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\begin{document}

\title{Outcomes of Uncomplicated Type B Intramural Hematoma Patients with Type
2 Diabetes Mellitus}



\author[1]{Zhonggui Shan}%
\author[2]{Qu Chen}%
\author[3]{Dandan Jiang}%
\author[2]{Feng Kuang}%
\author[2]{Fan Yang}%
\affil[1]{Teaching Hospital of Fujian Medical University, The First Affiliated Hospital of Xiamen University}%
\affil[2]{The First Affiliated Hospital of Xiamen University}%
\affil[3]{Xinglin Branch of The First Affiliated Hospital of Xiamen University}%


\vspace{-1em}



  
  \date{May 22, 2024}


\begingroup
\let\center\flushleft
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\selectlanguage{english}
\begin{abstract}
Objectives We aimed to summarize the clinical presentations, therapeutic
approaches, and outcomes of type B intramural hematoma (IMHB) patients
with and without type 2 diabetes mellitus (DM). Methods Patients with
uncomplicated IMHBs were included between January 2016 and January 2018
and divided into two groups according to whether or not they had DM. Cox
proportional hazard analysis was utilized to investigate the risk
factors for aortic-related mortality. Kaplan-Meier survival analysis was
used to estimate cumulative mortality and aortic-related mortality.
Results A total of 149 patients were included and were divided into the
two groups (DM group {[}n=60{]} and non-DM group {[}n=89{]}). Patients
in the non-DM group underwent thoracic endovascular aortic repair
treatment more frequently (12\% vs 2\%, P=0.028) and had a higher
reintervention rate during the follow-up (9 in 81 patients, 11\% vs 2\%,
P=0.043). There were significant differences between the two groups
regarding the aorta-related mortality rate during the acute phase (9\%
vs 0\%, P=0.042) and the all-cause mortality rate (22\% vs 7\%,
P=0.011). Ulcer-like projection (ULP) development (during the acute
phase) (hazard ratio {[}HR{]}, 1.07; 95\% confidence interval {[}CI{]},
1.01-1.31, P=0.008), C-reactive protein (CRP) levels (HR, 1.92; 95\% CI,
1.51-2.49, P\textless{}0.001) and MMP-9 levels (HR, 16.82; 95\% CI,
7.52-28.71, P\textless{}0.001) were associated with an elevated risk for
aorta-related mortality. Conclusions IMHBs without DM are not benign and
have a considerably high aortic-related mortality rate. ULP development
(during the acute phase), CRP levels and maximum MMP-9 levels are
associated with an elevated risk for aorta-related mortality.%
\end{abstract}%



\sloppy


\textbf{Title:}Outcomes of Uncomplicated Type B Intramural Hematoma
Patients with Type 2 Diabetes Mellitus

\textbf{Authors:}

Qu Chen, MD\textsuperscript{ae}, Dandan Jiang, MD\textsuperscript{be},
Feng Kuang, MD, PhD\textsuperscript{a}, Fan Yang, MD\textsuperscript{c},
Zhonggui Shan, MD, PhD\textsuperscript{d},

\textsuperscript{a}: Department of Cardiovascular Surgery, The First
Affiliated Hospital of Xiamen University, Xiamen, Fujian Province,
People's Republic of China.

\textsuperscript{b}: Department of Internal Medicine, Xinglin Branch of
The First Affiliated Hospital of Xiamen University, Xiamen, Fujian
Province, People's Republic of China.

\textsuperscript{c}: Department of Radiology, The First Affiliated
Hospital of Xiamen University, Xiamen, Fujian Province, People's
Republic of China.

\textsuperscript{d}: Department of Cardiovascular Surgery, Teaching
Hospital of Fujian Medical University, The First Affiliated Hospital of
Xiamen University.

\textsuperscript{e}: The first two authors contributed equally to this
work.

\textbf{Email:}

Qu Chen: cmuchenqu@163.com

Dandan Jiang: jddcmu@163.com

Feng Kuang: tysonf@sina.com

Fan Yang: buyiwangdao@126.com

Zhonggui Shan: xmchenqu@163.com

\textbf{Disclosures:} The authors of this manuscript have no
relationships with industry to disclose.

\textbf{Sources of Funding:} None.

\textbf{Date Availability Statement:} The raw data required to reproduce
these findings cannot be shared at this time as the data also forms part
of an ongoing study.

