Clinical Features And Genetic Characteristics Of Hereditary Hemorrhagic Telangiectasia-associated Pulmonary Hypertension Patients

BackgroundHereditary hemorrhagic telangiectasia(HHT)is an autosomal dominant genetic disease that usually manifests as repeated nose bleeding,telangiectasia and the formation of arteriovenous malformations in the internal organs.It has been found that the ENG gene and the ALK1 gene are the most important pathogenic genes of hereditary hemorrhagic telangiectasia.Pulmonary hypertension(PAH)has received increasing attention as a disease associated with HHT in the past 10 years.The clinical features,hemodynamic characteristics and pathological features of HHT-associated PAH are very similar to IPAH.HHT-associated PAH significantly increased the risk of death in patients with HHT,and the prognosis of patients also appeared to be worse than patients with idiopathic pulmonary hypertension(IPAH).The current known ALK1 gene mutations,especially in the protein kinase domain,is closely related to HHT-related PAH.However,at present,these conclusions lack the support of large sample research,and there is no relevant comparative study on HHT-related PAH caused by different gene mutations.Aim1.Explore the clinical features and prognosis of patients with HHT-related PAH.2.Explore the genetic characteristics of patients with HHT-associated PAH.MethodThis study included patients NYHA fulfilled the inclusion and exclusion criteria and diagnosed as HHT-related PAH in the Shanghai Pulmonary Hospital and the Chinese Academy of Medical Sciences Fuwai Hospital from January 2006 to December 2018.The study collected previous medical history,clinical examination data,right heart catheterization data,and follow-up results.All patients were enrolled in a NYHAle exon or NYHAle genome sequencing.In addition,the IPAH patients diagnosed in the same center were included in the 1:1 ratio according to the principle of gender and age matching for comparative study.This study also summarizes the ALK1 mutations in patients with HHT-associated PAH in previous literature and compared them with the results of this study.This study used independent sample t-test,Mann-Whitney U test,chi-square test,Fisher exact test to compare component data.Differences in prognosis between the groups were compared using Kaplan-Merier survival analysis and log-rank test.The single-factor and multi-factor COX risk ratio models were used to find prognostic factors for patients with HHT-associated PAH.A P value of less than 0.05 is considered to be significant.ResultA total of 77 patients with HHT-related PAH were enrolled,with an average diagnosis interval duration of 24 months.The NYHA function grade of these patients was 0%for grade I,42.9%for grade II,49.3%for grade III,and 7.8%for grade IV.58%of patients had recurrent nasal discharge,75%had telangiectasia,27.3%and 27.9%had pulmonary arteriovenous malformations and hepatic arteriovenous malformations.The mean pulmonary artery pressure(mPAP)for these patients was 63.49±18.8 mm Hg,the median pulmonary wedge pressure(PAWP)was 10 mm Hg(8-11),and the median pulmonary vascular resistance(PVR)was 13.53 Wood units.The positive rate of acute pulmonary vasodilation test was 6%.Compared with patients with idiopathic pulmonary hypertension,patients with HHT-related PAH had a worse grade of NYHA,a significantly higher mPAP and heart index(CI),and a significantly lower positive rate of acute pulmonary vasodilation.The overall 1-,3-,and 5-year survival rates of patients were 90.4%,73.8%,and 60.2%.After controlling NYHA functional grading,NT-proBNP,mean right atrial pressure mRAP,cardiac index CI,pulmonary vascular resistance PVR,Sv02 and other variables,6-minute walking distance 6MWD is still a significant predictor of patient prognosis.75.3%of all HHT-related PAH patients had ALK1 gene mutations,10.4%carried ENG gene mutations,and 14.3%did not find related gene mutations.Patients with ENG mutations had significantly longer 6MWD than the other two groups and had lower levels of NT-proBNP.Survival analysis showed that patients with ENG mutations had significantly higher survival rates than the other two groups.Studies on mutations have found that ALK1,which causes HHT-associated PAH,is mainly present in the intracellular protein kinase domain and is mainly distributed in exons 7,8,and 10.There is a significant difference from the bimodal distribution of the ALK1 mutation in HHT(exon 3,exons 7 and 8).Conclusion1.The overall prognosis of patients with hereditary hemorrhagic telangiectasia-associated pulmonary hypertension is poor.2.ALK1 is the most important gene for hereditary hemorrhagic telangiectasia associated pulmonary artery hypertension,accounting for about 75%.Patients with AKL1 mutations have clinical function indicators and clinical prognosis that are inferior to those with ENG mutations.3.The ALK1 gene mutations located in the intracellular kinase domain of ALK-1 protein are more closely related to HHT-related PAH.