To the best of our knowledge, the present study is the first to report that serum Vcn and VEC may represent useful circulating biomarkers of AAD. AAD is a serious disease that requires vascular surgery and is characterized by a tear in the descending aorta, high mortality, and disability.(13) Endothelial injury is considered to be an important component of the pathogenesis of AAD.(14, 15) Vcn and VEC play crucial roles in the formation and stabilization of epithelial cell-cell adhesion.(16) Therefore, in the present study, the high serum concentrations of Vcn and VEC may reflect the severity of the aortic injury in AAD.
Vcn is an important component of the focal adhesion complex(9) and exists in active and inactive forms. The active form of Vcn is localized to focal adhesions at membranes and participates in their regulation.(17) The recruitment of Vcn is important for the maintenance of the epithelial barrier, which is achieved by protecting endothelial junctions from opening during force-dependent remodeling.(11) Zemljic-Harpf and colleagues reported that Vcn deficiency contributes to cardiomyopathy.(18) VEC is an endothelial-specific member of the cadherin family that can maintain the stability of endothelial cell-cell junctions.(19) Recent studies have shown that when endothelial junctions are disturbed, some VEC molecules can be released into the blood in a soluble form.(20, 21) The loss of VEC induces pathophysiological conditions, including inflammation, vascular leakage, and tumor-associated angiogenesis.(22, 23) It has also been previously reported that Vcn can protect VEC junctions from opening during their force-dependent remodeling.(16)
It has been reported that mechanical stretch can aggravate AAD in a β-aminopropionitrile-induced rat model.(24) Therefore, increases in the serum concentrations of VEC and Vcn may reflect dysfunction of endothelial junctions. Furthermore, if there are fewer or weaker Vcn-dependent VEC-based junctions, an appropriate response cannot be mounted to the higher force being exerted on the aortic wall in patients with AAD, which may promote its progression.
Previous studies have shown that when the connections between vascular endothelial cells are damaged, the permeability of endothelium increases, and immune cells are able to penetrate the vascular wall, which reduces its integrity and promotes aortic dissection.(25–27) During this process, vascular endothelial inflammation develops, which is characterized by an accumulation of innate immune cells.(28)
Serum C-reactive protein (CRP) and D-dimer concentrations are routinely measured to aid in the diagnosis of AAD. However, the serum CRP concentration is rarely high in the acute phase of onset of AD, which implies that it has low diagnostic value for the early diagnosis of AAD.(29, 30) In addition, the sensitivity and negative predictive value of serum D-dimer concentration are very high at the time of patient admission, but the associated specificity and positive predictive value are much lower.(31–33) Because AAD affects the aortic wall, biomarkers related to injury of the vascular endothelium may be of clinical value.
In the present study, having identified high serum VEC and Vcn concentrations in most of the participants with AAD, we next determined the value of serum VEC and Vcn and their combination for the diagnosis of AAD. According to the ROC curves, both Vcn and VEC have relatively high specificity for the diagnosis of AD, and the specificity of Vcn was higher than that of VEC. However, the sensitivities for the use of both proteins were unsatisfactory (35% and 43% respectively). Interestingly, the VEC-Vcn combination improved the diagnostic accuracy and sensitivity, and yielded a significantly higher AUC (0.739) than VEC or Vcn alone. These findings suggest that serum VEC and Vcn represent non-invasive markers of AAD, and the use of the two in combination may represent a promising means of improving the diagnosis of AAD, and especially the differential diagnosis of a high serum D-dimer concentration. We believe that the development of joint diagnostic kits in the future can further improve diagnostic efficiency.
In the present study, we also found that participants with a history of hypertension had a significantly higher serum Vcn concentration than those without hypertension. The serum VEC and Vcn concentrations significantly correlated and each concentration correlated with several other blood parameters. VEC concentration significantly correlated with that of D-dimer, and Vcn concentration significantly correlated with neutrophil count, and the serum HDL-C and TG concentrations. D-dimer is a cross-linked fibrin degradation product that appears in the serum after thrombolysis, and neutrophil count may reflect the acute-phase inflammatory status in AAD.(34) In addition, high serum HDL-C and TG concentrations are considered to be the risk factors for cardiovascular disease.(35–37)
Further multiple logistic regression analysis showed that the serum VEC and Vcn concentrations were associated with the prevalence of acute preoperative complications in patients with AAD. Of note, compared with patients with refractory pain, the adjusted OR for VEC concentration in patients without refractory pain increased to 1.172. However, high Vcn concentration is also indicative of a higher risk of poor visceral perfusion in patients with AD. Thus, although these parameters do not reflect all the aspects of the condition, it is clear that they provide at least a partial indication of the progress of the disease.
The present study had some limitations. First, the changes in the serum VEC and Vcn concentrations were not assessed. Second, the sample size was relatively small. Third, we were not able to measure many blood parameters in the control group. However, the future assessment of tissue expression levels and mechanistic research will provide more detailed information regarding the links between serum VEC and Vcn concentration and AAD.
In conclusion, we have shown that the serum concentrations of both serum Vcn and VEC are significantly higher in patients with AAD. In addition, there were close associations between Vcn and VEC and preoperative complications. Furthermore, we have provided evidence that both VEC or Vcn represent highly specific biomarkers for AAD and may be applicable to the differential diagnosis of AAD.