Study On Related Factors For Abdominal Aortic Aneurysm

Abdominal aortic aneurysm(AAA)is one of the significant cardiovascular disease burdens over the world.AAA is difficult to be detected at early stage,since it is typically asymptomatic before rupture,when it becomes life-threatening.And no drug is available for preventing it from formation and progression.Previous studies indicated that the benefit-harm balance of large-scale screening for AAA were debatable.So it is critical to explore the risk factors and pathogenesis for AAA,which could identify the population at high risk and then improve the efficiency of screening and prevention.In this thesis,based on a large prospective cohort,we found that high RDW is associated with an increased risk of AAA in the first project,and then by comparing the risk factors with CHD,we found the strong predictive value of RDW for AAA in the second project.In the third project,high su PAR,which was positively related to RDW,was observed to be associated with higher risk of incident AAA,and it could stimulate HASMC to express MMP-2,which may be one of mechanisms behind the observed association with AAA.In the fourth project,findings from both DM-PRS and experiments in vitro and in vivo further supported the protective effect of DM for AAA.In conclusion,this study explored the risk and protective factors for AAA,which is a prerequisite for tailored risk assessment and prevention as well as potential treatment approaches.Part Ⅰ Red Cell Distribution Width is Associated with Future Incidence of Abdominal Aortic Aneurysm in a Population-Based Cohort StudyObjective Red cell distribution width(RDW)has been suggested to have a predictive potential for several cardiovascular diseases,but the role in abdominal aortic aneurysm (AAA)development is largely unknown.We aimed to explore whether RDW was associated with the risk of AAA in a population-based study.Methods A total of 27,260 individuals were included in this prospective study based on the Malmo Diet and Cancer Study cohort.Data of baseline characteristics were collected during 1991-1996,incidence of AAA was prospectively identified from national patient register up to 2016.Cox regression was used to estimate hazard ratios(HR)with 95 % confidence intervals(CI)for AAA across quartile of RDW.Results During a median follow-up of 21.7 years,491 subjects developed AAA.After adjustment for age,sex,smoking,diabetes,blood pressure,apolipoprotein B/A1 ratio,hemoglobin,total leukocyte count,and other cardiovascular risk factors,participants with the highest quartile of RDW experienced 61% increased risk of AAA as compared to those with the lowest quartile(HR=1.61,95% CI=1.20–2.12).RDW showed similar relationship with severe(i.e.ruptured or surgically repaired)AAA or nonsevere AAA(adjusted HR 1.58 and 1.60,respectively).The observed association between RDW and AAA risk was stronger in current smokers(adjusted HR=1.68,95%CI=1.18-2.38)than in former smokers(adjusted HR=1.13,95%CI=0.72,1.79),or non-smokers(adjusted HR=1.77,95%CI=0.74,4.22).Conclusion Elevated RDW is associated with increased future incidence of AAA,independently of several traditional cardiovascular risk factors.The causal and pathophysiological mechanisms connecting RDW and AAA remain to be explored.Part Ⅱ Comparisons of Risk Factors for Abdominal Aortic Aneurysm and Coronary Heart Disease: A Prospective Cohort StudyObjective Even though both abdominal aortic aneurysm(AAA)and coronary heart disease(CHD)are related to atherosclerosis,there are important differences in risk factors between both diseases.This prospective study compared the risk profiles of AAA and CHD,respectively.Methods The Malmo Diet and Cancer Cohort was establised between 1991 and 1996.Incidence of AAA and CHD(fatal and non-fatal acute coronary events)was followed prospectively up to 2016 by linkage with national patient register.Cox regression was used to calculate the association of each factor with AAA and CHD and hazards ratios were compared using a modified Lunn-Mc Neil method.Results A total of 447 participants developed AAA(0.85 per 1000 person-years)and 3129 developed CHD(6.08 per 1000).After multivariate adjustments,smoking,anti-hypertensive medications,lipid-lowing medications,systolic and diastolic blood pressures,apolipoprotein(Apo)A1(inversely),Apo