POS0881 DETECTION OF THE GENE EXPRESSIONS IN PERIPHERAL BLOOD INVOLVED IN THE PROGRESSION OF PULMONARY VESSEL DISEASE AT THE SUBCLINICAL STAGE OF PULMONARY HYPERTENSION ASSOCIATED WITH SYSTEMIC SCLEROSIS

Abstract

Background:Pulmonary hypertension (PH) is prominent as a vascular involvement of systemic sclerosis (SSc), which remains a leading cause of death in spite of current best treatments. Recently, hemodynamic definition of PH was updated from mPAP≥25mmHg to mPAP>20mmHg and PVR≥3WU. Although new definition may improve the prognosis of PH associated with SSc by giving a chance to start management early, it may be insufficient as more than 2/3 of the pulmonary circulation is already impaired by the time of meeting the definition. Therefore, the ideal therapeutic intervention should be started at the subclinical stage of PH in SSc patients, but little is known about underlying pathological mechanisms at the stage. In this study, we investigate progression to exercise-induced PH (exPH)1), which is considered subclinical PH, in the prospective registry of high-risk population for developing PH associated with SSc.Objectives:To detect the gene expressions in peripheral blood involved in the progression of pulmonary vessel disease (PVD) at the subclinical stage of PH associated with SSc.Methods:Total of 180 patients who had not met PH criteria with Raynaud phenomenon, skin sclerosis or SSc-related autoantibody was registered. To detect the early PVD, exercise Doppler echocardiography (exDE) was carried out every 6 or 12 months for up to 6 years. The definition of exPH was maximum sPAP>40mmHg or increase in sPAP>20mmHg estimated by exDE during exercise. For gene expression analysis, total RNAs from whole peripheral blood cells were extracted by PAXgene system, and then multiplex sequencing was done. To identify candidate genes involved in the progression to exPH, random forest machine learning method was employed. Volcano plots, a scatter plots to visualize fold-changes and p-values of differentially expressed genes (DEGs) between exPH and others (exN), were also used for seeking the important genes for disease progression.Results:At the time of registration, 34.4% of patients met exPH criteria, and 15.6% of patients developed exPH during follow-up period (35.0±18.1 months). Expression of TNF gene was selected as the most useful genes to predict progression to exPH by random forest, and the accuracy of the model was about 87%. Volcano plots indicated that expressions of TMEM176A and TMEM176B were prominent (fold-change >2.4 and -log10 p-value >3.5) in exPH patients. The accuracy was improved to 90% if the expression of TNF and TMEMA/B were used for the prediction of progression to exPH. We found that statistically significant increase in the expression of TNF was eliminated at the time of fulfilling the exPH criteria, while increase in expressions of TMEM A/B were still kept.Conclusion:It was reported that TNFα drives pulmonary arterial hypertension by suppressing the BMP type-II receptor and altering NOTCH signalling2). Our findings suggest that TNFα plays important role only in the period of pre-exPH. On the other hand, increase in expressions of TMEM A/B were observed through the period of pre-exPH to post-exPH. It suggests that there are multiple phases before developing PH associated with SSc. It is very important to understand the phases for the precise treatment to arrest the progression of PVD.