Discussion
Intramural hematoma is part of the spectrum of acute aortic syndromes (5–25%) and is more common in the descending thoracic aorta (type B, 60–70%) than in the ascending aorta [1-3] . IMH without mal-perfusion syndrome are always regarded as a benign disease, and the “wait and watch strategy” (initial medical treatment plus necessary thoracic endovascular aortic repair treatment) is the first recommendation for these patients [1-3][17]. Many potential risk factors of IMHB have also been summarized, including a maximum aortic diameter larger than 45 mm, increased pleural effusion, hematoma thickening larger than 10 mm, ULP development, and elevated C-reactive protein (CRP) levels [1]. Overall, patients with IMHB have a more favorable long-term prognosis than patients with aortic dissection and an in-hospital mortality risk lower than 10% during the acute phase [1]. The mortality rate after TEVAR during the acute phase in our study was (Table 2 , 18% in the non-DM group) obviously lower than that in the report from Schoenhoff et al. (the mortality rate of TEVAR within and after the first two weeks was 25% and 29%, respectively) and was higher than that of type B aortic dissection patients who underwent TEVAR treatment (0% to 18%, and median 6%) [5] . Falconi et al. [18] reported that of 27 patients with type B IMH managed conservatively and followed for a mean of 33 months, 47% underwent regression, 14% remained stable, and 39% progressed to aortic dissection or enlargement. Motoyoshi et al. [18] reported that of 26 patients managed medically, 6 patients (23%) had spontaneous regression and 7 patients (27%) required a surgical procedure. Although the non-DM group in our study had a higher reintervention rate than the DM group during the follow-up [11% vs 2%, P =0.044], the reinvention rate was obviously lower than previous studies (60% [6] , 39%[18] , 27% [19] ).
One possible explanation for this higher mortality rate after receiving TEVAR treatment was the larger aorta diameters and thicker hematoma thickness in the non-DM group. Bischoff et al. [20]indicated that patients with larger ascending aorta diameters had a worse clinical outcome than those with smaller aortas. Ye et al. also recommended that patients with aortic diameters larger than 45 mm and hematoma thicknesses thicker than 10 mm should be included in the “complicated” group, and that a more aggressive TEVAR treatment was required in these patients to prevent a fatal evolution of the IMHB[21] . In addition, the geometry of the aorta can be influenced by TEVAR, which could result in a poor outcome, especially in those with ascending aortas larger than 40 mm (who are more likely to suffer from retrograde type A aortic dissection after TEVAR)[22] . In the non-DM group, one patient died of retrograde type A aortic dissection after TEVAR during the acute phase. All the two patients who died after TEVAR in the non-DM group all had ascending aorta larger than 40 mm (Supplement 1 ). Perhaps, an ascending aorta larger than 40 mm is another potential evolution predictor of IMHB.
The other possible explanation for this higher mortality rate was the improper timing of TEVAR and the stent graft size. The current timing of TEVAR for uncomplicated IMHBs is in line with that for the uncomplicated type B aortic dissections (patients with expansion of the IMH despite medical therapy, and the disruption of the intimal tear on CTA scans with contrast enhancement) [1][4] . However, the disease progression of IMHB is highly unpredictable, and the current guidelines were based on good outcomes of TEVAR for type B aortic dissections[23][24] and on some small sample studies for IMHBs[1][4][25][26] . In other large sample studies, up to 62% of IMHB patients required TEVAR treatment (43% underwent TEVAR during the first two weeks and 19% after acute phase and during the first year), and the mortality rate within and after the first two weeks were 25% and 29%, respectively [5] . In our study, all 12 patients with uncontrollable symptoms (especially refractory pain) underwent TEVAR. All the two patients who finally died of aorta-related complications still complained of refractory pain after TEVAR (Supplement 1 ). Juvonen et al. [27] reported that patients with uncharacteristic or atypical pain have a higher risk of rupture over time than those without pain. Medical management of such patients is unwarranted unless their life expectancy and quality of life were markedly impaired [28] . A more aggressive TEVAR procedure (while the symptoms are still controllable) would likely have better outcomes (acute phase mortality: 0%, Bischoff et al.[20] , 0%, Ye et al. [21] ), and this more aggressive strategy is likely to prevent the progression of IMHBs and result in a better prognosis than medical treatment plus necessary TEVAR (for patients with uncontrollable symptoms and fatal evolution). Further studies are necessary to evaluate whether uncomplicated IMHBs without diabetes mellitus could benefit from more aggressive TEVAR treatment while the symptoms are still controllable. In addition, in our study, the diameter of the stent graft was oversized by less than 10% which was smaller than those in the study of Schoenhoff et al. (10% to 15%).[5]. However, both in our study and in the study of Schoenhoff et al. [5] , the mortalities rates were higher than those after TEVAR for type B aortic dissection[4][29] . For aortic dissections, there is a general agreement in the current guidelines that the oversizing factor should not exceed 5% [29] . Is it necessary to utilize less oversizing (not exceeding 5% [29] ) for stent grafts like the recommendations for aortic dissection for patients with IMHB?
