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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.

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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.

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