Evaluation of sCD163 and sTWEAK in patients with stable peripheral arterial disease and association with disease severity as well as long-term mortality.

BACKGROUND AND AIMS: The TNF-superfamily member sTWEAK and its scavenger receptor sCD163 are potentially involved in pathophysiological processes of atherosclerosis. In patients with peripheral arterial disease, previous research has shown that sTWEAK and the sCD163/sTWEAK ratio were independently associated with long term all-cause and cardiovascular survival. Since previous investigations emphasized on symptomatic peripheral arterial disease including critical limb ischemia, this study evaluates sTWEAK and sCD163 in a cohort of stable peripheral arterial disease including asymptomatic (Fontaine stage I) and intermittent claudication (Fontaine stage II) patients. METHODS: sTWEAK concentrations of 354 patients were measured using a commercially available ELISA kit. sCD163 was quantified using a multiplex bead assay. Cox proportional hazards regression was used to assess outcome after a seven-year follow-up. Hazard ratios are given as interquartile range. RESULTS: Patients with intermittent claudication exhibited increased sCD163 levels in comparison to asymptomatic patients (p = 0.002). However, sTWEAK was not related to peripheral arterial disease severity (p = 0.740). A multivariable Cox-proportional hazard models including sTWEAK and cardiovascular risk factors (age, HbA1c, CRP, LDL-C, BMI, eGFR) revealed an inverse association with all-cause mortality (HR 0.775 (95% CI 0.623-0.965) and cardiovascular mortality (HR 0.710 (95% CI 0.534-0.944)). Further multivariable models including sCD163 or the sCD163/sTWEAK ratio and cardiovascular risk factors showed no association with mortality. CONCLUSIONS: This study highlights the use of sCD163 as a novel biomarker for PAD severity and supports sTWEAK as an independent predictor of all-cause and cardiovascular mortality even in stable peripheral arterial disease.

Vascular peroxidase 1 is independently associated with worse kidney function in patients with peripheral artery disease.

BACKGROUND: Oxidative stress is involved in cardiovascular disease such as peripheral artery disease (PAD). Vascular Peroxidase 1 (VPO1), a novel heme-containing peroxidase mainly expressed in the cardiovascular system, aggravates oxidative stress. Evidence in humans is limited. Current work aims to measure VPO1 in patients suffering from PAD, and to evaluate the association of VPO1 with conventional markers of cardiovascular risk factors (CVRF), including the estimated glomerular filtration rate (eGFR) and albuminuria categories. METHODS: This study is part of a longitudinal observational study. At baseline, 236 PAD-patients were included. VPO1 plasma levels (ng/mL) were measured by commercially available ELISA kits. A two-sided p level of < 0.05 was considered statistically significant. RESULTS: In the cross-sectional analysis (n = 236), VPO1 associated with ageing (p = 0.035) as well as with eGFR and albuminuria category, the markers of chronic kidney disease (CKD)-progression (p = 0.042). The longitudinal 18-months follow-up analysis (n = 152) demonstrated that baseline VPO1 predicts rapid kidney function decline (RKFD) (n = 49), defined as more than - 3 mL/min/1.73m2 eGFR loss per year, (OR per one SD VPO1 1.60 (1.11-2.30); p = 0.009). This association between VPO1 and kidney function withstood the multivariable adjustment for traditional CVRF including baseline eGFR and urine albumin-to-creatinine ratio (UACR), (adjOR per one SD VPO1 1.73 (1.14-2.61); p = 0.046). CONCLUSION: This study is first to reveal that VPO1 is independently associated with declining kidney function in patients with PAD. VPO1 shows a tighter association to kidney function than to other CVRF. This finding points to VPO1 as a potential target protein to assess CKD-progression.

The Association of Cortisol Excretion with Weight and Metabolic Parameters in Nondiabetic Patients with Morbid Obesity.