\textbf{Address for Correspondence}

Zhonggui Shan, MD, PhD

Department of Cardiovascular Surgery, Teaching Hospital of Fujian
Medical University, The First Affiliated Hospital of Xiamen University,
No. 55 Zhenhai Road, Siming District, Xiamen City, Fujian Province,
36100, People's Republic of China

Tel.: +86 15805908147

Fax: +86 0592-2137601

Email: xmchenqu@163.com

\textbf{Running Head:} Type B Intramural Hematoma with Diabetes Mellitus

\textbf{Word Coun} t: 3075

\textbf{Abstract}

\textbf{Objectives}

We aimed to summarize the clinical presentations, therapeutic
approaches, and outcomes of type B intramural hematoma (IMHB) patients
with and without type 2 diabetes mellitus (DM).

\textbf{Methods}

Patients with uncomplicated IMHBs were included between January 2016 and
January 2018 and divided into two groups according to whether or not
they had DM. Cox proportional hazard analysis was utilized to
investigate the risk factors for aortic-related mortality. Kaplan-Meier
survival analysis was used to estimate cumulative mortality and
aortic-related mortality.

\textbf{Results}

A total of 149 patients were included and were divided into the two
groups (DM group {[}n=60{]} and non-DM group {[}n=89{]}). Patients in
the non-DM group underwent thoracic endovascular aortic repair treatment
more frequently (12\% vs 2\%, \emph{P} =0.028) and had a higher
reintervention rate during the follow-up (9 in 81 patients, 11\% vs 2\%,
\emph{P} =0.043). There were significant differences between the two
groups regarding the aorta-related mortality rate during the acute phase
(9\% vs 0\%,\emph{P} =0.042) and the all-cause mortality rate (22\% vs
7\%,\emph{P} =0.011). Ulcer-like projection (ULP) development (during
the acute phase) (hazard ratio {[}HR{]}, 1.07; 95\% confidence interval
{[}CI{]}, 1.01-1.31, \emph{P} =0.008), C-reactive protein (CRP) levels
(HR, 1.92; 95\% CI, 1.51-2.49, \emph{P} \textless{}0.001) and MMP-9
levels (HR, 16.82; 95\% CI, 7.52-28.71, \emph{P} \textless{}0.001) were
associated with an elevated risk for aorta-related mortality.

\textbf{Conclusions}

IMHBs without DM are not benign and have a considerably high
aortic-related mortality rate. ULP development (during the acute phase),
CRP levels and maximum MMP-9 levels are associated with an elevated risk
for aorta-related mortality.

\textbf{Abbreviations:}

CRP: C-reactive protein

ULP: Ulcer-like projection

IMH: Intramural hematoma

IMHB: Type B intramural hematoma

TEVAR: Thoracic endovascular aortic repair

\textbf{Key words:} IMH, Diabetes Mellitus, Mortality, Outcome

\textbf{Introduction}

Although the current treatment strategy (wait-and-watch strategy) for
type B intramural hematoma (IMHB) is in line with the management of type
B dissection, the long-term outcomes of IMHB are not as good as those of
type B dissection \textbf{{[}1-4{]}} . The cause of this phenomenon is
that the evolution of IMHB is highly unpredictable and can vary from
complete resolution to abrupt rupture. Schoenhoff et al.\textbf{{[}5{]}}
reported that 43\% of IMHB patients underwent thoracic endovascular
aortic repair (TEVAR) during the first two weeks because of
visualization of an entry tear and development of an aneurysm, and 19\%
of patients received TEVAR after the acute phase and during the first
year\textbf{.} Durham and colleagues also reported that the survival
rate of IMHB patients who underwent interventional treatment was only
76\%, and only 40\% of patients did not require reintervention

\textbf{{[}6{]}}

The prevalence of diabetes mellitus (DM) in patients requiring cardiac
surgery is significantly increasing, and achieving tight perioperative
glycemic control in DM patients may decrease perioperative morbidity and
improve survival \textbf{{[}7{]}} . Current studies have demonstrated a
negative correlation between DM and the occurrence of aortic
diseases\textbf{{[}8-11{]}} . However, previous studies are
contradictory in that patients with DM were found to have poorer
outcomes after abdominal aortic aneurysm repair \textbf{{[}12{]},}
whereas mortality and clinical complications in type B aortic dissection
patients after TEVAR were significantly reduced in DM patients
\textbf{{[}13{]}} . In our previous study, we demonstrated that
uncomplicated type A IMH patients with DM (receiving the
``wait-and-watch strategy'' and tight glycemic control) may have lower
aorta-related mortality and rates of aorta-related adverse events and
reintervention than patients in the non-DM group\textbf{{[}14{]}} .

