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Takayasu Arteritis with Dyslipidemia Increases Risk of Aneurysm

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Takayasu Arteritis with Dyslipidemia Increases Risk of Aneurysm www.nature.com/scientificreports OPEN Takayasu Arteritis with Dyslipidemia Increases Risk of Aneurysm Received: 13 May 2019 Lili Pan1, Juan Du1, Dong Chen2, Yanli Zhao2, Xi Guo3, Guanming Qi4, Tian Wang1 & Jie Du5,6 Accepted: 23 August 2019 Low-density lipoprotein cholesterol (LDL-C) has been associated with the occurrence of abdominal Published: xx xx xxxx aortic aneurysm. However, whether LDL-C elevation associated with aneurysms in large vessel vasculitis is unknown. The aim of this study is to investigate the clinical and laboratory features of Takayasu arteritis (TAK) and explore the risk factors that associated with aneurysm in these patients. This retrospective study compared the clinical manifestations, laboratory parameters, and imaging results of 103 TAK patients with or without aneurysms and analyzed the risk factors of aneurysm formation. 20.4% of TAK patients were found to have aneurysms. The LDL-C levels was higher in the aneurysm group than in the non-aneurysm group (2.9 ± 0.9 mmol/l vs. 2.4 ± 0.9 mmol/l, p = 0.032). Elevated serum LDL-C levels increased the risk of aneurysm by 5.8-fold (p = 0.021, odds ratio [OR] = 5.767, 95% confdence interval [CI]: 1.302–25.543), and the cutof value of level of serum LDL-C was 3.08 mmol/l. The risk of aneurysm was 4.2-fold higher in patients with disease duration >5 years (p = 0.042, OR = 4.237, 95% CI: 1.055–17.023), and 2.9-fold higher when an elevated erythrocyte sedimentation rate was present (p = 0.077, OR = 2.851, 95% CI: 0.891–9.115). In this study, elevated LDL-C levels increased the risk of developing aneurysms in patients with TAK. Aneurysmal disease is a life-threatening condition which frequently afects large elastic arteries such as the aorta. Previously, it was considered a “degenerative” condition. Te risk factors of development of abdominal aortic aneurysms (AAA) include advanced age, male sex, smoking, hypertension, atherosclerosis and peripheral vas- cular disease1,2. Recently, a 24 year prospective study revealed that elevated low-density lipoprotein cholesterol (LDL-C) level did not only increased the future risk of clinical AAA, but was also associated with asymptomatic AAA3. Another genetic study confrmed the association of elevated LDL-C with AAA risk, and indicated that lowering LDL-C levels could be an efective therapeutic approach for prevention and management of AAA4. However, AAA is not associated with any single gene mutation or genetic locus, suggesting that it is a complex disorder, and so, management may require consideration of several factors. Enhanced magnetic resonance imag- ing (MRI) with the use of ultra-small superparamagnetic iron oxide particles has demonstrated that aortic wall infammation can predict the rate of aneurysm growth and the risk of aneurysm rupture or repair, as well as all-cause and aneurysm-related mortality5. Te infuence of large vessel vasculitis on the incidence of aneurysm formation is unclear in patients with traditional cardiovascular risk factors. Takayasu arteritis (TAK) is an autoimmune, large-vessel vasculitis that is mainly involved in the aorta and its major branches. It has unknown etiology and typically afects Asian women under the age of 40 years. Chronic infammation may induce intimal hyperplasia and fbrosis of the media and intima, resulting in luminal stenosis and occlusion in more than 90% of patients with TAK. Te formation of aneurysms is not rare in TAK patients, a multicenter study in France indicating the prevalence of aneurysms in such patients is 24%6. Although TAK is typically characterized by stenotic lesions, autopsy-based research has shown that over 50% of individuals with TAK may also develop aneurysms7. Aneurysmal lesions occur from the aortic root to the arch at a higher frequency in Asian people than in Western people8, and are one of the main causes of death in Chinese TAK 1Department of Rheumatology and Immunology, Beijing Anzhen Hospital, Capital Medical University, Beijing, China. 2Department of Pathology, Beijing Anzhen Hospital, Capital Medical University, Beijing, China. 3Department of Interventional Radiology, Beijing Anzhen Hospital, Capital Medical University, Beijing, China. 4Pulmonary and Critical Care Division, Tufts Medical Center, Boston, MA, USA. 5Beijing Institute of Heart, Lung and Blood Vessel Disease, Beijing, China. 