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.

Introduction: Trefoil factor 3 (TFF3), first described in the intestine has general growth but also angiogenic properties. Recently a role in cancer and inflammation was found. Classic cardiovascular risk factors have less predictive power for morbidity and mortality in patients with peripheral arterial disease (PAD) compared to patients with coronary heart disease (CHD). Hypothesis: Serum TFF3 levels are able to predict major adverse cardiovascular events (MACE) in patients with PAD. Methods: We applied bead array technology to assess the serum levels of TFF3 in 359 patients of a prospective, on-going, long-term follow-up PAD study. First MACE was used as outcome parameter, defined as occurrence of any death, non-fatal myocardial infarction or non-fatal stroke. Statistical analysis were performed including univariate correlations, Receiver Operating Characteristic (ROC) curves, students t-test , ANOVA, Kaplan-Meier (KM)-analysis and Cox-regression. Results: Patients with systemic atherosclerosis defined as concomitant PAD, CHD and cerebrovascular disease had significant higher levels of TFF3 (59.38±20.86 ng/ml) at baseline compared to patients with only one (47.22±18.10 ng/ml; p=0.001) or two (49.12±19.43 ng/ml; p=0.006) manifestations of atherosclerosis. KM-analysis demonstrated a significant lower event-free survival for the fourth quartile of TFF3 (71.1%) compared to the other (88.1%) (Log-rank: p<0.001). By using ROC a cut-off for TFF3 of 56.18 ng/ml was defined (sensitivity 56.9%; specifity 72.1%). A multivariable Cox regression model adjusted for age, gender, LDL-Cholesterol, systolic blood pressure, eGFR, diabetes status, smoking status and CRP showed that patients with TFF3 levels higher than 56.18 ng/ml had a hazard ratio of 2.77 (95%Cl: 1.38 - 5.58) for experiencing MACE. Conclusions: Our data imply a significant association of serum Trefoil Factor 3 and the occurrence of MACE in patients with atherosclerosis. This association of Trefoil Factor 3 and MACE was unchanged by C-reactive protein. Whether the association of Trefoil Factor 3 is causal, or a consequence of advanced atherosclerosis should be investigated in future trials containing time courses of Trefoil Factor 3 and MACE.

Introduction: Proteins which are involved in the bone metabolism have recently been discovered to have significant implications in the development of vascular disease and complications. Osteopontin (OPN) has been suggested as a biomarker of atherosclerosis and vascular calcification. Hypothesis: OPN levels may be used for risk stratification in patients with peripheral artery disease (PAD). Methods: 361 patients suffering from PAD were studied and followed-up for five years. 60 outcome events, defined as death, non-fatal myocardial infarction or non-fatal stroke, were observed. Multiplex bead array technology was used to measure serum levels of OPN at baseline. For basic analysis, the patients were divided into quartiles according to OPN levels. A Cox regression model was used to identify confounding variables. Results: A significantly different event-free survival could be observed between all groups (log-rank: p=0.049). When comparing the highest quartile to the rest of the cohort, a further increase in significance could be observed (log-rank: p=0.017). A cut-off point accommodating the most favorable sensitivity (50.0%) and specificity (66.4%) was determined for regression analysis. The hazard ratio was 2.13 (1.26-3.60) in the unadjusted model and reached 2.16 (1.21-3.84) after adjustment for age, gender, diabetes, low-density lipoprotein cholesterol, blood pressure, smoking, c-reactive protein and renal function. Conclusions: Our results suggest an association between OPN levels and the rate of cardiovascular events in high risk patients. In our observations this relation was independent of established risk factors.

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Introduction: Angiopoietin 2 (ANG2) is a pro-inflammatory protein which is elevated in several inflammatory conditions and associated with increased morbidity and mortality. Hypothesis: ANG2 is associated with the composite of death, non-fatal myocardial infarction and non-fatal stroke (MACE) in patients with peripheral arterial disease (PAD). Methods: We measured serum ANG2 levels at baseline in 363 consecutive PAD patients with using multiplex bead array technology. Follow-up was five years. In Cox regression, confounding was evaluated by examining the relative change in coefficients (delta-beta) for ANG2 after the omission of the respective potential confounder from the fully adjusted model. Significant Confounding was defined as a delta-beta > 10%. Results: Using receiver operating characteristics, ANG2 exhibited an area under the curve of 0.6 (95%CI: 0.522 - 0.678) for the proper discrimination between MACE and non-events. A cut-off of 3.74 ng/ml resulted in the highest possible combination of specifity (57.5%) and sensitivity (63.3%) leading to an unadjusted hazard ratio (HR) of 2.17 (95%CI: 1.28 - 3.67) in Cox regression (p=0.004). Adjusting for age, sex, diabetes, systolic blood pressure, smoking status and renal function lead to a HR of 1.89 (95%CI: 1.11 - 3.24) for ANG2 >3.74 ng/ml (p=0.020). The additional adjustment for c-reactive protein (CRP) resulted in a no more significant HR of 1.68 (95%CI: 0.97 - 2.92)for high ANG2 (p=0.067). Diabetes and CRP, both significant predictors of MACE in our cohort, proved to be significant confounders with concomitant delta-betas of 19.7% and 22.9%, respectively. Conclusions: We are the first to demonstrate that elevated ANG2 levels are interrelated with MACE in patients with PAD. Inflammation and glucose hemostasis seem to influence this association.