INTRODUCTION: Cortisol is involved in the regulation of gluconeogenesis and glucose utilization. In morbid obesity (MO), the association of cortisol excretion with metabolic parameters is not well-characterized. In our study, we evaluated cortisol excretion in nondiabetic subjects with MO and its effect on glucose metabolism. METHODS: We included 1,249 nondiabetic patients with MO (79.8% females, mean BMI 44.9 ± 6.5 kg/m2, mean age 38 ± 11 years). Anthropometric data and cardiovascular risk factors were assessed, and an oral glucose tolerance test for calculation of insulin resistance was performed. Cortisol excretion was assessed on 2 consecutive days (24 h urine specimens). RESULTS: Regarding cortisol excretion, patients were divided into 3 tertiles (urinary cortisol ≤51.6, >51.6 and <117.6, and ≥117.6 µg/24 h, respectively). Patients in the highest tertile were younger (p = 0.003), more obese (BMI: p = 0.040), had lower diastolic blood pressure ([DBP]; p = 0.012), lower total (p = 0.032) and LDL cholesterol (p = 0.021), fasting (p = 0.049) and 2-h glycemia (p = 0.028), 2-h insulinemia (p = 0.020), and HbA1c (p < 0.001), and a higher estimated glomerular filtration rate (eGFR) (p < 0.001). The glucose (p < 0.001) and insulin (p = 0.011) area under the curve (AUC) were also lower. Urinary cortisol excretion adjusted for age, sex, and eGFR was positively correlated with body weight (BW, beta = 0.076, p = 0.004) and overall glucose tolerance (oral disposition index, beta = 0.090, p = 0.011), and negatively with HbA1c (beta = -0.179, p < 0.001), 2-h glycemia (beta = -0.075, p = 0.032), AUC glucose (beta = -0.103, p = 0.002), and DBP (beta = -0.139, p < 0.001). HbA1c, BW, and DBP remained significant after multivariable analysis. DISCUSSION/CONCLUSION: Despite being more obese, patients with higher cortisol excretion have a more favorable metabolic profile. These results deserve further attention regarding the respective mechanisms.

Peripheral arterial disease and type 2 diabetes: Older patients still exhibit a survival benefit from glucose control.

OBJECTIVE: To investigate a possible beneficial effect of strict glycaemic control on all-cause mortality in patients with peripheral arterial disease and type 2 diabetes mellitus. METHODS: A total of 367 mainly older peripheral arterial disease patients [age: 69 (62-78) years, 34% women, Fontaine stage I-II] were categorized according to glycaemic control, that is, (a) no type 2 diabetes mellitus, (b) strict glucose control (HbA1c < 53 mmol/mol) and (c) lenient glucose control (HbA1c ⩾ 53 mmol/mol) at inclusion and by mean HbA1c over the first study year. Mortality was analysed using Kaplan-Meier and Cox-regression analyses after 7 years. RESULTS: The combination of type 2 diabetes mellitus and peripheral arterial disease reduced survival from 78.8% to 68.9% in comparison to patients without type 2 diabetes mellitus (p = 0.023). Patients with strict glucose control (75%) were associated with increased survival in comparison to patients with lenient glucose control (58.9%) stratified by mean HbA1c (p = 0.042). Baseline cardiovascular risk factors were similar in those type 2 diabetes mellitus patients. In this peripheral arterial disease cohort HbA1c (hazard ratio: 1.3, 1.04-1.63), age (hazard ratio: 1.7, 1.3-2.3) and C-reactive protein (hazard ratio: 1.5, 1.2-2.0) remained independent associates for mortality adjusted for cardiovascular risk factors and diabetes duration. CONCLUSION: Older patients with peripheral arterial disease and type 2 diabetes mellitus still benefit from strict glucose control in a cohort of patients with similar distribution of cardiovascular risk factors.

Albuminuria in Patients with Morbid Obesity and the Effect of Weight Loss Following Bariatric Surgery.

BACKGROUND AND OBJECTIVES: Patients with morbid obesity are at an increased risk for cardiovascular and renal complications, which are not only linked to traditional cardiovascular risk factors. Thus, we evaluated (a) the prevalence of albuminuria in non-diabetic and diabetic morbidly obese patients and (b) the effect of weight loss following bariatric surgery. MATERIAL AND METHODS: We included 1307 patients (77% women, mean age 40 ± 12 years, BMI 45.6 ± 6.6 kg/m2) in a cross-sectional study. A subgroup (n = 318) was followed up for 2 years after bariatric surgery. Weight, cardiovascular risk markers and a 75-g glucose tolerance test were determined. Albuminuria was assessed by collecting 24-h urine on three consecutive days. RESULTS: In the cross-sectional study, the prevalence of microalbuminuria was 16.0% (n = 209), of macroalbuminuria 3.1% (n = 41). The chi-square for the association of albuminuria and diabetes was 31.937 (p < 0.001). Of all patients with albuminuria, 42.0% exhibited normal glucose tolerance. In a multivariate regression analysis, systolic blood pressure (beta = 0.236; p < 0.001), log fasting insulin (beta = 0.309; p < 0.001) and log 2-h postprandial insulin (beta = - 0.173; p = 0.033) were predictive risk factors for albuminuria. Longitudinally, albumin excretion decreased significantly from 11.1 (6.4, 18.4 mg/24 h) to 7.8 mg/24 h (4.9, 13.0 mg/24 h; p < 0.001). In the group with albuminuria preoperatively, albumin excretion decreased from 65.7 (38.2, 147.1 mg/24 h) to 13.5 mg/24 h (8.4, 36.8 mg/24 h; p < 0.001). After adjusting for age, sex and baseline albuminuria, patients with lower creatinine clearance showed a smaller decrease of albuminuria (beta = 0.117; p = 0.021). CONCLUSION: A substantial portion of patients with morbid obesity exhibits microalbuminuria, nearly half of those present with normal glucose tolerance. After weight loss, we found a significant decrease of albuminuria, potentially indicating or even contributing to the known reduction of cardiovascular mortality after bariatric surgery.

