Association between Diabetes and Risk of Aortic Dissection: A Case-Control Study in a Chinese Population
Association between Diabetes and Risk of Aortic Dissection: A Case-Control Study in a Chinese Population
Xingwei He 0 1
Xintian Liu 0 1
Wanjun Liu 0 1
Bei Wang 0 1
Yujian Liu 0 1
Zhuxi Li 0 1
Tao Wang 0 1
Rong Tan 0 1
Bo Gao 0 1
Hesong Zeng 0 1
0 Editor: Yingmei Feng, Katholieke Universiteit Leuven , BELGIUM
1 1 Department of Cardiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology , Wuhan , China , 2 Department of Cardiology, Suizhou Affiliated Hospital of Hubei Medical College , Suizhou , China
The aim of this case-control study was to evaluate the association between diabetes and risk of AD in Chinese population. A hospital-based case-control study, consisting of 2160 AD patients and 4320 controls, was conducted in a Chinese population. Demographic, clinical characteristics and risk factors were collected. Diabetes rate of patients with overall AD, Stanford type A AD and type B AD group was compared with that of corresponding matched control groups. Logistic regression analysis was used to estimate the odds ratios (OR) and 95% confidence intervals (95% CI) for relationship between diabetes and AD risk. The prevalence of diabetes was lower in AD cases than that of control subjects, whether it is the overall AD, type A AD or type B AD group (4.7% vs. 10.0%, 2.9% vs. 8.8%, 5.9% vs. 10.9%, all P<0.001). Furthermore, in multivariate model, diabetes was found to be associated with lower AD risk, which not only applies to the overall AD (OR = 0.2, 95%CI: 0.150.26), but also type A AD (OR = 0.12, 95% CI: 0.07-0.20) and type B AD (OR = 0.25, 95% CI: 0.18-0.33).
It is well-recognized that diabetes represents a powerful independent risk factor for
cardiovascular diseases. However, very few studies have investigated the relationship between
diabetes and risk of aortic dissection (AD).
We observed the paradoxical inverse relationship between DM and risk of AD in the
Chinese population. These results suggest diabetes may play a protective role in the
development of AD. However, further studies are needed to enrich related evidence, especially with
regard to underlying mechanisms for these trends.
Aortic dissection (AD) is a potentially critical break in the lining of the main arterial outflow
from the heart . As a relatively uncommon yet catastrophic disease, it affects 5 to 30 per 1
million people annually, amounting to nearly 10,000 cases in the United States [2–4].
According to the literature, 20% of the patients with AD die before reaching hospital and 30% die
during hospital admission . Although AD is frequently fatal, the precise etiology remains
unclear and many diseases are considered to be associated with it. Data from International
Registration Aortic Dissection (IRAD) revealed that hypertension and atherosclerosis were the
most common predisposing factors for AD, followed by old age, and previous cardiovascular
surgery, Marfan syndrome, and iatrogenic causes [1, 2, 6].
Diabetes is a high risk factor for the development of cardiovascular diseases (CVD)and
atherosclerosis [7, 8]. Numerous clinical studies have shown a direct correlation between the level
of hyperglycemia and CVD morbidity and mortality. Besides, it has also been shown that there
exists a significant association between the degree of hyperglycaemia and increased risk of
microvascular complications, macrovascular mortality, and all-cause mortality in patients with
diabetes [9–12]. Based on the above analysis, diabetes seemed to be considered as a risk factor
However, opposed to the assumption, a few recent studies indicated that diabetes has a
protective effect against aortic diseases, including AD [13–15]. The result is, to a certain extent,
beyond many researchers’ expectation and has brought about significant impacts. Therefore, it
can be noted that those studies reached inconsistent conclusions on the relationship between
diabetes and AD risk. In this study the hypothesis is that diabetes serves a positive role in the
development of AD risk and we performed a retrospective case-control study with Chinese
population as subjects.
Materials and Methods
The study was approved by the Ethics Committee of the Tongji hospital of Huazhong
University of Science and Technology. All aspects of the study comply with the Declaration of
Helsinki. Ethics Committee of Tongji hospital of Huazhong University of Science and Technology
specially approved that not informed consent was required because data were going to be
This project was designed as a hospital-based retrospective 1:2 case—control study. Between 1
January 2003 and 1 December 2013, a total of 2160 consecutive AD patients at Tongji Hospital
(Wuhan, China) were enrolled in the study. Cases were diagnosed by imaging, surgical
visualization, or autopsy. Patients with traumatic aortic dissection and iatrogenic aortic dissection
were excluded. According to the Stanford classification system , the cases were divided into
two categories: those involving the ascending aorta (type A AD, n = 861) and those not
involving the ascending aorta (type B AD, n = 1299).