6Beijing Anzhen Hospital, Capital Medical University, Key Laboratory of Remodeling-Related Cardiovascular Diseases, Ministry of Education, Beijing Collaborative Innovation Center for Cardiovascular Disorders, Beijing, China. Correspondence and requests for materials should be addressed to J.D. (email: [email protected]) SCIENTIFIC REPORTS | (2019) 9:14083 | https://doi.org/10.1038/s41598-019-50527-z 1 www.nature.com/scientificreports/ www.nature.com/scientificreports patients9. Tere is a lack of knowledge about aneurysm risk in TAK patients due to the rarity of the disease. Previous studies have found that prevalent of dyslipidemia in patients with TAK was 19–47%10–13, and that lipids disorders are related to the activity of TAK14. Te purpose of this study was to investigate the clinical and labo- ratory features of TAK and to analyze the combination of TAK and dyslipidemia as a risk factor for aneurysm formation. Methods Ethics. Tis retrospective study was conducted in accordance with the ethical principles of the Declaration of Helsinki and approved by the Ethics Committee of Beijing Anzhen Hospital (approval number:2018013X), Capital Medical University. All experiments were performed in accordance with relevant named guidelines and regulations and consent was obtained from all participants and/or their legal guardians. Participants. Tis retrospective cross-sectional study recruited 103 consecutive patients with TAK from the Department of Rheumatology and Immunology, Beijing Anzhen Hospital, from January 2012 to December 2017. Inclusion criteria was decided according to the criteria for classifcation of TAK developed by the American College of Rheumatology in 199015. Exclusion criteria was: patients with other autoimmune diseases, cancer, or infection. Disease activity was assessed using a modifed version of Kerr’s criteria16 and the Indian Takayasu Clinical Activity Score (ITAS)17. Patients were divided into two groups according to the presence or absence of aneurysm (the aneurysm and non-aneurysm groups). We retrospectively reviewed the patients’ baseline general information, medical history, clinical manifesta- tions, laboratory parameters, and angiographic fndings. We defned dyslipidemia as range of lipid abnormal- ities and may involve a combination of increased total cholesterol (>5.20 mmol/l), LDL-C(>3.12 mmol/l), and triglyceride levels (>1.7 mmol/l) or decreased HDL-C (<1.04 mmol/l). Hypertension was defned as a systolic blood pressure ≥140 mmHg and/or a diastolic blood pressure ≥90 mmHg and/or use of blood pressure lowering medication. We obtained information of aorta and its branches using magnetic resonance angiography (MRA), computed tomography angiography (CTA) or Doppler ultrasound. Heart failure defned as lef ventricular EF <40% by echocardiogram. Angiographic classifcation and features. Aneurysm was defned as arterial dilation to more than 50% of the normal diameter of the artery18. Te MRA was used to evaluate the thoracic aorta and its branches, CTA or Doppler ultrasound to measure the abdominal aorta and its branches and peripheral arteries. Lesions were classifed according to the angiographic classifcation of the 1994 International TAK Conference in Tokyo19. Te distribution of lesions was classifed as follows: Numano type I (branches of the aortic arch), type IIa (ascending aorta, aortic arch, and its branches), type IIb (ascending aorta, aortic arch and its branches, and thoracic descend- ing aorta), type III (thoracic descending aorta, abdominal aorta, and/or renal arteries), type IV (abdominal aorta and/or renal arteries), and type V (combined features of types IIb and IV). Collection of blood samples. For each subject, 4 mL of venous blood was drawn in the morning afer a 12-hour fasting period. Blood was placed into a tube without anticoagulant. Afer the blood coagulated, it was centrifuged at 3,000 r/m for 5 minutes, and the serum was collected. A Hitachi 7600–120 automatic biochemi- cal analyzer (Tokyo, Japan) was used to analyze serum parameters. Te ESR was measured using the modifed Westergren method in a standardized manner. Pathological staining of aortic tissue. Specimens were fxed in 4% neutral formalin for 24 hours, embed- ded in parafn, sectioned, and stained with hematoxylin and eosin. Masson stains and Verhoef-van Gieson elastic stains were also evaluated to demonstrate areas of degeneration, elastic fber disorder and fragmentation, and accumulation of collagen, proteoglycans and mucopolysaccharids. Statistical analysis. Values are expressed as the mean ± standard error. Diferences between measured parameters in the two groups were assessed using an unpaired t test. When data were not normally distributed, the Mann-Whitney U test was used, and these values are expressed as quartiles. Qualitative parameters were assessed using the χ2 test. All statistical tests were two-tailed, and p-values < 0.05 were considered to indicate statistical signifcance. To investigate the potential risk factors of aneurysm, following variables were included the in the logistic regression model: age at disease onset (years) (≤19 = 1, 20–39 = 2, 40–59 = 3, ≥60 = 4), male gender, disease duration (months) (≤60 = 0, >60 = 1), fever, chest pain, arteriosclerosis, hypertension, serum total cholesterol (TC), LDL-C levels, C-reactive protein (CRP) levels, ESR, Kerr’s Score, ITAS and treatment with glucocorticoids (GCs). We calculated the cutof values of TC and LDL-C by using ROC curve. Backward stepwise regression was used with odds ratios (ORs) and the corresponding 95% confdence intervals (CIs) in the model (p = 0.05 entry and p = 0.10 removal criteria), p-values < 0.05 were considered to indicate statistical signifcance. All statistical analyses were performed using SPSS 20.0 statistical sofware (SPSS Inc., Chicago, IL, USA). Results The demographic and clinical features of Takayasu Arteritis patients with and without aneu- rysms.
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