Whether patients with uncomplicated IMHB (receiving the ``wait-and-watch
strategy'') may benefit from tight glycemic control remains unclear.
Thus, we hypothesized that among uncomplicated IMHB patients receiving
the ``wait-and-watch strategy'' (combined with tight glucose
management), patients with DM (compared with patients without DM) would
benefit from such a treatment strategy. In this study, we aimed to
summarize the clinical presentations, therapeutic approaches, and
outcomes of IMHB patients with and without DM.

\textbf{Methods}

\textbf{Patient Characteristics}

Individual informed consent was obtained from each patient, and
institutional review board approval was obtained from Xiamen University.
Patients with uncomplicated IMHBs were included between January 2016 and
January 2018 (see the details of the CONSORT diagram in \textbf{Figure
1} ).

\textbf{Blood Glucose Management}

Newly diagnosed type 2 DM patients without standard antidiabetic
treatments before the onset of IMHB were included. The target blood
glucose level included proper blood glucose levels during fasting and
premeal states (80-130 mg/dL) and the postprandial state (less than 180
mg/dL) \textbf{{[}7{]}} . After TEVAR or open surgery, patients with
persistently elevated serum glucose levels (\textgreater{} 180 mg/dL)
received continuous intravenous insulin perfusion to maintain a serum
glucose level \textless{} 180 mg/dL during their stay in the intensive
care unit \textbf{{[}7{]}} .

\textbf{Treatment Strategy for Intramural Hematoma}

Patients with uncomplicated IMHBs received medical therapy to control
their pain (intravenous opiate analgesia), heart rate (less than 80
beats per minute), and blood pressure (systolic blood pressure between
100 and 120 mmHg) \textbf{{[}1{]}} . The acute phase was defined as the
first fourteen days from the onset of IMHB, and the disease was
considered stable after fourteen uneventful days (patients were
discharged) \textbf{{[}1{]}} . Electrocardiographic-triggered CTA (GE
Healthcare, Milwaukee, WI) was performed at least twice during the acute
phase (once upon admission and once before discharge) in patients
without disease progression and in those with well-controlled blood
pressure, heart rate and pain; in eventful cases (uncontrollable back
pain combined with hemodynamic instability), CTA examinations were
adjusted accordingly \textbf{{[}1{]}} . The patients were followed
clinically according to standard surveillance protocols \textbf{{[}1{]}
{[}15-17{]}} . During the follow-up, CTA was also performed at 1, 3, 6,
and 12 months and then annually during the extended follow-up. Disease
progression was defined as increased pleural effusion, hematoma
thickening (thickness [?]10 mm), development of an aortic pseudoaneurysm,
aortic dissection or signs of aortic rupture. Under the following
situations, patients would receive TEVAR or surgery treatment: during
the acute phase, expansion of IMH and development of pseudoaneurysms
despite medical therapy, development of ulcer-like projections (ULP),
and signs of aortic rupture (uncontrollable back pain combined with a
precipitous decrease in blood pressure); and during the chronic phase,
development of aortic dissection, rapid growth of ULPs or aorta
diameters (\textgreater{}5 mm/year), maximum aorta diameters
\textgreater{} 55 mm, and signs of aortic rupture \textbf{{[}1{]}} .

\textbf{Detection of Serum Matrix Metalloproteinase-9}

Matrix metalloproteinase-9 (MMP-9) is an important diagnostic biomarker
in aortic pathophysiology, and MMP-9 can weaken the aortic media by
degrading multiple extracellular components; DM patients have a 2-fold
decreased level of MMP-9, which can restrict degradation of the aortic
wall \textbf{{[}16{]}} . Plasma MMP-9 was measured by using an
enzyme-linked immunosorbent assay (ELISA). The MMP-9 level was measured
on admission, at day 14 (after the acute phase) and day 90 (after the
subacute phase), at 6 and 12 months and then annually during follow-up.

\textbf{Follow-up and Study Endpoints}

All patients were followed for at least three years. The remodeling
process was confirmed by the latest CTA scan. The definition of IMHB
evolution in the chronic phase included hematoma stability, resolution
and worsening. The primary outcome was aortic-related mortality
(confirmed by autopsy or CTA examination), and the secondary outcomes
were all-cause mortality and aortic remodeling.

\textbf{Statistical Analysis}

Comparisons between groups were performed by the \emph{t} -test or
Mann-Whitney U test when necessary. Categorical variables are expressed
as frequencies and percentages and were compared with the \selectlanguage{greek}χ\selectlanguage{english}2 test and
Fisher's exact test when appropriate. A Cox proportional hazard analysis
was used to calculate the hazard ratios (HRs) and investigate the risk
factors for aorta-related mortality. In the multivariate Cox
proportional hazard models, the entry and removal criteria were set
at\emph{P} =0.05 and \emph{P} =0.20. Kaplan-Meier survival analysis with
the log-rank test was used to estimate the cumulative mortality and
aortic-related mortality in different groups. We used the
Kolmogorov--Smirnov test to evaluate the normality of the continuous
variables\textbf{.} Differences with \emph{P} values \textless{}0.05
were considered statistically significant. IBM SPSS for Windows version
26.0 (IBM Corp, Armonk, New York) was used for statistical analysis.