In addition to describing case subject’s characteristics, a case—control approach was
performed. 4,320 controls (3,352 males and 968 females) were selected at random by frequency
matching age (plus or minus 1 year) and gender from 22,430 people (12,084 males and 10,346
females), who had received a health examination in Tongji hospital in 2011. All patients with
previous history of aortic dissection, aneurysm and active inflammatory disease were excluded
to remove elements of confounding bias. The ratio of cases to controls was 1:2. The controls
were divided in groups according to the different case groups. The corresponding controls for
overall AD group were controls group (n = 4,320), for type A AD group were control A group
(n = 1,722) and for type B AD group were control B group (n = 2,598). Information on
demographic and other variables, such as diabetes mellitus (type 2), hypertension, hyperlipidemia,
history of smoking, Marfan syndrome, bicuspid aortic valve, COPD, etc, were abstracted from
hospital charts. The prevalence of diabetes in each AD group was compared with that of the
corresponding control groups, respectively. Finally, the odds ratios (OR) and 95% confidence
intervals (95% CI) for relationship between diabetes and risk of AD in each case/control group
Definitions used in the study. History of smoking was assumed if the patient had smoked
within the last 10 years. Hypertension was defined as blood pressure 140/90 mmHg or
treatment for hypertension before admission; hyperlipidemia was defined as cholesterol level >220
mg/dl or treatment for hyperlipidemia; According to the WHO criteria , diabetes was
defined either by fasting plasma glucose levels 126 mg/dl, 2-h post-load glucose levels 200
mg/dl after a 75goral glucose tolerance test, or by physician diagnosis; Marfan syndrome was
diagnosed according to the revised Ghent criteria . Patients were evaluated according to
the ACC/AHA guidelines in order to assess the presence of coronary artery disease (CAD).
Continuous variables are presented as mean ± SD, and categorical variables are presented as
frequencies. All comparisons between two groups of continuous variables were made using a
two-sample t-test or nonparametric test; the Chi-square test was employed when comparing
categorical variables. To study the association between diabetes and AD risk, logistic regression
method was used for the calculation of odds ratio (OR) as well as its 95% confident interval
(95% CI). Adjusted ORs were computed using multivariate logistic regression with adjustment
for history of smoking, hyperlipidemia, hypertension, coronary heart disease, peripheral
vascular disease, drug abuse, Marfan syndrome, bicuspid aortic valve and COPD. P<0.05 was taken
to indicate statistical significance. The statistical analyses above were performed with the SPSS
Software version 16.0 (SPSS, Chicago, IL, USA) and were based on two-tailed probability.
The baseline characteristics of the case/control samples are shown in Table 1. The mean ages of
case and control group were 53.6±12.0 and 53.6±12.2 years respectively with males accounting
for 77.6% of each group. No significant difference in age and gender was detected between each
case/control group, which shows that the frequency matching was adequate. In terms of
comorbidities, history of smoking, hypertension, hyperlipidemia, Marfan syndrome, bicuspid
aortic valve, coronary heart disease, drug abuse and COPD were observed more frequently in
the AD patients. However, the control subjects presented with diabetes more frequently than
the AD patients (10% vs 4.7%, p<0.001) (Fig 1). According to the national survey in 2010 ,
Data are presented as the means ± SD or %; AD, aortic dissection; BMI, body mass index; CHD, coronary heart disease; PVD, peripheral vascular
disease; COPD, chronic obstructive pulmonary disease.
the incidence of diabetes in Chinese adults aged over 18 years old was 11.6%. The diabetes rate
in control group was close to that of general Chinese adults.