B,Apo B/Apo A1 ratio,total leukocyte count,neutrophil count and neutrophil/lymphocyte ratio were associated with the risks of both AAA and CHD.Individuals with diabetes and unmarried status had increased risk of CHD but not AAA.When comparing risk factor profiles for the two diseases,smoking,diastolic blood pressure,Apo A1,and Apo B/Apo A1 ratio had stronger associations with risk of AAA than with risk of CHD(all p values for equal association <0.01).Similar result was also observed when exploring the effect of RDW.Conclusions The risk profiles for AAA and CHD showed many similarities,but also several important differences.This study also confirmed the strong predictive power of RDW for AAA.Our results contributed to distinguish individuals at increased risk of AAA and those at increased risk of CHD,which is a prerequisite for tailored risk assessment and prevention.Part Ⅲ Soluble Urokinase-type Plasminogen Activator Receptor and Abdominal Aortic AneurysmsObjective Elevated circulating soluble urokinase-type plasminogen activator receptor(su PAR)has been suggested to be a risk factor of several cardiovascular diseases,and it could stimulate some certain cells biologically.However the association with abdominal aortic aneurysm(AAA)is largely unknown,neither the effects on human aortic smooth muscle cell(HASMC).Methods A total of 4686 individuals were included in this study based on the Malmo Diet and Cancer Study – Cardiovascular sub-cohort.Data of baseline characteristics were collected during 1991-1996,incidence of AAA was prospectively identified up to 2016.Cox regression was used to estimate hazard ratios(HR)with 95 % confidence intervals(CI)for AAA across quartile of su PAR.Recombinant human su PAR protein was used to stimulate HASMC directly,with or without MAPK signaling.The Western blot and ELISA were conducted to identify the expressions of aimed proteins.Results During a mean follow-up of 21.3 years,76 subjects developed AAA.After adjustment potential confounders,participants with the highest quartile of su PAR experienced 156% increased risk of AAA as compared to those with the lowest quartile(HR=2.56,95% CI=1.23–5.13).In cell study,su PAR could promote proliferation and migration of HASMC,as well as the expression of MMP-2.In addition,su PAR could lead to phosphorylation of MAPK signaling.However,only inhibiting the ERK1/2 pathway could decrease the expression of MMP-2 induced by su PAR,but not P38 or JNK-1 ptahway.Conclusion Elevated su PAR is associated with increased future incidence of AAA,independently of several traditional cardiovascular risk factors.Su PAR could induce HASMC to express MMP-2 via MAPK-ERK1/2 pathway,which could be involved in the pathophysiological process of AAA.Part Ⅳ Diabetes Mellitus and Abdominal Aortic AneurysmObjective Previous studies have suggested that diabetes mellitus(DM)was negatively associated with the incidence of abdominal aortic aneurysm(AAA)disease.However the causality is unknown.Methods Using incidence density sampling approach matched by sex,age and smoking status,we generated a 1:1 nested case control study comprising 392 AAA cases and 392 controls from Malmo Diet and Cancer Study.A weighted polygenic risk score(PRS)was created by summing the number of risk alleles for 231 singlenucleotide polymorphisms associated with DM.Conditional logistic regression was used to analyze the relation between DM-PRS tertiles and AAA.Mouses with DM(induced by streptozocin)or not were infused by angiotensin Ⅱ pump for 4 weeks.And HASMC was stimulated by angiotensin Ⅱ under different glucose environment.Results Increased the DM-PRS was associated with increased risk of incident AAA after adjustment for smoking and other established risk factors for AAA.The highest tertile of DM-PRS had an odds ratio of 0.53(95% confidence interval 0.36,0.80)for incident AAA,compared with the lowest tertile.In animal model,DM largely suppressed the formation of AAA.In-vitro experiment,hyperglycemia alleviated the expression of MMP-2 when stimulated by angiotensin Ⅱ.Conclusions Genetic predisposition to DM is associated with a lower risk of incident AAA.In-vivo and in-vitro experiments found that the protective effects of DM might be caused by hyperglycemia.However the pathophysiological mechanisms remain to be investigated.