T2DM patients with PAD have a higher risk of cardiovascular complications than T2DM patients without peripheral vascular involvement[2]. Despite multiple therapeutic approaches and multidisciplinary management, definite biomarkers, useful to stratify the risk for T2DM patients with PAD and CLTI are not available[24, 25]. Regarding follow-up after revascularization, even less clear evidence is available[26]. In fact, outcomes after LER vary widely among T2DM patients[6]. Despite similar baseline clinical characteristics―in terms of risk factor control and PAD severity―and the same endovascular approach, some patients do not encounter complications for years while other patients may have complications, even fatal, within a few months[26]. Several potential biomarkers have been proposed, some linked to patient's genetic characteristics[25, 27–29], many linked metabolic and inflammatory parameters[19, 25, 30–33]. Among the possible candidates, the pathways linked to adipose tissue represent a promising field of study. In particular, adipokines have been extensively studied and a strong relationship between these bioactive molecules and the mechanisms underlying vascular complications of T2DM[25]. In this scenario, Omentin-1 could be an ideal biomarker.
The most important result of this study is that baseline Omentin-1 levels correlate with the incidence of MACE during the period following LER in T2DM patients with PAD and with CLTI. Patients with lower Omentin-1 levels had more myocardial infarctions, strokes and deaths. Amongst the explanations for our results, compelling evidence exists that demonstrates an inverse relationship between Omentin-1 levels and some traditional risk factors for diabetic complications, including the amount and distribution of adipose tissue and glycemic control[34, 35]. In this sense, it is possible that reduced Omentin-1 levels indirectly influenced the outcomes of our population, through the action of other risk factors. However, we did not observe differences in terms of BMI and glycemic balance in patients who had MACE compared to patients who did not. An additional possible explanation is that Omentin-1 per se is a direct cardiovascular risk factor. This suggestion is in line with several previous evidences which demonstrate that Omentin-1 levels are inversely correlated with the presence of CAD[9]. Indeed, Omentin-1 levels are inversely related to the presence and extent of coronary artery atherosclerosis. Furthermore, the serum levels of this protein are independently correlated with carotid atherosclerosis and the presence of carotid plaque, increasing the risk of stroke[36, 37]. Accordingly, in our cohort, Omentin-1 levels significantly increased not only in the composite MACE outcome, but also in the three distinct adverse events―myocardial infarction, stroke and death―strengthening our findings further. An additional interesting result of our study, emerging from the ROC and Kaplan-Meier curve analysis, is that cut-off values exist identifying higher risk patients that could develop early vascular complication. This could allow physicians to design a personalized follow-up, based on Omentin-1 levels before LER procedure.
The molecular mechanisms underlying the effects observed could be numerous. Omentin-1 can determine several important protective effects on the vascular system through nitric oxide, Akt and the AMP-activated protein kinase pathways [38]. In particular, by reducing endothelial dysfunction[39], oxidative stress and neointimal proliferation[40]. Omentin-1 can reduce the atherosclerotic process and the development of the myocardial infarction itself[41].
A further finding of this study is that baseline Omentin-1 levels correlate with the incidence of MALE during the follow-up period. This result is of particular interest in T2DM patients frequently facing numerous complications associated to PAD during their clinical history. One of the possible explanations can be found in the initial stratification that demonstrates how Omentin-1 levels correlate with PAD severity, in terms of ABI and Rutherford staging, which is in agreement with previous studies. The new and most interesting result is that the prospective nature of the study allows assigning a predictive significance to the initial Omentin-1 levels. Additionally, multivariate analyzes confirm an effect independent of other vascular risk factors, such as smoking or increased LDL-C.
Amongst the limitations of our study, the relatively small, single-center patient cohort and the impossibility to establish whether the results are replicable in a larger number of patients. Furthermore, it is unfeasible to determine whether Omentin-1 levels play a direct role on the vascular risk of our cohort or if it is only an epiphenomenon. However, the aim of the investigation was to explore a risk stratification biomarker and, in this perspective, the study design was appropriate. A further limitation is that the association between statin therapy and Omentin-1 levels, which may have affected the LDL-C target during follow-up, has not been evaluated.
Finally, an accurate analysis on the relationship between localization of initial arterial stenosis, restenosis and MALE has not been performed. The restrictive selection criteria, also excluding 17 patients where revascularization failed, reduced bias.