Study On Aortic Disease And Aortic Valve Disease Associated With Bicuspid Aortic Valve Malformatio

Part 1 Clinical Characteristic and Risk Factors of Valve Dysfunction and Aortopathy in Patients with Bicuspid Aortic ValveBackgroundBicuspid aortic valve(BAV)is the most common congenital heart defect.BAV is often complicated by valve dysfunction and aortopathy involving the aortic root to the arch,and significantly increases the risk of adverse cardiovascular events.Previous studies reported that valve disease and aortopathy related with BAV were a result of genetic,hemodynamics and other factors.However,the role of clinical characteristics in valve disease and ascending aortic dilation in BAV patients remains unclear,especially whether hypertension is associated with increased risk of aortopathy needs to be further studied.ObjectivesThis study intends to systematically describe the clinical characteristics of BAV patients in a large contemporary BAV cohort,and also to analyze the risk factors of aortic valve disease and aortopathy for patients with BAV,particularly focuses on the role of blood pressure in those patients.MethodsThis study included consecutive patients who were admitted to Fuwai hospital and diagnosed with BAV from January 1,2013 to December 31,2018.Data on patients’demographic and clinical characteristics were collected.Multivariate logistic regression methods were used to explore the risk factors of valve diseases and aortopathy in BAV patients,with hypertension being thoroughly analyzed.ResultsA total of 1776 BAV patients were included in this study,with an average age of 50.9±14.4 years,and 75.7%were male.The most common comorbidity is hypertension,and about 25%of patients have hyperlipidemia or coronary heart disease.Right coronary and left coronary cusp fusion is the most common BAV type.The incidence of BAV aortopathy was 63.6%,and ascending aortic dilation was 62.4%,aortic root dilation was 9.0%.The risk of BAV aortopathy increases significantly with age.Aortic stenosis was presented in 62%of BAV patients,and aortic regurgitation in 58%of BAV patients.After adjusted for demographic characteristics,clinical comorbidities,medications,and other factors,BAV aortopathy was associated with older age,higher BMI,moderate to severe aortic stenosis,and higher systolic blood pressure or diastolic blood pressure.Moderate to severe aortic valve stenosis was the greatest risk factor for ascending aortic dilatation(OR 2.34,95%CI 1.80-2.96;P<0.001).For every 10 mmHg increase in systolic blood pressure,the risk of aortopathy increased by 8%(OR 1.08,95%CI 1.00-1.1 7;P=0.044).Moderate to severe aortic valve stenosis in BAV patients is related to age,BAV classification,and diastolic blood pressure.ConclusionsPatients with BAV often have higher risk of aortic disease and valve disease,and the risk increases significantly with age.Various clinical factors such as age and blood pressure may significantly increase the risk of aortopathy and aortic valve disease.Controlling blood pressure is expected to reduce the risk of aortopathy in BAV patients and improve the prognosis of patients.Part 2 Clinical Characteristics and Management of Coexistent Cardiomyopathy in Patients with Bicuspid Aortic ValveBackgroundBicuspid aortic valve(BAV)is the most common congenital heart disease.BAV malformation can occur independently,or it can be combined with other congenital heart diseases or genetic syndromes.Previous studies have reported that the prevalence of cardiomyopathy in the population with bicuspid aortic valve is higher than that in the general population,and some studies have suggested that the occurrence of BAV and cardiomyopathy may have the same genetic basis.In addition,dysfunction caused by aortic valve malformation also affects the development of the myocardium,and cardiomyopathy can also affect valve function.At present,most of the researches on BAV combined with cardiomyopathy are case reports,and their clinical characteristics and clinical management need further research.ObjectivesBAV is the most common congenital heart disease.Inherited cardiomyopathy,including hypertrophic cardiomyopathy(HCM),dilated cardiomyopathy(DCM),and left ventricular noncompaction cardiomyopathy(LVNC).However,the prevalence,clinical characteristics,and current management of BAV associated with inherited cardiomyopathy have not been well described.This study investigated the incidence,corresponding clinical features,and treatment of cardiomyopathy in the largest BAV population,and provided data support for future research.MethodsConsecutive 3533 patients diagnosed with BAV at Fuwai hospital between January 1,2009 and December 31,2018 were retrospectively assessed for HCM,DCM,and LVNC based on echocardiographic criteria and pathological results according to guidelines.The clinical