We further divided cases into two subgroups, Stanford type A and type B. The
corresponding controls for type A AD group were control A group and for type B AD group were control
B group. Similarly, the prevalence of diabetes in Stanford type A AD and type B AD group
were lower than that of control A and control B group (8.8% vs. 2.9% and 10.9% vs. 5.9%, all
Table 2 presents the difference between diabetes and non-diabetes groups in the study
population. For both AD patients and control subjects, patient with diabetes were older in age than
those without; Hypertension and Peripheral vascular disease (PVD) were higher in diabetes
group (P<0.001); Furthermore, in the control subjects, hyperlipidemia and CHD were higher
in diabetes group than in those without (p <0.001). However, there was no significant
difference with regard to other demographic variables.
In multivariate logistic regression analysis, after adjustment for hypertension, history of
smoking, Marfan syndrome, hyperlipidemia, bicuspid aortic valve, drug abuse, CHD, PVD and
COPD, DM was related to the reduced risk of AD (adjusted OR = 0.20, 95%CI: 0.15–0.26).
Furthermore, the inverse association also remained significant in the Stanford type A/case A
group (OR = 0.12, 95%CI: 0.07–0.20) and type B/case B group (OR = 0.25, 95%: 0.18–0.33).
Other factors that were independently associated with risk of AD are shown in Table 3.
Finally, we compared the incidence of in-hospital death between diabetes and non-diabetes
in AD patients. As shown in Table 4, there was no significant difference among the groups
with respect to the incidence of in-hospital death. 223 of 2058 (10.8%) non-diabetic patient
died due to AD, whereas 14 of 102 diabetic patients (13.7%) died (P>0.05).
Diabetes has been known to be a powerful risk factor for associated cardiovascular diseases
(CVD) and the development of atherosclerosis. Patients with type 2 diabetes have a 2- to
4Fig 1. Differences of diabetes rate between AD patients and control subjects.
fold higher risk of CVD death compared with patients without . Furthermore, to our
knowledge, diabetes is also highly related with hypertension. In our study, for all patients with
AD, diabetes group were at higher risk of developing hypertension and PVD, and they are
older in age compared with non-diabetics group. It has been reported that history of
hypertension, old age, and atherosclerosis are the most common risk factors for AD . Hence, diabetes
seems to be considered as a risk factor for AD. But this is not the case.
Previous studies have shown that for patients with high risk of atherosclerosis, forbidding
smoking and controlling the blood pressure and blood lipid in normal level can significantly
reduce cardiovascular morbidity and mortality. However, with the hemoglobin A1c (HbA1c)
controlled at normal level for patients with diabetes and high risk of atherosclerosis, the
Patients with AD
Data are presented as the means ± SD or %. AD, aortic dissection; BMI, body mass index; CHD, coronary heart disease; PVD, peripheral vascular
disease; COPD, chronic obstructive pulmonary disease.
incidence of micro-vascular disease may be reduced, but a significant increase in mortality of
macro-vascular can be brought about [20, 21]. In 1997, Lederle et al. stated that diabetes
was negatively associated with risk of abdominal aortic aneurysm (AAA) for the first time in
the Aneurysm Detection and Management Veterans Affairs Cooperative Study. Moreover,
some studies have reported that the AAA enlargement progresses more slowly in diabetes
patients than in non-diabetes [22, 23].
Recently, increasing evidence has suggested the inverse relationship between diabetes and
aortic diseases, including aortic aneurysm and AD. population study suggest that the overall
pooled incidence rate of thoracic aortic aneurysm (TAA) and AAA was 15% lower in the type
2 diabetes cohort than non-diabetes cohort (3.85 vs 4.51 per 10 000 person-years), with an
Overall AD (n = 2,160)
Type A AD (n = 861)
Type B AD (n = 1,299)
AD, aortic dissection; CHD, coronary heart disease; PVD, peripheral vascular disease; COPD, chronic obstructive pulmonary disease. AOR, adjusted
odds ratio; CI, confidence interval.
Mortality in overall AD
Mortality in type A AD
Mortality in type B AD
AD, aortic dissection.
adjusted HR of 0.65 (95% CI: 0.56–0.74). In the meta-analysis of 17 large population
prevalence studies, diabetes was also associated with decreased risk of AAA, with a pooled OR = 0.80
(95% CI: 0.70–0.90). Furthermore, a nationwide case-control study by the center for
clinical research and evidence-based medicine at the university of Texas in Houston, indicated that
diabetes was associated with decreased risk of TAA and AD . Also, a very recent study
revealed that diabetes patients are significantly less likely to have AD . These findings
suggested that diabetes may play a protective role in the development of AD. Our research showed
consistent results with those studies. Although those studies are with some designing or
methodological flaws, like incomplete data, relatively small samples, the underestimation of the
diabetes incidence, etc , the results are interesting and favorable. This inverse relationship of
diabetes between risks of aortic disease may question the traditional view of AD as a
manifestation of atherosclerosis, especially in diabetes patients.
