| Objective:The aim of this study was to evaluate the right heart remodeling of patients with connective tissue disease associated pulmonary arterial hypertension(CTD-PAH)with different heart functional status and right ventricular reverse remodeling after short-term therapy using multi-mode echocardiography and to further evaluate the association of the right heart remodeling and prognosis.Methods:We enrolled consecutive patients with CTD-PAH who were admitted to the Department of Rheumatology of our hospital from July 1 2015 to December 31 2018.Inclusion criteria was patients with high echocardiographic probability of pulmonary hypertension(PH)according to 2015 ESC/ERS guidelines for PH.Exclusion criteria were serious pulmonary interstitial disease,congenital heart disease and left heart diseases.30 healthy controls with consistent age,gender and body surface area were enrolled.All subjects were underwent conventional echocardiographic examination,2D-STE and RT-3DE in sinus rhythm.Hemodynamic parameters including pulmonary artery systolic pressure(PASP),mean pulmonary artery pressure(mPAP)and pulmonary vascular resistance(PVR)were evaluated by Doppler echocardiography.The measurements of right ventricular remodeling included right ventricular end-diastolic volume index(RVEDVi),end-systolic volume index(RVESVi)and ejection fraction(RVEF)derived from RT-3DE,left ventricular end-systolic and end-diastolic eccentric index(LV-EIs and LV-EId)derived from 2DE,right ventricular global and free-wall longitudinal strain(RVGLS/RVFW-LS)derived from 2D-STE.The measurement of right atrial function was right atrial global longitudinal strain(RALS)derived from 2D-STE.Clinical data were collected simultaneously,including duration of disease,World Health Organization functional class(WHO FC),six-minute walk distance(6MWD),and plasma brain natriuretic peptide(BNP)level.All patients were evaluated regularly at 3-6month intervals by complete echocardiography including 2D-STE and RT-3DE and clinical data including adverse events were recorded.Conventional,2D-STE and RT-3DE parameters at baseline were compared between the patients with different WHO functional class.Clinical improvement and adverse events were defined according the follow-up to analyze the reverse remodeling of the right heart in patients with clinical improvement.Finally,predictive utility of clinical and echocardiographic parameters for adverse outcomes was evaluated by survival analysis.Results:1.Clinical characteristics of the subjects:A total of 63 consecutive CTD-PAH patients were enrolled.Systemic lupus erythematosus(SLE)was the most common underlying CTD(25,39.7%),followed by mixed connective tissue disease(20,31.7%),primary sclerositis(15,23.8%)and systemic sclerosis(3,4.8%).There were 18 cases(28.6%)with WHO functional class I/?,28 cases with WHO functional class?and 17cases(27.0%)with WHO functional class?.2.Analysis of right heart remodeling in CTD patients with different heart functional class:Serum BNP significantly increased and 6MWD significantly decreased with the increase of WHO functional class.PASP and mPAP in WHO-FC?groups were significantly different from WHO-FC?groups(P<0.01).PVR in WHO FC?groups were significantly different for WHO-FC?group(P<0.01).Analysis for right heart remodeling:There were significant statistical differences in measurements of RV volume including RVEDVi and RVESVi between WHO-FCI/?and WHO-FC?groups,but no statistical differences between WHO-FC?and WHO-FC?.RV and RA myocardial mechanical function measurements including RVGLS/RVFW-LS and RALS,RV morphological parameter LV-EId were significantly different between each two groups.Correlation analysis showed RALS had the best correlation with WHO-FC(r=-0.684,P<0.001).ROC curve analysis showed that area under the curve(AUC)of RVESVi,LV-EId,RVFW-LS and RALS for diagnosis of WHO-FC?and above were 0.865,0.917,0.833 and 0.867.The AUC of these parameters for diagnosis of WHO-FCIV were 0.699,0.793,0.855 and 0.866.Multivariable Logistic regression