Risk Factors Of Aortic Aneurysmal Diseases And The Expression Of Extracellular Matrix Metalloproteinase Inducer (EMMPRIN) In Human Aneurysmal Aorta

Aortic aneurysms are the major disease processes affecting the aorta and becominga relatively common cause of death because of rupture or dissection. Early recognitionand management are crucial.The most common location for aneurysms is the infrarenalabdominal aorta, followed by the ascending thoracic aorta.The aim of this study was to investigate the risk factors of aortic aneurysmaldieases and the possible underlying mechanism. Firstly, we detected the independentrisk facoters for aortic aneurysmal diseases (including aortic dissection, abdominalaortic dilatation, aortic root dilatation) in Chinese population, and compare them withthe traditional risk factors of atherosclerostic diseases. Secondly, we determinedwhether EMMPRIN is present and is upregulated in the wall of human TAA and AAA,and to assess possible association with AngⅡ-induced aneurysm formation.PartⅠRisk factors of aortic aneurysmal diseases in Chinese population(一) clinical study of risk factors for aortic dissection—Increased levels of lipoprotein(a) in non-smoking aortic dissection patientsBackground: Aortic dissection (AD) is a life-threatening cause of acute chest, back andabdominal pain. Early recognition and management are crucial. Chronic hypertension,smoking, dyslipidaemia, diabetes, pregnancy, cocaine abuse, inherited connective tissuedisorders and iatrogenic manoeuvres have been shown to cause damage the aortic wall and lead to dissection. Despite extensive research, the mechanisms responsible forinitiating dissection remain elusive. Additional risk factors and potential alternativepathomechanisms for the development of AD need to be further explored. Increasedplasma Lp(a) has been shown to be an independent risk factor for many forms ofvascular disease, including peripheral vascular disease (PVD),ischaemic stroke,coronary artery disease (CAD) and abdominal aortic aneurysm (AAA). However, to thebest of our knowledge, until now, limited data are available on the association of Lp(a)and AD. Methods: An age- and sex-matched case-control study was conducted.HDL-C,LDL-C,TC,TG,Lipoprotein(a),creatinine and uric acid levels in aorticdissection patients(n=52) and healthy subjects (n=104) were studied. The strength ofassociations between lipids, Lipoprotein(a) serum levels, other risk factors and aorticdissection were assessed by means of multivariate logistic regression analysis. Results:Patients with aortic dissection had significantly higher Lp(a)serum levels (Median,17.6mg/dL; range, 6.4-88.7 mg/dL) compared with healthy individuals (median, 12.4mg/dL; range, 4.9-26.4 mg/dL) (P=0.005). The Lipoprotein(a) concentration innon-smoking aortic dissection patients (median, 19.1 mg/dL, range, 10.5-88.7mg/dL)surpassed significantly that of the smoking aortic dissection patients of comparable age(median, 10.7 mg/dL, range, 6.4-22.1 mg/dL) (P<0.0001). Multivariate analysisconfirmed an independent association between Lipoprotein(a) and aortic dissection innon-smoking population (P=0.001).(二) Prevalence of Abdominal Aortic Aneurysms in Chinese Coronary ArteryDisease PatientsBackground: Abdominal aortic aneurysm (AAA) is a common cause of morbidity andmortality among Caucasians and the incidence increases rapidly after age 60. It wasreported by Madaric et al that the prevalence of AAA was much higher (14%) incoronary artery disease (CAD) patients over 60 years of age. However, little information is available on the incidence of AAA for Asian patients with CAD.Methods: We studied the prevalence of AAAs in 209 coronary artery disease (CAD)patients > 60 years of age. A group of 261 patients without CAD served as controls.Results: The prevalence of AAAs in patients with CAD was 0.48%, compared to0.77% in controls (P > 0.05). These findings demonstrate a low incidence of AAA inChinese patients with CAD.(三) Epidemiolo gy of infrarenal aortic diameter in China—Relationship of heavy drinking, lipoprotein (a) and lipid profile to infrarenal aorticdiameterBackground: Infrarenal aortic diameter is central to the diagnosis of AAA. Studies ofpatients with AAAs have shown that morbidity increases with aneurysmal diameter.There was independent graded relationship between aortic diameter and all-causemortality for the whole range of diameter values, not just those in the aneurysmal range.However, up to now, there are limited studies on the epidemiology of aortic diameter.Risk factors and potential alternative pathomechanisms for the development ofinfrarenal aortic dilatation need to be further explored. Methods: The diameter of theinfrarenal aorta was measured using ultrasound in 395 subjects (mean 66.6±10.3 yrs)with atherosclerotic diseases or risk factors. The associations between heavy drinking,serum lipoprotein(a) levels, lipid profile and infrarenal aorta diameters were examined.Results: Heavy drinking and lipoprotein (a) were positively related with infrarenalaortic dimension. While LDL-C/HDL-C, LDL-C and TC/HDL-C were negativelyassociated with infrarenal aortic diameter (19<0.05). In addition, there were negativeassociations of diabetes and positive association of COPD with aortic dimension(p<0.05).