Discussion
IMH 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 malperfusion
syndrome is 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 for IMHB have also been summarized, including a
maximum aorta diameter larger than 45 mm, increased pleural effusion,
hematoma thickening larger than 10 mm, ULP development, and elevated 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 18% in the non-DM group (Table 2 ), similar to
the report by Schoenhoff et al. (the mortality rates of TEVAR within and
after the first two weeks were 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 type B IMHs in patients
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 that in
previous studies (60% [6] , 39% [18] , 27%[19] ).
Newly diagnosed type 2 DM patients with IMHBs probably benefit from
antidiabetic treatments, and tight glycemic control may influence IMHB
evolution. The potentially protective value of DM has been well
described [8-11], and the possible explanations include the
increasing matrix of the aortic wall (suppression of plasmin and
decreased levels/activity of MMP-9) and decreasing 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 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 widely studied. Tessaro et al.
demonstrated that the administration of exogenous insulin in diabetes
may enhance the immune activity of macrophages [20], and
insulin treatment may diminish this protective effect of hyperglycemia
that prevents aortic aneurysm development (under laboratory conditions)[21]. For these reasons, it seems that the administration
of insulin is probably a risk factor for disease progression in type 2
DM patients with IMHBs. In our study, after receiving tight glycemic
control recommended by guidelines [7], patients in 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 reached the
highest level earlier in the DM group than in the non-DM group. However,
the MMP-9 levels in the DM group were lower than those in the non-DM
group at each timepoint (P< 0. 001, Figure
2 ), and patients in the non-DM group had a 2-fold higher level of MMP-9
after day 90 than patients in the DM group, which likely indicated that
the potentially protective effect of hyperglycemia did not decrease
after the administration of insulin, which could likely 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 and the administration of insulin and other antidiabetic
treatments in aortic diseases has remained unclear and requires further
study.
For
this higher mortality rate in the non-DM group than in the DM group
after TEVAR treatment, one possible explanation was the larger aorta
diameters and greater hematoma thickness in the non-DM group. Bischoff
et al. [22] 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 aorta diameters
larger than 45 mm and hematoma thicknesses greater than 10 mm should be
included in the “complicated” group, and more aggressive TEVAR
treatment was required in these patients to prevent fatal IMHB evolution[23] . In addition, the geometry of the aorta can be
influenced by TEVAR, which can 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)[24] . In the non-DM group, one patient died of retrograde
type A aortic dissection after TEVAR during the acute phase. Both
patients who died after TEVAR in the non-DM group had ascending aorta
diameters larger than 40 mm (Supplement 1 ). Thus, an ascending
aorta diameter larger than 40 mm is another potential evolutionary
predictor of IMHB.
The
other possible explanation for this higher mortality rate in the non-DM
group is the improper timing of TEVAR and the stent graft size. The
current timing of TEVAR for uncomplicated IMHB is in line with that for
uncomplicated type B aortic dissection (patients with IMH expansion
despite medical therapy and ULP development) [1][4] .
However, the disease progression of IMHB is highly unpredictable,
and the current guidelines are
based on good outcomes of TEVAR for type B aortic dissection[25][26] and on some small sample studies for IMHBs[1][4][27][28] . In our study, all 12 patients
with uncontrollable symptoms (especially refractory pain) underwent
TEVAR. The two patients who finally died of aorta-related complications
still complained of refractory pain after TEVAR (Supplement 1 ).
Juvonen et al. [29] reported that patients with
uncharacteristic or atypical pain had 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 are
markedly impaired [30] . A more aggressive TEVAR procedure
(while the symptoms are still controllable) would likely have better
outcomes (acute phase mortality: 0%, Bischoff et al. [22] ,
0%, Ye et al. [23] ), and this more aggressive strategy is
likely to prevent the progression of IMHB 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 patients with 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 the diameters in the study by Schoenhoff et al. (10%
to 15%). [5]. However, both in our study and in the study
by Schoenhoff et al. [5] , the mortality rates were higher
than those after TEVAR for type B aortic dissection[4][31] . For aortic dissection, there is a general
agreement in the current guidelines that the oversizing factor should
not exceed 5% [31] . Is it necessary to utilize less
oversizing (not exceeding 5% [31] ) for stent grafts
similar to the recommendations for aortic dissection in patients with
IMHB?
In addition, ULP development during the acute phase and CRP levels were
associated with an elevated risk for aorta-related mortality. Moral et
al. [32] reported that 10% of patients with uncomplicated
IMHBs suffered from ULP development during the acute phase; among these
patients, the disease progression rate was as high as 91%, and 36% of
them died of aortic-related complications. Kitai et al. reported that
71% of patients with IMHBs had ULPs during the acute phase, of which
76% showed progression (enlargement or progression to an aortic
aneurysm) and required further treatment [33] . The
potential risk factors for ULP development are large aorta diameters and
hematoma thicknesses, which are also evolutionary predictors of IMHB[30]. In addition, a higher CRP level may be indirect
evidence that could represent the degree of inflammation and
pathophysiological changes in the aortic wall under such unstable
hemodynamic conditions; a sustained, high CRP level has significant
prognostic value in IMHB patients [34].
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 upon admission and once
before discharge), and the diagnosis of ULPs could have been influenced
by the preciseness of the CTA images. Closer monitoring for the
development of ULPs 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.