Abstract
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.
Highlights
Peripheral arterial disease (PAD) is caused by atherosclerosis of the lower limb arteries in over 90% of patients
There was no significant difference in traditional cardiovascular risk factor for patients according to TSP-4 tertiles
A trend was seen with increased age (p = 0.052), reduced creatinine clearance (p = 0.087), reduced estimated glomerular filtration rate (eGFR) (p = 0.075) and the combination of prediabetes and type 2 diabetes mellitus (DGT, p = 0.073) in the highest versus the lowest tertile
Summary
Peripheral arterial disease (PAD) is caused by atherosclerosis of the lower limb arteries in over 90% of patients. PAD itself can be considered a marker for systemic atherosclerotic processes [1]. Atherosclerosis is postulated to be an inflammatory process promoted by several given and some modifiable risk factors such as hypercholesterinaemia, diabetes, smoking and arterial hypertension [2]. Specific determinants of the development of symptoms on the other hand are not fully understood yet. The ability to form novel vessels (angiogenesis) is hypothesized to be a major contributor in relieving IC symptoms [4]. A major characteristic of atherosclerotic progression into a vulnerable plaque is intraplaque haemorrhage caused by immature intraplaque vessel formation [5]. There is no consensus on how to measure angiogenesis in the clinical setting
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