Urinary vanin-1 as a novel biomarker for survival in peripheral artery disease.

BACKGROUND: Chronic kidney disease is associated with increased rates of incidence, morbidity, and mortality in lower-extremity peripheral artery disease (PAD). No specific marker for a functional risk assessment of kidney disease in PAD is known, especially at the early stages. Thus, we speculated that urinary vanin-1 (uVNN1), a marker of oxidative stress even in early kidney injury, could further stratify outcome assessment in patients with PAD. METHODS: Patients with stable PAD (n = 304) of the Vienna medical cohort were followed up for up to 10 years and the outcome was assessed by central death database queries. uVNN1 was measured by enzyme-linked immunosorbent assay (ELISA) at study inclusion and normalized to urinary creatinine (uVNN1/Cr). During the observation time (9.3, 7.0-9.8 years), 104 patients died, 54.8% of which were due to cardiovascular causes. RESULTS: uVNN1/Cr was associated with a urine albumin-creatinine ratio (UACR) (R = 0.166, p = 0.004) but not with an estimated glomerular filtration rate (R = 0.102, p = 0.077). Levels of uVNN1/Cr did not differ between asymptomatic and symptomatic PAD (p = 0.406). Kaplan-Meier curves showed a clear-cut association with higher all-cause (log-rank p = 0.034) and cardiovascular mortality (log-rank p = 0.032) with higher uVNN1/Cr levels. Similarly, significant associations for all-cause (hazard ratio [HR] 1.34, 95% CI [1.08-1.67], p = 0.009) and cardiovascular mortality (HR 1.45, 95% CI [1.06-1.99], p = 0.020) could be seen in multivariable Cox regression models. CONCLUSIONS: uVNN1/Cr showed an independent association with both all-cause and cardiovascular mortality in patients with PAD and was associated with early kidney disease. Thus, uVNN1 could be a useful marker for risk stratification of kidney disease in PAD.

NT-proBNP as a surrogate for unknown heart failure and its predictive power for peripheral artery disease outcome and phenotype.

Patients with peripheral artery disease (PAD) are at high risk of excess mortality despite major improvements in multimodal pharmacotherapy for cardiovascular disease. However, little is known about co-prevalences and implications for the combination of heart failure (HF) and PAD. Thus, NT-proBNP as a suggested surrogate for HF was evaluated in symptomatic PAD regarding long-term mortality. After approval by the institutional ethics committee a total of 1028 patients with PAD, both with intermittent claudication or critical limb ischemia were included after admission for endovascular repair and were followed up for a median of 4.6 years. Survival information was obtained from central death database queries. During the observation period a total of 336 patients died (calculated annual death rate of 7.1%). NT-proBNP (per one standard deviation increase) was highly associated with outcome in the general cohort in crude (HR 1.86, 95%CI 1.73-2.01) and multivariable-adjusted Cox-regression analyses with all-cause mortality (HR 1.71, 95%CI 1.56-1.89) and CV mortality (HR 1.86, 95% CI 1.55-2.15). Similar HR's were found in patients with previously documented HF (HR 1.90, 95% CI 1.54-2.38) and without (HR 1.88, 95%CI 1.72-2.05). NT-proBNP levels were independently associated with below-the-knee lesions or multisite target lesions (OR 1.14, 95% CI 1.01-1.30). Our data indicate that increasing NT-proBNP levels are independently associated with long-term mortality in symptomatic PAD patients irrespective of a previously documented HF diagnosis. HF might thus be highly underreported in PAD, especially in patients with the need for below-the-knee revascularization.

Secondary calciprotein particle size is associated with patient mortality in peripheral artery disease.

BACKGROUND AND AIMS: Secondary calciprotein particles (CPP-II) induce inflammation and contribute to vascular calcification. CPP-II size is associated with vascular calcification in patients with chronic kidney disease (CKD) and all-cause mortality in hemodialysis patients. Here, we investigate for the first time a possible role of CPP-II size in patients with peripheral artery disease (PAD) without severe CKD. METHODS: We measured the hydrodynamic radius (Rh) of CPP-II by using dynamic light scattering in a cohort of 281 PAD patients. Mortality was evaluated over a period of ten years by central death registry queries. 35% of patients died during the observation period (median of 8.8 (6.2-9.0) years). Cox-regression analyses were performed to estimate hazard ratios (HR) and 95% confidence intervals (CI) and to allow for multivariable adjustment. RESULTS: The mean CPP-II size was 188 (162-218) nm. Older patients, patients with reduced kidney function, and those with media sclerosis had larger CPP-II (p < 0.001, p = 0.008, and p = 0.043, retrospectively). There was no association between CPP-II size and overall atherosclerotic disease burden (p = 0.551). CPP-II size was independently significantly associated with all-cause (HR 1.33 (CI 1.01-1.74), p = 0.039) and cardiovascular mortality (HR 1.52 (CI 1.05-2.20), p = 0.026) in multivariable regression analyses. CONCLUSIONS: Large CPP-II size is associated with mortality in PAD patients and might be a new feasible biomarker for the presence of media sclerosis in this patient population.