(四) Clinical study of risk factors for aortic root dilatation —Diabetes Mellitus: Is It Protective against Aortic Root Dilatation?Background: Aortic root dilatation is a major pathophysiological mechanism for aorticregurgitation and is also frequently associated with aneurysm and dissection of thethoracic aorta. The usual underlying histopathologic changes in aortic tissue associatedwith aortic dilatation are summarized as cystic medial necrosis and vary in severity. Theaortic root diameter is strongly related to age and body size, and, less strongly, to bloodpressure. However, only a small proportion of the variance of the aortic root size can beexplained by all of its known clinical and demographic variables.There is evidence of anegative association between diabetes and both abdominal aortic aneurysm (AAA) andaortic diameter. However, little information is available on the relationship betweendiabetes and aortic root diameter. Methods: We studied 109 patients with type 2diabetes,Two-dimensional echocardiography was used to measure the aortic root at theaortic annulus, the sinus of Valsalva, the sinotubular junction and the proximal part ofthe ascending aorta. Measured mean values were compared with 218 ageandsex-matched patients without diabetes. Total cholesterol, high-density lipoproteincholesterol, low-density lipoprotein cholesterol, triglycerides, creatinine and fastingglucose concentrations were measured by commercially available standardized methods.Multiple linear regression was used to evaluate the influence of diabetes and cardiacrisk factors on aortic root dimensions. Results: Aortic root diameters at all levels weresignificantly related to sex, height, weight, body surface area and infrarenal aorticdiameter. Aortic diameters at all levels were also significantly negatively related todiabetes when the entire population was considered (p<0.05).The prevalence of aorticroot dilatation was significantly higher in nondiabetic subjects than in patients withdiabetes (9.63 vs. 2.75%; p = 0.025). In multiple regression analysis involving theentire study population, with age, height (the anthropometric variable resulting in thebest model), hypertension and diabetes entered as variables, height was the strongestpredictor of aortic diameter at all levels (p<0.005 for all). Diabetes was also an independent negative determinant of all aortic diameters. Additionally, hypertensionentered the model for diameters at the sinuses of Valsalva and the ascending aorta.PartⅡThe expression of extracellular matrix metalloproteinase inducer(EMMPRIN) in human aneurysmal aortaBackground: Although abdominal aortic aneurysm (AAA) and thoracic aorticaneurysm (TAA) with or without dissection display some important differences inpathology, these three types of aneurysmal diseases shared some similar pathologicalphenotypes including the remodeling of the aortic wall, involving fragmentation anddecreased elastic fibers in the tunica media. From experimental and clinical studies, it isknown that matrix conservation and degradation by matrix metalloproteinases (MMPs)plays a major role in aortic aneurysmal diseases formation and progression.Extracellular matrix metalloproteinase inducer (EMMPRIN, basigin, CD147) is a cellsurface glycoprotein that belongs to the immunoglobulin superfamily. Recently,EMMPRIN has been reported to induce and activate the expression of MMPs inmyocardium and atherosclerotic plaque and play an important role in the ventricularremodeling and atherogenic cell differentiation. Similarly, EMMPRIN may beexpressed in human aortic aneurysm and play a role in the extracellular matrix (ECM)remodeling and the pathogenesis of aortic aneurysmal diseases. However, the potentialrole of EMMPRIN in aneurysmal pathologies has not yet been characterized.Methods: Presence of EMMPRIN was assessed in 41 surgical specimens from patientswith thoracic aortic aneurysm (TAA, Type-A aortic dissection, n=12; Type-B aorticdissection, n=7; TAA without dissection, n=7) or abdominal aortic aneurysm (AAA,n=15)by immunohistochemistry. EMMPRIN expression in aortic aneurysm tissues wascompared with 12 autopsy aortas (free of any vascular diseases), and scored for bothstaining intensity and percentage of vascular cells stained. EMMPRIN protein levels incultured human aortic smooth muscle cells (SMCs) with the stimulation of AngⅡwere analyzed by western blot.Results: EMMPRIN showed significant immunoreactivity in aortic aneurism lesionsfrom patients with TAA and AAA. In the aneurysmal wall,α-actin-positive SMCs arethe main source of EMMPRIN. The frequency of EMMPRIN overexpression wassignificantly higher in TAA with dissection (68.4%) than TAA without dissection(14.3%) (P=0.026). AngⅡstimulation upregulated the expression of EMMPIRN incultured human aortic SMCs, which could be suppressed by addition of the AngⅡreceptor type 1 (AT1-R) antagonist losartan.Conclusions:1. Serum Lipoprotein(a) level is significantly elevated in non-smoking patients withaortic dissection independently of other cardiovascular risk factors. Derterminationof Lipoprotein(a) levels may be important in identifying subjects at risk of aorticdissection among non-smokers.2. Our findings demonstrated that there is low prevalence of AAAs in Chinese patientswith CAD, which Was regarded as a high risk group for AAAs in Caucasians.3. There was a positive association between infrarenal aortic diameters and heavydrinking, as well as lipoprotein (a) levels. Furthermore, the novel and unexpectedinverse association between LDL-C/HDL-C, LDL-C, TC/HDL-C and abdominalaortic diameter may suggest a possible role for anti-atherogenic lipid profile(characterized by higher level of HDL-C, and lower level of LDL-C) in aorticdilatation processes, which need to be clarified by further studies.4. In patients with diabetes, the aortic dimension is significantly smaller than inpatients without diabetes.