Peripheral arterial disease usually seriously affects the daily life quality of patients and imposes huge personal and societal healthcare burdens [21, 22]. Considering the certain relevance of the disease, effective earlier screening and diagnosis of PAD for diabetic patients has become increasingly important. However, there is still a lack of effective biomarkers with high sensitivity and specificity for early diagnosis, and often a patient consults the specialist when the disease is already significantly worsened. To the best of our knowledge, this is the first study to evaluate the association between serum Cyr61 level and the risk of PAD. Among a population of 306 patients with type 2 diabetes, we observed a positive correlation of serum Cyr61 with the prevalence of all stages of PAD.
ABI is a commonly used clinical examination tool, simple to operate and it can identify PAD very effectively. However, in most cases, when ABI is indicative of PAD, the patient is usually already at an advanced stage [23]. As PAD in diabetic patients can be more aggressive and may manifest more severe symptoms later, the research for early diagnosis tools for PAD is essential [3]. Recent years, several potential biomarkers were found to identify PAD in diabetic patients. For instance, serum high mobility group box 1 (HMGB1), fibroblast growth factor (FGF) 23 and osteopontin (OPN) have been correlated with the presence of PAD in diabetic patients [24, 25]. In addition, thrombospondin-4 (TSP-4) levels were significantly increased with PAD severity in patients with concomitant diabetes and could be a novel marker of atherosclerotic activity [26]. Lately, the association between circulating serum growth differentiation factor 15 (GDF15) and lower extremity atherosclerotic disease (LEAD) has been investigated in Chinese diabetes subjects [27]. Furthermore, Hayashi, A. et al. reported a method for accurate skin temperature measurement using noncontact, handheld infrared skin thermometer, which could serve as a new, cost-effective screening strategy for earlier diagnosis of PAD [28]. In the present study, Cyr61 has potential clinical significance as a simple, easy-to-measure biochemical marker of atherosclerosis.
Previous studies have demonstrated that CyrR61 is overexpressed in vascular smooth muscle cells of atherosclerotic lesions both in humans and in animal models [19, 29, 30], and could stimulate adhesion of vascular smooth muscle cells in a dose-dependent manner [11]. In particular, it has been evidenced that inhibition of Cyr61 in rat models of carotid balloon injury decreased proliferation of vascular smooth muscle cells and in turn intimal hyperplasia [16]. Therefore, we speculated that in the diabetic population of this study, higher Cyr61 levels are involved, at least in part, in the occurrence of atherosclerotic lesions of the lower limbs. To our knowledge, this is the first clinical study that serum Cyr61 levels were assessed as a potential biomarker for PAD in a diabetic population. Of particular interest, we also found that serum Cyr61 levels increase according to severity of PAD, as if there were a dose-dependent relationship. Therefore, values of Cyr61 may help to stratify patients to facilitate a more accurate diagnosis and individualized treatment. In addition, we still demonstrated that the relationship between higher Cyr61 levels and PAD in T2DM remains significant also after adjustment for potential confounding variables such as age, BMI, smoking status, diabetes duration, hypertension, eGFR and serum lipid profile. The ROC curve confirms that Cyr61 levels are able to predict the presence of PAD in our participants. If the results are confirmed, serum Cyr61 concentration could become a new biomarker with excellent sensitivity and specificity for early diagnosis and effective follow-up of PAD in diabetic subjects.
The study has several major limitations that should be noted. First, due to the cross sectional design of the study, we could not establish a causal relationship between serum Cyr61 and the development of PAD. Even so, our results support the hypothesis that Cyr61 is important in the peripheral atherosclerosis physiopathology. Second, the cross-sectional measurements may not represent the participant’s stable level of serum Cyr61. Therefore the results of this study should be interpreted with caution. Third, the enrolled individuals were hospitalized diabetic patients in Suzhou area (Jiangsu, China), the generalizability of the results to other diabetic populations needs to be tested. A further limitation is that we need prospective data to confirm whether higher Cyr61 levels may suffice as an effective biomarker for PAD in type 2 diabetes patients. In addition, we did not use healthy controls to determine normal level of Cyr61. In fact, there is no unequivocal report regarding the normal level of serum Cyr61 in humans, and we believe that our results can provide a relative reference for future studies on a large scale.