Lipoprotein (a) and long-term outcome in patients with peripheral artery disease undergoing revascularization.

BACKGROUND AND AIMS: Despite low LDL-C goals, the residual risk for further cardiovascular (CV) events in patients with peripheral artery disease (PAD) remains high. Lipoprotein (a) (Lp(a)) is a known risk factor for PAD incidence, but little is known regarding the outcome in patients with symptomatic PAD. Thus, this study investigates Lp(a) and CV mortality in PAD after endovascular repair. METHODS: A total of 1222 patients with PAD in two cohorts according to Lp(a) assay in nmol/L (n = 964, Lip-LEAD-A) or mg/dl (n = 258, Lip-LEAD-B) were followed up for 4.3 (IQR 3.0-5.6) or 7.6 (IQR 3.2-8.1) years. Lp(a) was measured before endovascular repair for either intermittent claudication (IC) or critical limb ischemia (CLI). Outcome information was obtained from the federal death registry. RESULTS: In Lip-LEAD-A, 141 CV-deaths occurred (annual calculated CV-death rate 3.4%), whereas 64 CV-deaths were registered in Lip-LEAD-B (annual calculated CV-death rate 3.3%). After adjustment for traditional CV risk factors Lp(a) was neither associated with outcome in Lip-LEAD-A (highest tertile HR 1.47, 95%CI [0.96-2.24]) nor in Lip-LEAD-B (highest tertile HR 1.34 [0.70-2.58]). Subanalyses for IC (HR 1.37 [0.74-2.55]; HR 1.10 [0.44-2.80], CLI (HR 1.55 [0.86-2.80], HR 3.01 [0.99-9.10]), or concomitant coronary artery disease (CAD; HR 1.34 [0.71-2.54]; HR 1.21 [0.46-3.17]) failed to show a significant association between Lp(a) and CV-mortality. CONCLUSIONS: In this large-scale cohort of symptomatic PAD no association of elevated Lp(a) with CV mortality was found over a median observation period of 5 years. Thus, an even longer study including asymptomatic patients is warranted.

High-Density Lipoprotein Particle Subclasses in Statin-Treated Patients with Peripheral Artery Disease Predict Long-Term Survival.

Low-density lipoprotein-cholesterol reduction showed a strong reduction of cardiovascular (CV) event rates in CV disease. However, the residual risk of future CV events remains high, which especially extends to peripheral arterial disease (PAD). Nuclear magnetic resonance (NMR) spectroscopy offers a novel method for analysis of the lipoprotein spectrum. This study investigates lipoprotein subclasses using NMR spectroscopy and assesses implications for long-term survival in PAD. NMR spectroscopy was performed by Nightingale Inc., in 319 patients with stable PAD and well-controlled CV risk factors. Patients were followed-up for 10 years. During that period, 123 patients (38.5%) died, of those 68 (21.3%) were defined as CV deaths. Outcome data were analyzed by the Kaplan-Meier method and multivariable Cox-regression for lipoprotein particles. Small and medium high-density lipoprotein-particles (S-HDL-P and M-HDL-P) showed a significant inverse association with all-cause mortality in Cox-regression analyses after multivariable adjustment (S-HDL-P, hazard ratio [HR]: 0.71, 95% confidence interval [CI]: 0.57-0.88; M-HDL-P, HR: 0.72, 95% CI: 0.58-0.90) for each increase of one standard deviation. In contrast, cholesterol-rich X-large HDL-particles (XL-HDL-P) showed a positive association with all-cause mortality (HR: 1.51, 95% CI: 1.20-1.89). Only the association between XL-HDL-P and CV death sustained multivariable adjustment (HR: 1.49, 95% CI: 1.10-2.02), whereas associations for S-HDL-P and M-HDL-P were attenuated (HR: 0.76, 95% CI: 0.57-1.01; HR: 0.80, 95% CI: 0.60-1.06). This study shows a novel association for a beneficial role of S-HDL-P and M-HDL-P but a negative association with higher cholesterol-rich XL-HDL-P for long-term outcome in well-treated patients with PAD. Thus, these results provide evidence that NMR-measured HDL particles identify patients at high CV residual risk beyond adequate lipid-lowering therapy.