\textbf{Results}

\textbf{Patient Characteristics}

After excluding patients with incomplete follow-up data, 149 patients
remained, and their data were analyzed (\textbf{Figure 1} ). These
patients were classified into two groups (DM group {[}n=60{]} and non-DM
group {[}n=89{]}) according to whether or not they had DM\textbf{.} The
median follow-up times for each group were as follows: DM group (38.0
months, 95\% confidence interval {[}CI{]}, 36.8-39.1 months) and non-DM
group (39.0 months, 95\% CI, 36.7-41.2 months). Compared to those
without DM, patients with DM had a higher hypertension rate (72\% vs
53\%, \emph{P} =0.021) as well as lower CRP levels (5.7\selectlanguage{ngerman}±1.5 vs 11.3±2.9
mg/dL, \emph{P} \textless{}0.001) and white blood cell counts (14.2±1.9
vs 18.3±3.7 10\^{}9/L, \emph{P} \textless{}0.001). The geometric
measurements of the aorta indicated that patients in the non-DM group
had larger ascending aortas (39.9±3.8 vs 37.9±2.5 mm,\emph{P}
\textless{}0.001) and descending aortas (37.9±3.5 vs 34.9±2.8 mm,
\emph{P} \textless{}0.001) as well as thicker hematomas (9.5±1.2 vs
7.0±1.3 mm, \emph{P} \textless{}0.001) than those in the DM group. The
other demographic characteristics, such as concomitant diseases and
medical treatment strategy, were similar between the two groups
(\textbf{Table 1} ). The MMP-9 levels in the DM group were lower than
those in the non-DM group at each timepoint (\emph{P\textless{}}
0\emph{.} 001, \textbf{Figure 2} ).

\textbf{Disease Progression, Treatment and Follow-up}

During the acute phase, the occurrence rate of disease progression (20
of 89 patients) was higher in the non-DM group than in the DM group (4
of 60 patients) (22\% vs 7\%, \emph{P} =0.011), and disease progression
occurred significantly earlier in the non-DM group than in the DM group
(6.4±1.3 vs 12.0±1.4 days, \emph{P} \textless{}0.001). The incidence of
disease progression was greater in non-DM patients than in DM patients,
and the types of disease progression are listed in \textbf{Table 2.}
Compared to those in the DM group, more patients in the non-DM group
received TEVAR treatment during the acute phase (12\% vs 2\%, \emph{P}
=0.028). The two deaths after TEVAR treatment in the non-DM group
included one patient who died of retrograde type A aortic dissection and
one patient who died of aortic rupture (\textbf{Figure 2 and Figure 3}
).

The aorta-related mortality in patients with IMHBs is also summarized
in\textbf{Table 2} and \textbf{Figure 4.} There were significant
differences in aorta-related death among the DM and non-DM groups during
the acute phase (\textless{}14 days) (0\% vs 9\%, \emph{P} =0.042)
(\textbf{Table 2} ). The non-DM group also had a higher reintervention
rate during follow-up than the DM group (9 in 81 patients, 11\% vs
2\%,\emph{P} =0.043). Additionally, the non-DM group had a higher
probability of hematoma worsening (22\% vs 5\%, \emph{P} =0.004) and a
higher rate of aorta-related mortality during the follow-up period (11\%
vs 2\%,\emph{P} =0.043) than the DM group (\textbf{Table 2} ).

The Cox regression analysis revealed that ULP development (during the
acute phase) (HR, 1.07; 95\% CI, 1.01-1.31, P=0.008), CRP level (HR,
1.92; 95\% CI, 1.51-2.49, P\textless{}0.001) and MMP-9 level (HR, 16.82;
95\% CI, 7.52-28.71, P\textless{}0.001) were associated with an elevated
risk for aorta-related mortality (\textbf{Table 3} ). The Kaplan-Meier
survival analysis revealed a significant increase in the aortic-related
mortality rate in the DM group compared with that in the non-DM group
(\emph{P} =0.0023, \textbf{Figure 4} ).