One thing meriting our consideration, however, is that only the inverse relationship
between diabetes and risk of AD was shown and the exact mechanism for the beneficial effect
by which diabetes may protect against the development of AD is still ambiguous. One of the
possible mechanisms is that the biologic of aortic wall may be changed by diabetes. According
to the recent studies, hyperglycemia associated with diabetes plays the role of stabilizing the
collagen network through giving rise to cross-linking of collagen network in the aortic wall
media. As for this cross-linking, it resists proteolysis and inhibits secretion of matrix
metalloprotei-nases (MMPs) which is deemed as with regulating effect on aortic aneurysm formation
and promoting effect on atherosclerotic plaque rupture . Additionally, it was also revealed
that diabetes could restrain plasm in that activates the matrix MMPs . These effects could
directly reduce aortic wall degradation and may also account for the thicker abdominal aortic
wall observed in diabetes , as well as the potential protection of diabetes mellitus against
AD. Another mechanism is that hyperglycemia is also associated with reduced adventitial
neovascularization and decreased infiltration of inflammatory cells into the medial layer of the
aorta. These processes could restrain the progression of AD by reduction of vascular smooth
muscle cell death and extracellular matrix degradation . Besides, medication taken by
diabetes patients may contribute to the protective effect of aortic disease. According to previous
study, metformin, one of the most wildly used anti-diabetic drugs, provides cardiovascular
protection independent of its hypoglycemic effects by activating the AMP-activated protein kinase
(AMPK) and reducing autophagy [29, 30]. Further exploration of the potential possibilities is
needed to help understand the protective effects of these two conditions.
A key strength of this study is that it is one of the first to assess the correlation between AD
risk and diabetes in a non-western case-control study with sizeable samples. Drawn from the
same geography and population, both AD cases and control subjects were likely to be
representative of the general population. Furthermore, effective methods were used to control biases
which may influence the quality of case-control study. For controlling selection bias, all the AD
cases were strictly chosen according to the inclusive criteria while control subjects were
randomly selected. For decreasing confounding bias, all controls were matched by age and gender.
Moreover, a 1: 2 matching design method was adopted to increase the statistical power. More
importantly, our study will leave a foundation for future studies about the relationship between
diabetes and risk of aortic dissection. Future research might focus on further identifying the
exact mechanisms related to beneficial effect with a view to developing targeted
pharmacological therapy or precaution for aortic dissection.
Nevertheless, a few limitations of our study deserve our consideration. First, as this is a
retrospective case-control study, it is not appropriate for any casual association to be established
between variables. Also, it was difficult to avoid residual unrecognized confounding variables
influence and thus a large, multi-center, prospective study is necessary. Second, it is possible
that control patients had been receiving regular medical care and thus were more likely to have
diabetes diagnosed. Yet, compared with control patients, the acute aortic dissection may not
have been previously cared for or diagnosed. Therefore, diabetes prevalence in aortic dissection
group may be underestimated. Finally, due to the lack of research on relevant mechanisms in
our part, further researches involving underlying mechanism related to the protective role of
hyperglycemia in AD are required to reach a more definitive conclusion. Despite these
limitations, our study may leave a foundation for future studies about the relationship between
diabetes and risk of aortic diseases.
In conclusion, our findings indicated that diabetes was significantly associated with
decreased risk of AD in our Chinese subjects. Further confirmatory results from other research
conducted in different populations with different research designs (e.g. cohort studies) are
required to establish this association; however, results from this investigation have
demonstrated that diabetes may play a protective role in the development of AD and that relevant
mechanisms related to the beneficial effect may provide a new insight into the causes,
prevention and treatment of AD.
S1 Appendix. The individual data of the case group.
S2 Appendix. The individual data of the control group.
Conceived and designed the experiments: XWH HSZ. Performed the experiments: XWH ZXL
RT WJL. Analyzed the data: XWH XTL BG TW. Contributed reagents/materials/analysis
tools: YJL BW. Wrote the paper: XWH.
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