Preclinical atherosclerosis and cardiovascular events: Do we have a consensus about the role of preclinical atherosclerosis in the prediction of cardiovascular events?

Atherosclerosis has a long preclinical phase, and the risk of cardiovascular (CV) events may be high in asymptomatic subjects. Conventional risk factors provide information for the statistical probability of developing CV events, but they lack precision in asymptomatic subjects. This review aims to summarize the role of some widely publicized indicators of early atherosclerosis in predicting CV events. The earliest measurable indicator of the atherosclerotic process is endothelial dysfunction, measured by flow-mediated dilation (FMD) of the brachial artery. However, reduced FMD is a stronger predictor of future CV events in patients with existing CV disease than in apparently healthy persons. Alternatively, measurement of carotid artery intima-media thickness does not improve the predictive value of risk factor scores, while detection of asymptomatic atherosclerotic plaques in carotid or common femoral arteries by ultrasound indicates high CV risk. Coronary calcium is a robust and validated help in the estimation of vascular changes and risk, which may improve risk stratification beyond traditional risk factors with relatively low radiation exposure. Arterial stiffness of the aorta, measured as the carotid-femoral pulse wave velocity is an independent marker of CV risk at the population level, but it is not recommended as a routine procedure because of measurement difficulties. Low ankle-brachial index (ABI) indicates flow-limiting atherosclerosis in the lower limbs and indicates high CV risk, while normal ABI does not rule out advanced asymptomatic atherosclerosis. Novel circulating biomarkers are associated with the atherosclerotic process. However, because of limited specificity, their ability to improve risk classification at present remains low.

Calcification Propensity in Serum and Cardiovascular Outcome in Peripheral Artery Disease.

Peripheral artery disease (PAD) has been shown to be linked to elevated cardiovascular risk. The novel T50 test quantifies calcification propensity of serum and has been associated with cardiovascular events and mortality in patients with chronic kidney disease (CKD) and in the general population. This study investigated the association of calcification propensity measured by the T50 test in 287 patients with PAD without severe CKD. Major cardiovascular events (MACEs) including nonfatal stroke and nonfatal myocardial infarction and all-cause death (MACE + ) were evaluated after a median follow-up of 4 years and long-term cardiovascular and all-cause mortality after a median follow-up of 8.7 years by Kaplan-Meier and Cox regression analyses. Mean T50 time was 268 ± 63 minutes in the study cohort (age 69 ± 10 years, 32% women, 47% diabetes). Low T50 values that signify high calcification propensity were significantly associated with the occurrence of MACE+ (hazard ratio [HR]: 0.72; 95% confidence interval [CI]: 0.55-0.94). This association sustained multivariate adjustment for cardiovascular risk factors (CVRFs), Fontaine PAD stage, and prevalent media sclerosis (HR: 0.65; CI: 0.47-0.91). Cardiovascular mortality was significantly associated with T50 after multivariate adjustment for CVRF (HR: 0.72; CI 0.53-0.99), but not all-cause mortality (HR: 0.80; CI: 0.64-1.01). In conclusion, calcification propensity associates with MACE+ and cardiovascular mortality in patients with PAD.

Galectin-3 is linked to peripheral artery disease severity, and urinary excretion is associated with long-term mortality.

BACKGROUND AND AIMS: Galectin-3 (Gal-3) is a biomarker involved in fibrosis and vascular inflammation. Gal-3 has been linked to chronic kidney disease (CKD) and patients with peripheral artery disease (PAD). Conflicting reports exist about the relevance of Gal-3 in PAD. The study aims to elucidate a possible link between serum and urinary Gal-3 and long-term survival in PAD patients without critical limb ischemia and mild to moderate CKD. METHODS: Galectin-3 (Gal-3) was measured in serum (n = 311) and urine (n = 266) of PAD patients (age 69 (62-77) years) by bead-based multiplex assay. Urinary Gal-3 concentration was normalized to urine creatinine (cr) levels. Mortality data were retrieved from the Austrian central death registry after a median observation period of 9.2 years. Survival analyses were performed by the Kaplan-Meier method and Cox-regression. RESULTS: Serum Gal-3 was higher in patients with claudication symptoms (p = 0.001) and correlated inversely with the patients' ankle-brachial index (R = -0.168, p = 0.009). Serum Gal-3 and urinary Gal-3 (uGal-3/cr) were associated with the estimated glomerular filtration rate (R = -0.359, p < 0.001; R = -0.285, p < 0.001). Serum Gal-3 was not linked to all-cause mortality [HR 1.17 (CI 0.96-1.42)] over 9.2 years. However, uGal-3/cr was associated with all-cause mortality [HR 1.60 (CI 1.31-1.95)]. This association sustained multivariable adjustment for cardiovascular risk factors and renal function [HR 1.71 (CI 1.35-2.17)]. CONCLUSIONS: This study is the first to show an association of uGal-3/cr and long-term mortality in patients with PAD. Gal-3 was not predictive of long-term mortality but seems to be a marker of PAD severity in patients without critical limb ischemia.