showed LV-EId(OR 1.361,P=0.018)and RALS(OR 0.840,P=0.005)independently predicted WHO-FC?.3.Analysis of right heart reverse remodeling after short-term therapy in patients with CTD-PAH:A total of 57 CTD-PAH patients were enrolled with 56.1%of them achieved clinical improvement in an average follow-up time of 4.2±0.9 months.Patients with clinical improvement showed lower plasma BNP level,lower PASP and PVR,better RVFW-LS than patients without clinical improvement at baseline(p<0.01).In the clinical improvement group,WHO FC,plasma BNP,PASP,PVR,RAA,RVEDVi and RVESVi were significantly reduced and 6MWD,RA LS,RVEF,absolute value of RV FW-LS and RV GLS were significantly increased(p<0.001).There was no significant correlation between the change of PASP and BNP in the clinical improvement group(r=0.232,P=0.210).Change in BNP levels during follow-up correlated significantly with changes in RAA,RVEDVi,RVESVi,RVEF,RV GLS,RV FW-LS and RALS,correlation was strongest significant with RVESVi(r=0.651,P<0.001).4.Analysis of the predictive utility of clinical and echocardiographic parameters for adverse outcomes.A total of 53 CTD-PAH patients were enrolled with 20(37.7%)underwent clinical adverse events during an average follow-up period of 19.3±10.9months.Patients with adverse events showed higher WHO-FC and plasma BNP,larger RVEDVi,RVESVi,lower 6MWD,RA LS,RVEF,absolute value of RV FW-LS and RV GLS than patients without adverse events.Kaplan-meier curve analysis showed that WHO FC,PASP,RVESVi,LV-EId,RVFW-LS,RALS at baseline as well as clinical improvement and right ventricular reverse remodeling in short-term follow-up were significantly correlated with event-free survival rate.Predictive utility of RV FW-LS and RA LS for prognosis were enhanced when combined with RV reverse remodeling.The pattern that patients with higher RALS or absolute value of RVFW-LS and RV reverse remodeling was associated with better prognosis.The pattern that RALS combined with right ventricular reverse remodeling was better than the pattern RVFW-LS combined with right ventricular reverse remodeling for prediction of prognosis.Multivariate COX analysis showed that change rate of RVESVi(per1%,HR 0.973,p=0.002)and RALS(HR 0.892,p=0.003)were independent predictors of adverse events.Sequential COX models for prediction of long-term outcome showed the incremental benefit.One of the sequential Cox models,which was based on WHO FC of clinical variables(?~2=10.99)was improved by addition of hemodynamic parameters of PASP(?~2=24.12,p<0.001),and RA LS(?~2=37.54,p<0.001),and further improved by addition of RVRR(?~2=47.98,p=0.0012).Conclusion:1:Right heart significantly expanded and functions significantly impaired in CTD-PAH patient were associated with WHO-FCIII.The RV diastolic significantly morphologic abnormality and RA function significantly impaired were associated with WHO-FC?.RVESVi,LV-EId and RVGLS/RVFW-LS represent RV remodeling in terms of size,shape and function respectively.RALS is a good supplementary indicator and can independently reflect severe right heart failure.2:CTD-PAH patients with less elevated PASP,less impaired RV function and shorter course of disease are more likely to achieve clinical improvement in a short-term therapy.The change of PASP was not significantly correlated with the change of BNP.RA and RV size reduction and function improvement were significantly correlated with BNP reduction,and RVESVi changes showed the best correlation with BNP changes,which can be used as an indicator to evaluate reverse remodeling of RV.3:RVFW-LS can predict adverse clinical events independent of RV volume and morphological abnormality.RALS and RVESVi change rate after short-term treatment can predict adverse clinical events independent of WHO-FC,RVFW-LS and PASP.Combination of baseline RALS and RVESVi change rate after short-term treatment can obtain better disease risk prediction,which is conducive to the disease assessment and management of CTD-PAH patients. |
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