In addition, ULP development during the acute phase and the CRP level was associated with an elevated risk for aorta-related mortality. Moral et al. [30] reported that 10% of the patients with uncomplicated IMHBs suffered from the development of an ULP during the acute phase; among these patients, the disease progression rate was as high as to 91%, and 36% of them died of aortic-related complications. Kitai et al. reported that 71% of the patients with IMHBs had an ULP during the acute phase, and 76% of them showed progression (enlargement or progression to aortic aneurysm) that required further treatment[31] . The potential risk factors of ULP development are large aortic diameters and hematoma thicknesses, which are also the non-DM patients of IMHBs [30]. In addition, in the clinical work, a higher CRP level may be indirect evidence that could represent the degree of the inflammatory reaction and pathophysiological changes in the aortic wall under such unstable hemodynamic conditions; a sustained high CRP level has significant prognostic value in IMHB patients [32].
Newly diagnosed type 2 DM patients with IMHB probably benefit from antidiabetic treatments and tight glycemic control may influence the evolution of IMHB. The potentially protective value of DM has been well described [8-11], and the possible explanations included the increasing matrix of the aortic wall (suppression of plasmin and decreased levels/activity of MMP-9), and decreased aortic mural macrophage infiltration and neovascularization [16] . MMP-9 is involved in tissue degradation and remodeling in aortic dissection and is significantly increased in aortic dissection patients, and a higher level of MMP-9 can weaken the aortic media by degrading multiple extracellular components; DM patients have a 2-fold decreased level of MMP-9, which may restrict the degradation of the aortic wall[16]. Unlike the effect of hyperglycemia on immune cell activity in type 2 DM, the impact of insulin deficiency in type 2 DM on macrophage activity has not been wildly studied. Tessaro et al. demonstrated that the administration of exogenous insulin in diabetes may enhance the immune activity of macrophage [33] and the insulin treatment may diminish this protective effect of hyperglycemia that prevent the aortic aneurysm development process (under laboratory conditions) [34]. For these reasons, it seems that the administration of insulin is probably a risk factor of disease progression in type 2 DM patient with IMHB. In our study, after receiving tight glycemic control recommended by guidelines[7], the DM group had an MMP-9 level that was dramatically increased (reached the highest value) during the acute phase and the MMP-9 level of DM group reached the highest level early than that in the non-DM group. But, the MMP-9 levels of DM group were lower than non-DM group at each timepoint (P< 0. 001, Figure 2A ) and non-DM group had a 2-fold higher level of MMP-9 after the day 90 than DM group, which probably indicated the potentially protective effect of hyperglycemia probably not decreased after the administration of insulin which probably could explain the significantly lower aorta-related mortality in the DM group during the follow-up period. Until now, the mechanism of the protective effect of hyperglycemia, administration of insulin and other antidiabetics treatment in aortic diseases are still unclear and require further studies.
There are several limitations to this study. First, in this study, the majority of patients received only two CTA examinations during the acute phase (once on admission and once before discharge), and the diagnosis of ULP could be influenced by the preciseness of CTA images. Closer monitoring for the development of an ULP is necessary in further studies. Second, in future studies, we should enroll more patients with different medical treatment strategies, which may provide more meaningful insight into the influence of these strategies on IMHBs.