Purpose: The aim of this study is to evaluate plasma biomarkers as predictors for peripheral arterial disease (PAD). Materials and methods: Prospective longitudinal cohort study of middle-aged individuals from the cardiovascular cohort of the Malm€ o Diet and Cancer study (MDCS) (n ¼ 5550; 1991-94). Cystatin C, copeptin, N-terminal pro-B-type natriuretic peptide (N-BNP), midregional proatrial natriuretic peptide (MR-proANP), mid-regional proadrenomedullin (MR-proADM), and conventional risk factors were measured at baseline. The diagnosis of symptomatic PAD was validated in 97% of the cases. Results: Cumulative incidence of PAD during median follow up of 23.4 years was 4.4% (men 5.9%, women 3.3%). Adjusted for age, sex, smoking, body mass index, hypertension, diabetes mellitus and total cholesterol, copeptin (hazard ratio [HR] 1.46; 95% confidence interval [CI] 1.19-1.80), N-BNP (HR 1.28; 95% CI 1.11-1.48), and cystatin C (HR 1.19; 95% CI 1.10-1.29) were independently associated with incident PAD. Subjects with the three biomarkers copeptin, N-BNP, and cystatin C in the highest quartiles, ran a high risk of incident PAD (HR 3.29; 95% CI 1.76-6.17) compared to those with no biomarker in the highest quartile. Conclusion: Copeptin, N-BNP, and cystatin C were associated with incident symptomatic PAD, implying that these biomarkers are sensitive indicators of early subclinical PAD. CLINICAL SIGNIFICANCE First prospective longitudinal cohort study evaluating Cystatin C, copeptin, N-terminal pro-B-type natriuretic peptide (N-BNP), midregional proatrial natriuretic peptide (MR-proANP), and mid-regional proadrenomedullin (MR-proADM) as predictors for peripheral arterial disease (PAD). Copeptin, N-BNP, and Cystatin C where independently associated with incident symptomatic PAD after adjustment for conventional risk factors. Copeptin, N-BNP, and Cystatin C seem to be sensitive indicators of early subclinical PAD.

We evaluated if plasma biomarkers can predict incident peripheral arterial disease (PAD) and mortality in a longitudinal cohort study. Men (n = 3618) and women (n = 1542) were included in the Malmö Preventive Project and underwent analysis of: C-terminal endothelin-1 (CT-proET-1), N-Terminal prosomatostatin (NT-proSST), midregional proatrial natriuretic peptide (MR-proANP), procalcitonin (PCT), and copeptin. Participants were followed up for incident PAD and mortality until December 31, 2016. Median follow-up was 11.2 years (interquartile range 9.4-12.2). Cumulative incidence of PAD was 4.3% (221/5160), 4.5% in men (164/3618) and 3.7% in women (57/1542; P = .174). In an adjusted Cox proportional hazards regression model, higher CT-proET-1 (hazard ratio [HR] 1.8; 95% confidence interval [CI] 1.4-2.3), NT-proSST (HR 1.5; 95% CI 1.2-2.0), and MR-proANP (HR 1.7; 95% CI 1.3-2.3) were independently associated with incident PAD, and higher CT-proET-1 (HR 1.3; 95% CI 1.2-1.5), NT-proSST (HR 1.2; 95% CI 1.1-1.3), MR-proANP (HR 1.4; 95% CI 1.3-1.6), PCT (HR 1.1; 95% CI 1.0-1.2), and copeptin (HR 1.2; 95% CI 1.1-1.4) were independently associated with mortality. Increased levels of CT-proET-1, NT-proSST, and MR-proANP were independently associated with incident PAD, whereas all the vasoactive biomarkers were independently associated with mortality during follow-up.

Summary: Background: Peripheral arterial disease (PAD) is a common atherosclerotic disease with severity ranging from asymptomatic to chronic limb threatening ischemia. The aim of the present cross-sectional study was to identify novel biomarkers associated with PAD. Patients and methods: Levels of 91 cardiovascular specific proteins in plasma samples were measured by the Proseek Multiplex CVD III96x96 panel from a cohort consisting of 267 65-year-old men recruited from a screening program for abdominal aortic aneurysm (AAA) Levels of protein biomarkers were compared in men with and without PAD (defined as an ankle brachial index of <0.9) and their diagnostic potential was calculated by receiver-operating characteristic analysis. Results: The prevalence of PAD was 14.2% (38/267). After adjustment for multiple comparisons, levels of the following 11 biomarkers remained significantly higher ( p<0.0001) in patients with PAD: secretoglobin family 3A member 2, osteoprotegerin, urokinase-type plasminogen activator surface receptor, serum macrophage chemokine ligand 16, matrix metalloproteinase 9, p-selectin, growth differentiation factor 15, elafin, cystatin B, trefoil factor 3, and fatty acid-binding protein 4. Multivariable logistic regression analysis (adjusted for smoking, use of antihypertensive and lipid-lowering medication, and metformin) showed that 11 biomarkers were significantly associated with higher risk of PAD with odds ratios ranging from 1.6 to 2.4. Area under curve calculated by receiver operating characteristic curve analysis (diagnostic value) for each protein biomarker ranged from 0.63 to 0.74. Conclusions: We have identified multiple proteins with a potential to be diagnostic biomarkers for PAD, and further research is warranted to clarify their potential predictive and prognostic value.