Angiogenin-A Proposed Biomarker for Cardiovascular Disease-Is Not Associated With Long-Term Survival in Patients With Peripheral Artery Disease.

We evaluated angiogenin as a prospective biomarker in peripheral artery disease (PAD) patients with and without claudication symptoms. A pilot study suggested an elevation of angiogenin in critical limb ischemia. However, in PAD patients, the predictive value of angiogenin has not yet been evaluated. For this purpose, 342 patients with PAD (age: 69 ± 10 years, 34.5% women) were followed-up for 7 years in a cross-sectional study. Angiogenin was measured by enzyme-linked immunosorbent assay. All-cause and cardiovascular mortality were analyzed by Cox regression. Angiogenin levels were higher in men (P = .001) and were associated with patient waist-to-hip ratio (P < .001), fasting triglycerides (P = .011), and inversely with estimated glomerular filtration rate (P = .009). However, angiogenin showed no association with age, characteristics of diabetes, markers of lipid metabolism, or C-reactive protein. Angiogenin did not correlate with markers of angiogenesis such as vascular endothelial growth factor, angiopoietin-2, or tie-2. Furthermore, angiogenin was not associated with PAD Fontaine stages or with patient ankle-brachial index in addition to all-cause mortality (hazard ratio [HR] = 1.09 [95% CI: 0.89-1.34]) or cardiovascular morality (HR = 1.05 [0.82-1.35]). These results suggest that angiogenin does not provide further information regarding outcome prediction in patients with PAD.

Soluble urokinase-type plasminogen activator receptor predicts peripheral artery disease severity and outcomes.

Soluble urokinase-type plasminogen activator receptor (suPAR) is associated with chronic kidney disease (CKD) severity and peripheral artery disease (PAD). We hypothesize an association of PAD severity and suPAR in patients without advanced CKD and further risk stratification according to the Kidney Disease: Improving Global Outcomes (KDIGO) guidelines. For study purposes, suPAR was measured in 334 PAD patients (34% women, age 69 (62-78) years, eGFR 68 ± 20 mL/min/1.72 m2) by commercial ELISA. Patients were followed for 10 years to assess long-term all-cause survival by Cox regression. Higher suPAR levels were associated with lower ankle-brachial index (R = -0.215, p = 0.001) in patients with PAD without media-sclerosis (n = 236). suPAR levels inversely correlated with decreased glomerular filtration rate (R = -0.476, p < 0.001) and directly correlated with urinary albumin-to-creatinine ratio (R = 0.207, p < 0.001). Furthermore, higher suPAR levels associated with a higher KDIGO risk score (p < 0.001). Baseline suPAR was significantly associated with all-cause mortality (HR 1.40 (95% CI 1.16-1.68), p < 0.001) over 10 years. suPAR remained associated with mortality (HR 1.29 (1.03-1.61), p = 0.026) after multivariable adjustment for age, sex, cardiovascular risk factors, and eGFR. Future research may define a standard role for suPAR assessment in PAD's work-up and treatment, especially in patients with CKD.

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.

GlycA for long-term outcome in T2DM secondary prevention.