Angiopoietin-2 and Survival in Peripheral Artery Disease Patients.

Survival of peripheral arterial disease (PAD) patients increased over the last decade due to increased use of secondary preventive medication and rapid revascularization of PAD patients. Angiogenetic markers such as vascular endothelial growth factor (VEGF), angiopoietin-2 (Ang-2) and its receptor Tie-2 might be useful markers to assess the residual risk for mortality in PAD patients. The aim of this study was to evaluate angiogenetic markers for the prediction of mortality in a PAD cohort. For this purpose, 366 patients (mean age: 69 ± 10 years) with PAD Fontaine stage I or II were included and followed up over a 5-year study period. Serum Ang-2, Tie-2 and VEGF levels were measured by bead-based multiplex assay. All-cause mortality and major cardiovascular events (MACE) including all-cause death, non-fatal stroke and non-fatal myocardial infarction were analysed by Kaplan-Meier and Cox regression analyses after 5 years. Ang-2 was associated with Tie-2 (R = 0.151, p = 0.006) and VEGF levels (R = 0.160, p = 0.002). However, only Ang-2 was linked to all all-cause mortality in PAD patients (hazard ratio [HR]: 1.55 [1.23-2.15], p = 0.008) even after adjustment for age and gender, haemoglobin A1c, low-density lipoprotein cholesterol, systolic blood pressure and glomerular filtration rate (HR: 1.44 [1.03-2.00], p = 0.032). Furthermore, an association of Ang-2 and MACE in PAD patients (HR: 1.36 (1.03-1.78), p = 0.028) was found. This result implies that Ang-2 might be used as an additional marker to stratify PAD patients to predict poor mid-term life expectancy.

YKL-40 levels increase with declining ankle-brachial index and are associated with long-term cardiovascular mortality in peripheral arterial disease patients.

BACKGROUND AND AIMS: YKL-40 is an inflammatory marker secreted by macrophages and is expressed in atherosclerotic plaques. YKL-40 increases in coronary artery disease (CAD) with poor coronary collateral vessel development. Higher levels are linked to reduced survival in CAD patients. Studies evaluating YKL-40 in patients with peripheral arterial disease (PAD) are scarce. This study aims to elucidate a possible link between YKL-40 and PAD severity as well as cardiovascular long-term mortality. METHODS: YKL-40 was measured at baseline in 365 elderly PAD patients (age 69 ±â€¯10.4, 33.7% women, Fontaine stage I-II) by bead-based multiplex assay. Patients were followed for seven years to assess long-term cardiovascular and all-cause survival by Kaplan-Meier and Cox regression. RESULTS: YKL-40 levels were associated with declining ankle-brachial index (ABI) in PAD patients without Moenckeberg's mediasclerosis (R = -0.189, p=0.002). PAD patients with mediasclerosis exhibited higher YKL-40 levels (p=0.002). Baseline YKL-40 levels were significantly associated with cardiovascular mortality (HR 1.52 (1.21-1.91), p < 0.001) and all-cause mortality (HR 1.45 (1.20-1.75), p < 0.001) over a seven-year observation period. After multivariable adjustment for gender, patient age, known carotid artery disease, known coronary artery disease, smoking status, systolic blood pressure, HbA1c, low density lipoprotein cholesterol, estimated glomerular filtration rate, aspartate aminotransferase, and C-reactive protein, YKL-40 remained significantly associated with cardiovascular (HR 1.34 (1.02-1.75), p=0.033) and all-cause mortality (HR 1.25 (1.01-1.55), p=0.039). CONCLUSIONS: Increased YKL-40 levels are independently associated with poor long-term cardiovascular survival in peripheral arterial disease patients. Furthermore, YKL-40 correlates with patients' ABI in PAD in the absence of mediasclerosis.

FABP4 and Cardiovascular Events in Peripheral Arterial Disease.

