is present in obese subjects with SAHS, and chronic intermittent hypoxia is pointed as an independent risk factor for the development of this early step of atheromatous disease.

Association of the rs495392 Klotho polymorphism with atheromatosis progression in patients with chronic kidney disease.

BACKGROUND: Prevalence of atherosclerotic cardiovascular disease and its rate of progression are higher in patients with chronic kidney disease (CKD) compared with the general population. Mineral metabolism parameters have been shown to be involved in the increased velocity of atheromatosis progression. The aim of this study is to determine the role of 11 single-nucleotide polymorphisms (SNPs) of the Klotho gene on the rate of atherosclerosis progression in CKD. METHODS: This was a multicentre, prospective, observational study of 1439 CKD patients from the NEFRONA cohort. Carotid and femoral ultrasounds were performed at baseline and after 24 months in 10 arterial territories. Progression of atheromatosis was defined as an increase in the number of territories with plaque. Genotyping of 11 SNPs of the Klotho gene was performed and its association with atheromatosis progression was determined by multivariate logistic regression. RESULTS: Bivariate analysis showed that none of the 11 SNPs was associated with atheroma plaque prevalence, but 3 of them (rs495392, rs562020 and rs567170) showed association with atheromatosis progression. The multivariate analysis revealed that only rs495392 showed a statistically significant association with atheromatosis progression, after adjustment for several parameters known to affect it in CKD patients. Thus, the presence of one allele T was associated with a reduction of 30% of the odds of progression, whereas the presence of the two T alleles was associated with a decrease close to 50%. CONCLUSIONS: The presence of the allele T of the SNP rs495392 of the Klotho gene is associated with a decrease in the odds of progression of atheromatosis in CKD patients.