\textbf{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 \textbf{{[}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 \textbf{{[}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 \textbf{{[}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\textbf{{[}1{]}.} The mortality rate after TEVAR during the acute
phase in our study was 18\% in the non-DM group (\textbf{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\%) \textbf{{[}5{]}}
. Falconi et al. \textbf{{[}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.
\textbf{{[}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\%,\emph{P} =0.044), the reinvention rate was obviously lower
than that in previous studies (60\% \textbf{{[}6{]}} , 39\%
\textbf{{[}18{]}} , 27\%\textbf{{[}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 \textbf{{[}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 \textbf{{[}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\textbf{{[}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 \textbf{{[}20{]},} and
insulin treatment may diminish this protective effect of hyperglycemia
that prevents aortic aneurysm development (under laboratory
conditions)\textbf{{[}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
\textbf{{[}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
(\emph{P\textless{}} 0\emph{.} 001, \textbf{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. \textbf{{[}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\textbf{{[}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)\textbf{{[}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 (\textbf{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) \textbf{{[}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\textbf{{[}25{]}{[}26{]}} and on some small sample
studies for IMHBs\textbf{{[}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 (\textbf{Supplement 1} ). Juvonen et al. \textbf{{[}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 \textbf{{[}30{]}} . A more
aggressive TEVAR procedure (while the symptoms are still controllable)
would likely have better outcomes (acute phase mortality: 0\%, Bischoff
et al. \textbf{{[}22{]}} , 0\%, Ye et al. \textbf{{[}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\%). \textbf{{[}5{]}.} However, both in our
study and in the study by Schoenhoff et al. \textbf{{[}5{]}} , the
mortality rates were higher than those after TEVAR for type B aortic
dissection\textbf{{[}4{]}{[}31{]}} . For aortic dissection, there is a
general agreement in the current guidelines that the oversizing factor
should not exceed 5\% \textbf{{[}31{]}} . Is it necessary to utilize
less oversizing (not exceeding 5\% \textbf{{[}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. \textbf{{[}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 \textbf{{[}33{]}} . The
potential risk factors for ULP development are large aorta diameters and
hematoma thicknesses, which are also evolutionary predictors of
IMHB\textbf{{[}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 \textbf{{[}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.

\textbf{Summary}

Our study suggests that IMHB without diabetes mellitus is not a benign
disease and has considerably high aortic-related mortality rates both in
the acute phase and during long-term follow-up. Furthermore, ulcer-like
projection development (during the acute phase), C-reactive protein
levels and maximum matrix metalloproteinase-9 levels are associated with
an increased risk of aorta-related mortality.

\textbf{Acknowledgments}

The authors thank Dandan Jiang, a good wife and a loving mother of her
family, for her contributions to the data collection and statistical
review and for providing emotional support to Dr. Qu Chen.

\textbf{Figure 1} \textbf{CONSORT Diagram of Patient Selection}

The CONSORT diagram of the patient selection process is illustrated in
this figure. The definition of ``uncomplicated'' was based on the status
of the syndrome after medical treatment (without signs of aortic rupture
on admission and well controlled chest/back pain) and the radiographic
findings from computed tomography angiography examinations upon
admission (without periaortic hematoma or ulcer-like projection)
\textbf{{[}1{]}{[}4{]}.} Eligible uncomplicated type B IMH patients who
refused further medical treatments and those without complete imaging
records, laboratory test results and follow-up data were considered
missing data. Patients who refused further treatment, who had incomplete
imaging, etc., were excluded.

\textbf{Figure 2 Levels of Plasma Matrix Metalloproteinase-9 in the Two
Groups}

Plasma matrix metalloproteinase-9 (MMP-9) was measured by using an
enzyme-linked immunosorbent assay. The levels of MMP-9 were measured on
day 14 (after the acute phase), on day 90 (after the subacute phase), at
6 and 12 months and then annually during the follow-up. The MMP-9 levels
in the DM group were lower than those in the non-DM group at each
timepoint (\emph{P\textless{}} 0\emph{.} 001).

\textbf{Figure 3 Evolution of Type B Intramural Hematoma in the non-DM
Group}

\textbf{A)}This patient with diabetes mellitus (DM) suffered from
hematoma thickening.

\textbf{B)} This patient with ulcer-like projection (ULP) development
received emergency thoracic endovascular aortic repair (TEVAR).

\textbf{C)} This patient had increased pleural effusion.

\textbf{D)} This patient with a ULP and increased pleural effusion
underwent TEVAR because of aortic rupture signs and died of a retrograde
type A aortic dissection.

\textbf{E)} The rapid growth of a ULP that became an aneurysm during
follow-up.

\textbf{Figure 4 Kaplan--Meier Survival Analysis Results}

The Kaplan-Meier survival analysis revealed a significant increase in
the aortic-related mortality rate in the DM group compared with that in
the non-DM group (P=0.0023).

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