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.