The Prognostic Study Of Idiopathic Pulmonary Hypertension

PART 1-1:The Prognostic Value of 18F-FDG Uptake Ratio Between the Right and Left Ventricles in Idiopathic Pulmonary Arterial Hypertension(Clin Nucl Med 2015;40:859-863)Purpose:Metabolic changes occur in the right ventricle(RV)under increased afterload in pulmonary arterial hypertension.FDG PET imaging has potential to assess RV function.In this study,we aimed to determine the prognostic value of metabolic changes of RV using FDG PET imaging in idiopathic pulmonary arterial hypertension(IPAH).Patients and Methods:In this prospective investigation,patients newly diagnosed with IPAH were recruited.Patients underwent right heart catheterization,FDG PET imaging,and cardiac MR(CMR)within 1 week.Right ventricle hemodynamics,glucose metabolism derived from the FDG uptake levels,and functional parameters were obtained.The FDG uptake ratio between the RV and the left ventricle(LV)and its relation with the patients' survival were analyzed.Results:A total of 45 IPAH patients were enrolled in this study,which included 13male(28.9%)and 32 female(71.1%).The median follow-up time of this study was 1043 days.At the end of the follow-up,36 patients survived,whereas 9 patients were deceased because of right heart failure.Multivariate Cox proportional hazard analysis showed that the ratio between the corrected RV and LV FDG uptake(cRV/LV)in both glucose-loading(cRV/LVg)and fasting(cRV/LVf)conditions independently predicted the mortality after adjusting for pulmonary vascular resistance index,mean right atrial pressure,and World Health Organization functional class.Kaplan-Meier survival analysis showed that patients with cRV/LVf greater than 143.65%in fasting condition(log rank,P = 0.030)or cRV/LVg greater than 120.55%in glucose-loading condition(log rank,P = 0.014)had worse prognosis.Conclusions:The FDG uptake ratio between the RV and LV can be an independent predictor for long-term prognosis of IPAH patients.PART 1-2: Prognostic value of right ventricular ejection/filling parameters in IPAH using cardiac magnetic resonance: A prospective pilot study(Respirology.2017;22(1):172-178.)Background and objective:The potential prognostic value of cardiac magnetic resonance(CMR)-derived right ventricular(RV)ejection/filling parameters in the assessment of RV function remains to be fully established.The goal of this study was to explore the prognostic value of these parameters in idiopathic pulmonary arterial hypertension(IPAH)patients.Methods:In this prospective investigation,newly diagnosed IPAH patients without targeted therapy were recruited.Patients underwent right heart catheterization(RHC),6-min walk test and CMR imaging within 1 week.Cardiopulmonary haemodynamics derived from RHC,and RV ejection/filling parameters derived from CMR were collected.Results:A total of 41 IPAH patients were recruited with the median follow-up time of 824 days.During this period,13 patients significantly deteriorated and among them,7 patients died.CMR-derived RV peak ejection rate(PER)correlated significantly with CMR-derived RV stroke volume index(r = 0.574,P<0.001)and RV cardiac index(r =0.611,P<0.001),but had no significant correlation with RV end diastolic volume index(EDVI,r = 0.201,P = 0.208)and pulmonary vascular resistance(r =-0.134,P = 0.403).Multivariate Cox regression analysis showed that RV time to PER(TPER,hazard ratio(HR)= 1.010,95%CI:1.003-1.017,P = 0.005)and RV TPER/time of a cardiac cycle(TPER/TCC,HR = 1.085,95%CI:1.031-1.141,P = 0.002)were predictors of clinical deterioration after adjusting for N-terminal pro-brain natriuretic peptide(NT-proBNP)and RV EDVI.Kaplan-Meier survival analyses showed that patients with RV TPER>199.01 ms(log rank:P = 0.036)or RV TPER/TCC>20.02%(log rank:P = 0.007)had worse prognosis.Conclusion:CMR-derived RV TPER and TPER/TCC can reflect RV early systolic function,and may be promising predictors for long-term prognosis in IPAH patients.Background and Purpose:Recent studies found endothelial-to-mesenchymal transition(EndoMT)played an important role in the pathogenesis of pulmonary arterial hypertension.Our pilot research demonstrated the existence of Warburg effect in the lung tissue of idiopathic pulmonary arterial hypertension patients.However the relationships and the underlying mechanisms between EndoMT and Warburg effect have not been elucidated.Therefore,the purpose of this study is to determine whether metabolic reprogramming happens in EndoMT cells.We also want to investigate whether sodium dichloroacetate(DCA),a metabolic modulator,could prevent EndoMT by inhibiting Warburg effect.Methods and Results:PAECs were induced to undergo EndoMT by adding 5 ng/mL TGF-?1,5 ng/mL TNF-? and 0.1 ng/mL IL-1?.Induced-EndoMT(I-EndoMT)cells started to change to spindle shape and lost well-organized cobblestone-like shape since the second day.Western Blot analysis showed that I-EndoMT cells highly expressed mesenchymal markers,including ?-SMA and SM-22a,and TWIST,while the expressions of VE-cadherin and vWF,which are endothelial markers,were significantly decreased.We also observed the co-expression of vWF and ?-SMA or vWF and SM-22a in I-EndoMT cells by multiple immunofluorescence.Interestingly,in I-EndoMT cells,the expression of GLUT1,PDH-Ela and PDK1 were all decreased,and PDH-E1?/PDK1 was significantly lower than PAECs which indicates the preference of I-EndoMT cells to use aerobic glycolysis to produce energy.In the meanwhile,we observed the decreased proliferation capacity and elevated apoptosis level of I-EndoMT cells,reflected by the increased expression of Caspase 3,cytochrome C and high proportion of cells staining TUNEL,and decreased expression of PCNA,Osteopontin and low proportion of cells staining EdU.Then,we added DCA(2.5 mM or 5 mM)to I-EndoMT cells and found VE-cadherin levels were increased in I-EndoMT cells treated by 5 mM DCA than I-EndoMT cells,but other markers of EndoMT were not reversed.Moreover,we found both the proliferation capacity and the apoptosis levels of I-EndoMT cells treated with 5 mM DCA were enhanced than I-EndoMT cells.This indicates that DCA could prevent EndoMT by inducing the apoptosis of I-EndoMT cells.Conclusion:Targeting at Warburg effect might not only be an important method to inhibit EndoMT,but also a promising direction for the treatment of pulmonary hypertension.