AIMS: Glycosylated acetyls (GlycA), a systemic marker of inflammation, were associated both with incident type 2 diabetes mellitus (T2DM) and incident cardiovascular (CV) disease. This study evaluates the predictive value of GlycA for long-term survival in patients with T2DM and peripheral artery disease (PAD). METHODS: GlycA (mmol/l) levels were measured by nuclear magnetic resonance spectroscopy in a cross-sectional cohort of patients with PAD (n = 319). Both all-cause and CV mortality were evaluated after a follow-up of 9.0 (IQR 6.5-9.5) years. During the follow-up 117 patients died, of those 64 events were of CV origin (PAD-T2DM subgroup: all-cause mortality n = 60, CV-mortality n = 32). RESULTS: PAD-T2DM showed a tendency towards a worse CV risk factor profile and a higher percentage of known coronary artery disease (24.9% vs 43.5%, p < 0.001). GlycA levels were higher in PAD-T2DM (1.6 ± 0.2 vs. 1.53 ± 0.18, p = 0.002). GlycA predicted all-cause mortality after multivariable adjustment for traditional CV risk factors (HR for 1 SD increase 1.51, 95% confidence interval 1.03-2.19) in PAD-T2DM, while no association could be seen with CV-mortality (1.22, 0.73-2.06). CONCLUSIONS: GlycA was capable of predicting long-term outcome in PAD patients with T2DM. Thus, GlycA might reflect the added inflammatory burden of T2DM in systemic atherosclerosis.

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.

Predictive power of novel and established obesity indices for outcome in PAD during a five-year follow-up.

BACKGROUND AND AIMS: Previous data show contradicting results regarding relevance of obesity on outcome in peripheral arterial disease (PAD). Thus, this study aims to evaluate the predictive power of obesity as measured by established and novel obesity indices (waist circumference WC, waist-hip ratio WHR, body-mass index BMI, body adiposity index BAI, visceral adiposity index VAI, weight-adjusted waist index WWI) in a PAD cohort. METHODS AND RESULTS: In 367 patients with diagnosed PAD anthropometric parameters were assessed at study inclusion in an observational study. Mortality data was retrieved from the central death registry after five years. Outcome analyses were performed by multivariable Cox-regression models. 57 PAD patients (15.5%) died during the follow-up, of those 36 were categorized as cardiovascular origin. Patients from the all-cause mortality group were older, more often diabetics with a worse glucose control and had worse renal function. Obesity indices were not significantly different between the event and control group. None of the evaluated risk factors predicted cardiovascular or all-cause death after multivariable adjustment for age, gender, LDL-C, serum creatinine, systolic blood pressure, CRP, smoking habits, diabetes status and previous history of peripheral revascularisation (all-cause WC 1.007 (0.983-1.031), WHR 1.772 (0.106-29.595), BMI 1.006 (0.939-1.078), BAI 1.002 (0.945-1.063), VAI 1.019 (0.895-1.161), WWI 1.085 (0.831-1.416); cv-death WC 1.007 (0.978-1.036), WHR 0.382 (0.006-25.338), BMI 1.004 (0.918-1.098), BAI 1.034 (0.959-1.116), VAI 1.036 (0.885-1.213), WWI 1.061 (0.782-1.441)). CONCLUSION: Obesity as risk marker estimated by indices both for general and visceral adiposity, does not predict mortality in a secondary prevention cohort of PAD patients.

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.

Thrombospondin-4 increases with the severity of peripheral arterial disease and is associated with diabetes.

Thrombospondin-4 (TSP-4) is an extracellular matrix protein of the vessel wall. Despite bench evidence, its significance in the clinical setting of atherosclerosis is missing. TSP-4 (ng/ml) was measured in 365 PAD patientsusing a commercially available ELISA. PAD was diagnosed by the ankle-brachial index (ABI) and clinically graded using the Fontaine classification. TSP-4 levels were significantly higher in Fontaine II vs. Fontaine I (4.78 ± 0. 42, 4.69 ± 0.42, p = 0.043). TSP-4 significantly correlated with ABI (r = - 0.141, p = 0.023, n = 259) after the exclusion of mediasclerotic patients. Binary logistic regression analysis for Fontaine I vs. II showed an OR of 1.70 (1.02-2.82) in a multivariable model adjusted for traditional risk factors. Interestingly, TSP-4 levels were higher in patients with type 2 diabetes mellitus or prediabetes (DGT) compared with normal glucose tolerance (NGT) (4.76 ± 0.42 vs. 4.66 ± 0.41, p = 0.035). ANOVA for PAD and diabetes subgroups showed a linear increase with disease burden with the highest difference between Fontaine I-NGT and Fontaine II-DGT (4.59 ± 0.40, 4.79 ± 0.43, p = 0.015). TSP-4 levels increased with PAD severity and showed a former unknown association with diabetes. Thus, TSP-4 could be a novel marker of atherosclerotic activity, especially in the major subgroup of patients with concomitant diabetes.

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.