Background: Diabetes mellitus (DM) is an established risk factor for intermittent claudication (IC) and other manifestations of atherosclerotic peripheral arterial disease. Indications for surgery in infrainguinal IC are debated, and there are conflicting reports regarding its outcomes in patients with DM. Aims of this study were to compare both short- and long-term effects on total- and cardiovascular (CV) mortality, major adverse cardiovascular events (MACEs), acute myocardial infarction (AMI), stroke, and major amputation following infrainguinal endovascular surgery for IC in patients with and without DM. We also evaluated potential relationships between diabetic control and outcomes in patients with DM. Methods: Nationwide observational cohort study of patients registered in the Swedish Vascular Registry and the Swedish National Diabetes Registry. Propensity score adjusted comparison of total and CV mortality, MACE, AMI, stroke, and major amputation after elective infrainguinal endovascular surgery for IC in 626 patients with and 1112 without DM at 30 postoperative days and after median 5.2 [interquartile range (IQR) 4.2–6.3] years of follow-up for patients with DM, and 5.4 (IQR 4.3–6.5) years for those without. Results: In propensity score adjusted Cox regression after 30 postoperative days, there were no differences between groups in morbidity or mortality. At last follow-up, patients with DM showed higher rates of MACE [hazard ratio (HR) 1.26, confidence interval (CI) 1.07–1.48; p < 0.01], AMI (HR 1.48, CI 1.09–2.00; p = 0.01), and major amputation (HR 2.31, CI 1.24–4.32; p < 0.01). Among patients with DM, higher HbA1c was associated with higher total mortality during follow-up (HR 1.01, CI 1.00–1.03; p = 0.045). Conclusion: Patients with DM have higher rates of MACE, AMI, and major amputation in propensity score adjusted analysis during 5 years of follow-up after infrainguinal endovascular surgery for IC. Furthermore, HbA1c is associated with total mortality in patients with DM. Prevention and treatment of DM is important to improve cardiovascular and limb outcomes.

Summary: Background: Diabetes mellitus (DM) is a risk factor for peripheral arterial disease (PAD). Indications for open surgery in infrainguinal intermittent claudication (IC) are limited, and reports are lacking regarding outcomes in DM patients. Study aims were to compare short and long-term effects on major adverse cardiovascular events (MACE), acute myocardial infarction (AMI), stroke, major amputation, and mortality after infrainguinal open surgery for IC in patients with and without DM, and to evaluate relationships between glycaemic control and outcomes. Methods: Nationwide observational cohort study of all patients registered in the Swedish Vascular Registry after planned infrainguinal open surgery for IC from January 1st 2010 to December 31st 2014. Patients registered in the National Diabetes Registry were compared with patients without diabetes by propensity score adjusted comparison of MACE, AMI, stroke, major amputation, and mortality. Results: After 30 days, there were no differences in MACE, AMI, stroke, major amputation, or mortality between patients with (n = 323, mean age 70.5 [SD 7.4] years, 92 [28.5%] females) and without (n = 679, mean age 69.7 years [SD 11.2], 234 [34.5%] females) DM. At last follow-up after median 5.2 years, patients with DM showed higher rates of MACE (Hazard ratio [HR] 1.33, confidence interval [CI] 1.08–1.62; p < 0.01), and AMI (HR 2.21, CI 1.46–3.35; p < 0.01) than patients without diabetes. Among DM patients, higher glycated haemoglobin (HbA1c) was associated with higher rates of MACE (HR 1.02, CI 1.00–1.03; p = 0.02), stroke (HR 1.05, CI 1.00–1.11; p = 0.04), and total mortality (HR 1.03, CI 1.01–1.06; p < 0.01), during follow-up, whereas duration of diabetes was associated with higher rate of major amputation (HR 1.08, CI 1.02–1.15; p < 0.01). Conclusions: DM patients showed higher rates of MACE and AMI in propensity score adjusted analysis five years after planned infrainguinal open surgery for IC. Higher HbA1c was associated with MACE, stroke, and total mortality in patients with DM, whereas longer duration of DM was associated with major amputation.