Fatty acid-binding protein 4 (FABP4) is a possible biomarker of atherosclerosis. We evaluated FABP4 levels, for the first time, in patients with peripheral artery disease (PAD) and the possible association between baseline FABP4 levels and cardiovascular events over time. Patients (n = 327; mean age 69 ± 10 years) with stable PAD were enrolled in this study. Serum FABP4 was measured by bead-based multiplex assay. Cardiovascular events were analyzed by FABP4 tertiles using Kaplan-Meier and Cox regression analyses after 5 years. Serum FABP4 levels showed a significant association with the classical 3-point major adverse cardiovascular event (MACE) end point (including death, nonlethal myocardial infarction, or nonfatal stroke) in patients with PAD ( P = .038). A standard deviation increase of FABP4 resulted in a hazard ratio (HR) of 1.33 (95% confidence interval [95% CI]: 1.03-1.71) for MACE. This association increased (HR: 1.47, 95% CI: 1.03-1.71) after multivariable adjustment ( P = .020). Additionally, in multivariable linear regression analysis, FABP4 was linked to estimated glomerular filtration rate ( P < .001), gender ( P = .005), fasting triglycerides ( P = .048), and body mass index ( P < .001). Circulating FABP4 may be a useful additional biomarker to evaluate patients with stable PAD at risk of major cardiovascular complications.

Prevalence of Micronutrient Deficiency in Patients with Morbid Obesity Before Bariatric Surgery.

BACKGROUND: Postoperative micronutrient deficiency is a known side effect of bariatric surgery. In this study, we examined the prevalence of micronutrient deficiency in patients with morbid obesity (MO) preoperatively. METHODS: A total of 1732 patients with MO wishing to undergo bariatric surgery (age: 40 ± 12 years, mean BMI: 44 ± 9 kg/m2, means ± SD, 77.3% female) were analyzed in this cross-sectional examination. Iron state, vitamin B12, folic acid, 25hydroxy(OH)-vitamin D, PTH, vitamin A, and vitamin E levels were determined. Subsequently, patients underwent nutritional counseling and were substituted accordingly. RESULTS: A total of 63.2% (n = 1094) of the patients had a deficit in folic acid (< 5.3 ng/ml), 97.5% (n = 1689) in 25OHvitamin D (< 75 nmol/l), and 30.2% (n = 523) had a PTH elevation (> 56.9 pg/ml). A total of 5.1% (n = 88) of the patients presented with a deficit in vitamin B12 (< 188 pg/ml) and 6.2% (n = 107) in vitamin A (< 1.05 µmol/l). A total of 9.6% (n = 166) exhibited iron deficiency (ferritin < 15 µg/l). None of the patients had a deficit in vitamin E. There were no gender differences except for ferritin deficiency (women 11.8% vs. men 1.5%, p < 0.001). Patients in the highest BMI tertile had significantly more often a deficit in vitamin D (p = 0.033) and folic acid (p < 0.001). Patients in the lowest age tertile had significantly more often a deficit in folic acid (p < 0.001). CONCLUSIONS: Our data show a high prevalence of micronutrient deficiency in patients with morbid obesity preoperatively and emphasize the importance of exact preoperative evaluation and adequate substitution as well as postoperative surveillance.

Center-based patient care enhances survival of elderly patients suffering from peripheral arterial disease.

OBJECTIVES: Recent advances in catheter-based intervention in patients with symptomatic peripheral arterial disease (PAD) have halved mortality. Mortality of PAD patients still remains high compared to other clinical forms of atherosclerosis. Intensified patient care might increase adherence to medical management and benefit the survival of PAD patients. METHODS: Two patient cohorts were compared in a longitudinal prospective follow-up study. 370 PAD patients were included in the intensified center-based vascular medicine group (VMC group) and 332 PAD patients were treated by their usual primary care physician (PCP group). Survival in both groups was compared by Kaplan-Meier and Cox-regression analyses after 5 years. RESULTS: Survival of patients in the VMC group was 90.8% compared to 66% in the PCP group. Thus, survival was improved by 24.9% by center-based care (absolute risk CI: 19-30.7%; 38% relative risk). PCP treatment increased all-cause mortality by a hazard ratio of 3.7 (95% CI: 2.5-5.5; p < .001). Mortality in the VMC group was significantly associated with the non-modifiable risk factors age, C-reactive protein, and nephropathy in multivariable analyses. CONCLUSION: These data imply that multi-morbid elderly PAD patients still benefit by intensified specialist care compared to the usual primary care setting. KEY MESSAGES Center-based patient care improves survival in patients with peripheral arterial disease; mortality was reduced from 82 to 21 events per 1000 patient-years (rate ratio 0.26). Mortality was related to age (HR 1.46), CRP (HR 1.36), and nephropathy (HR 2.7). A multifactorial approach combining adequate drug prescription, accomplishment of agreed goals and repetitive training to initiate, implement, and persist treatment adaptations was applied.