features,management strategies,and in-hospital outcomes of patients with coexistent conditions were investigated further.The articles of clinical research were systematically reviewed with the Mesh keywords of BAV combined HCM,DCM or LVNC in Pubmed,Medline,Embase and Cochrane until December 31,2022.ResultsOf 3533 patients with BAV screened,57(1.6%)had concomitant cardiomyopathy.BAV was combined with HCM in 30 of these patients,with DCM in 19,and with LVNC in eight.Forty-six patients(80.7%)were male,and the mean age at first diagnosis was 47 years for BAV with HCM,49 years for BAV with DCM,and 35 years for BAV with LVNC.Heart failure and aortic valve dysfunction were common in these patients,and the prevalence of coexisting aortopathy was 43.3%,26.3%and 25.0%,respectively,for BAV with HCM,DCM and LVNC.During the index hospitalization,24 of the 57 patients(42.1%)underwent surgery,16(28%)underwent aortic valve and/or aortic surgery,and 16 of the 30 patients with HCM had a Morrow procedure.There were no deaths or other major adverse cardiovascular events.There were 25 papers were analyzed,including 21 case reports and 4 clinical studies.The prevalence and clinical characteristics of cardiomyopathy in BAV populations in different regions were different,but LVNC was the most common type of cardiomyopathy.ConclusionsThe prevalence of inherited cardiomyopathy in BAV population was 1.6%higher than in the general population,indicating that hereditary cardiomyopathy and BAV may have the same genetic basis or influence each other during process of disease.Aortopathy and heart failure were common,which may be related to complications caused by BAV and cardiomyopathy.Almost half of patients required surgical intervention at first diagnosis,and there were no on-hospital deaths or adverse cardiovascular events.Part 3 The Pathogenicity and Mechanism of PRDM 16 in in a Family with Bicuspid Aortic ValveBackgroundBicuspid aortic valve(BAV)is the most common congenital heart disease,which is an autosomal incomplete dominant inheritance disease.At present,the pathogenic genes and pathogenic mechanisms of BAV have not yet been fully clarified.In the previous work,a candidate mutation PRDM 16 c.1684G>A was screened out after whole-exome sequencing of a BAV family.There was no research reporting the pathogenicity of this mutation site and the correlation with BAV.ObjectivesThis study will first use computer simulation analysis technology to predict the impact of c.1684G>A on the structure of PRDM 16 protein to initially determine its pathogenicity.The mutant plasmid was constructed in vitro by molecular cloning,and the pathogenicity of the mutation site was further verified at the cellular and molecular levels to initially explore the relationship between PRDM 16 and BAV.MethodsIn this study,PRDM 16 structure was predicted by data retrieval,protein structure prediction and homology modeling,and the impact of c.1684G>A on amino acids and protein structure was analyzed.The wild PRDM 16 plasmid was synthesized in vitro,and the mutant plasmid was constructed by molecular cloning.Wild and mutant plasmid were transfected into HEK293 cells,and the expression of SMOC1,TGFb1,TGFb2,SMAD2,and ACTA2 in wild and mutant cells were detected by real-time fluorescent quantitative polymerase chain reaction.ResultsThe amino acid changes from valine to isoleucine at position 562 caused by PRDM 16 c.1684G>A mutation,which has an impact on the hydrophobic interface of the protein.the amino acid is far away from several functional domains of PRDM 16 protein,so it is difficult to predict the structure of protein.However,the mutation of p.Val562Ile resulted in an a helix at position 558-560 that is not found in the wild type.According to the structure prediction results of Genome 3D and UCSF Chimera,amino acid 562 may be closer to several amino acids within 100 amino acid residue upstream and downstream,and may further affect the formation of structure,which may be the potential mechanism of mutation site affecting the structure and function of PRDM 16.The wild and mutant plasmid was successfully transfected and the protein was successfully expressed,but there is no significant difference in the expression of SMOC1,TGFb1,TGFb2,SMAD2,and ACTA2 between wild and mutant cells,suggesting that the pathogenicity of the mutation site is weak but further researches are needed.ConclusionsProtein structure prediction by computer modeling can preliminarily predict that c.1684G>A causes the new alpha helix structure and may affect PRDM16 function,but the accuracy and precision of its prediction are affected by mutations,databases,and modeling methods.Experiments at the cellular or molecular level can further verify the pathogenicity of missense mutation.PRDM16 may be related to BAV,but further exploration and verification are needed.