Identifying PAD in DFUs patients is important, given its association with failure to heal, amputation, CVDs and increased risk of mortality. Earlier assessment of the severity of PAD is required to determine the need for revascularization to promote ulcer healing . However, most of the PAD in patients with diabetes is asymptomatic. Therefore, a profound understanding of potential risk factors in the severity of PAD in DFUs patients is imperiously needed, which might be helpful for early identification and subsequent initiation of therapy for subjects with severe PAD in DFUs patients.
The present study revealed a positive association between QTc interval and severe PAD in DFUs patients. Longer QTc and higher prevalence of prolonged QTc were found in DFUs patients with severe PAD. Longer QTc was significantly and independently associated with increased risks of severe PAD.
The Insulin Resistance Atherosclerosis Study including 1,577 subjects found that QT interval was prolonged in type 2 diabetes, even in newly diagnosed diabetes . A Japan study  found that neuropathy, nephropathy and the multiplicity of the microvascular complications were independently associated with QTc in patients with type 2 diabetes. Studies [19, 21] found associations between subclinical atherosclerosis marker: carotid intima media thickness and QTc prolongation in a clinically healthy population and in patients with type 2 diabetes. Pulse wave velocity is another established subclinical atherosclerosis marker. A link between pulse wave velocity and QTc have been found in clinically healthy population of Japanese. Prolonged QTc was found to be associated with an increased risk of newly developed and a higher incidence of PAD, which was diagnosed as ankle–brachial index (ABI) < 0.9 or > 1.4 at either side in a general population of china . Few studies have addressed the association of QTc with DFUs. Katarina Fagher et al found in DFUs patients, QTc prolongation was associated with increased mortality [17, 27] and hyperbaric oxygen therapy might protect against QTc prolongation . Shumin Wang found QTc prolongation was associated with a higher CVDs mortality in DFU patients, but it cannot predict ulcer healing or recurrence. The present study extends the associations to the severity of PAD in DFUs patients.
In accordance with previous studywhich found DFUs patients with prolonged QTc tended to have higher prevalence of severe DFUs (Wagner 3 to 5 degrees) in China, the present study found that the prevalence of severe DFUs (Wagner grade score ≥ 3) was positively correlated with QTc. The severity of DFUs maybe can be partly explained by the co-existing severe PAD. However, in this study, DFUs patients with severe PAD had higher prevalence of severe DFUs, but did not reach statistical significance.
PAD has been classified as an equal risk factor for CVDs. Patients with PAD have an equivalent cardiovascular risk to patients with previous myocardial infarction . Studies indicated that QTc was associated with the risk of CVDs in different populations [12, 13, 16, 31]. Patients with severe PAD have a high risk of CVDs, which might affect QTc.
Studies have indicated that QTc is associated with age , glycemic control , hypertension , hyperuricemia , hyperinsulinemia  and metabolic syndrome , which are risk factors for the occurrence of PAD events in patients with diabetes.
The mechanism underlying the association between QTc and severe PAD has not been fully elucidated. PAD is usually caused by atherosclerosis. Other causes may be inflammation , which can reduce vascular nitric oxide bioavailability . Then inhibit the Ca2+-ATPase and K+/Na+-ATPase, leading to an increase of cytosolic free calcium and a prolongation of myocardial repolarization .
The strengths of this study included a more precise measurement: duplex ultrasonography. Duplex ultrasonography is mostly used in detecting and localizing lesions in different territories of the vascular, and quantifying their grade of severity with the application of velocity and pressure gradient criteria. It can diagnose arterial disease at a very early stage . Duplex ultrasonography is often recommended as the first-line non-invasive investigation for people with PAD. It has 85–90% sensitivity and > 95% specificity to detect stenosis > 50% . To our knowledge, this is the first study to address the associations between QTc and severe PAD in DFUs patients based on the measurements of duplex ultrasonography. Second, the participants of the present study were from multi-center including six different medical institutions. Therefore, the results may be applicable to general DFUs populations. The present study also has some limitations. Firstly, the sample size is relatively small, the result needs to be verified in a more larger sample. Second, because of the basic features of the cross-sectional study, we could not determine a cause-effect relationship between QTc and severe PAD in DFUs patients. Larger prospective cohort studies are needed for further exploration.