| Part 1:Pulmonary Artery Denervation Reverses Pulmonary Remodeling in the Rat model of Left Ventricular DysfunctionBackgroundPulmonary hypertension associated with left ventricular dysfunction(PH-LVD)is the most common form of pulmonary hypertension(PH)and is associated with a poor prognosis.Studies have suggested some benefit of pulmonary denervation(PADN)in PH,although the mechanisms remain uncertain.We hypothesized that PADN could alleviate pulmonary hypertension and improve right ventricular function in heart failure(HF)by reducing pulmonary remodeling.Methods78 male Sprague-Dawley(SD)rats were radomly divided into the control group,the sham group,and the Supracoronary aortic banding group(SAB group).After 4 weeks,rats were randomly divided into 5 groups:the control group(n=6),SAB group(n=5),SAB+PADN group(n=6),sham group(n=6),and SAB+sham group(n=7).Morphological,echocardiographic,and hemodynamic analyses were assessed after next 4weeks later.Lung tissues were stained with hematoxylin eosin(HE),vWF and a-SMA immunohistochemic.The levels of PKA,PKC,AKT,eNOS and their phosphorylation were detected by Western Blot.The levels of NE,cAMP,cGMP,NO in pulmonary plasma were detected by ELISA.the mRNA expression of eNOS was detected by RT-qPCR.The level of nitric oxide was detected by nitric acid reduction method.ResultsThere was no significant difference between the control group and the sham group,and there was no significant difference between the SAB group and the SAB+ sham group.PADN reduced medial wall thickness(21.09±1.27%vs.24.43±1.03%),full muscularization(21.50±2.52%vs.47.75±2.06%),mPAP(21.92±1.64 vs.24.54±2.12mmHg),RVAW(0.83±0.04 vs.0.95±0.03mm)and improved PA VTI(29.29±2.34cm vs.25.19±1.26cm)compared with the SAB group(all P<0.001).The parameters of LVPWs,LVEDd,LVEDs,and LVEF did not differ significantly between the SAB+PADN group and the SAB group.PADN significantly increased the level of cAMP(44.39±4.83 vs.24.82±4.24 pmol/mg,P=0.001),cGMP(362.07±63.73 vs.185.8±27.22 fmol/mg,P=0.002),nitric oxide activity(9.22±2.32 vs.5.99± 1.96 U/ml,P=0.009)in lung tissue and decreased the level of NE in the lung(111.67±16.67 vs.147.72±38.44 ng/ml,P<0.001)Western blot and RT-qPCR revealed that PADN increased endothelial nitric oxide synthase(eNOS)expression in lung tissue at protein and mRNA levels compared with the SAB group.PADN enhanced the protein expression of PKA-dependent eNOS phosphorylation and AKT-dependent eNOS phosphorylation at Ser1177 and 633 sites,with the reduction of PKC-dependent eNOS phosphorylation at Thr495 compared with the SAB group.ConclusionsThis study suggested PADN significantly improved pulmonary hemodynamics and reversed pulmonary vascular remodeling.It may be related to the decrease of NE release and enhancement of eNOS-Ser633/1177 and inhibition of eNOS-Thr495 phosphorylation,thus increasing NO synthesis,and then improve the pulmonary artery endothelial function.Part 2:Clinical and biochemical characteristics of pulmonary hypertension in patients with left ventricular dysfunctionBackgroundPulmonary hypertension(PH)is one of the most common complications of left ventricular dysfunction.The purpose of this study was to analyze the clinical characteristics and prognostic factors in patients of pulmonary hypertension associated with left ventricular dysfunction.MethodsBetween January 2012 and Augest 2016,154 consecutive patients with pulmonary hypertension secondary to with left ventricular failure treated with right heart catheterization were prospectively followed up.According to the data of right heart catheterization,patients were divided into 3 groups:normal group(mPAP<25mmHg),postcapillary pulmonary hypertension group(Ipc-PH group,mPAP>25mmHg,PCWP>15mmHg,and PVR<3 WUs),the capillary before and after mixed pulmonary hypertension group(Cpc-PH group,mPAP>25mmHg,PCWP>15mmHg and PVR>3 WUs).The clinical data,biochemical parameters,echocardiographic parameters,right cardiac catheterization data,biochemical findings,and composite clinical endpoint events(defined as worsening of PAH,worsening of left ventricular dysfunction,death,rehospitalization,heart transplantation,or lung transplantation)and mortality were prospectively compared among the three groups.Linear regression analysis was used to determine the risk factors of elevated pulmonary vascular resistance in patients with left ventricular dysfunction.Regression analyses were used to assess the prognosis of patients with left ventricular failure associated with pulmonary hypertension.ResultsThe total of 154 patients were enrolled,including 102 males(66.2%)and 52 females(33.7%),with an average follow-up of 1.9 years.There was a statistically significant difference in uric acid among the normal group(n=40),the Ipc-PH group(n=43)and the Cpc-PH group(n=71)(P<0.001).The level of NT-proBNP and the 6-MWD were significantly different in the three groups.The level of uric acid in the Cpc-PH group was significantly higher than that in the normal group(P<0.001),and there was no difference between the Cpc-PH group and the Ipc-PH group(P=0.416).The level of NT-proBNP in the Cpc-PH group was significantly higher than that in the normal group(P=0.001)and that in the Ipc-PH group(P=0.021)respectively.The 6MWD in the Cpc-PH PH group was significantly lower than that in control group(P=0.001),and there was no difference between the Cpc-PH group and the Ipc-PH group(P=0.148).The level of RAP,RVSP,PASP,PADP,PAWP(LVEDP)and PVR in Cpc-PH group were significant increased,with PAC,CO,RVEDV,RVEF decreased.The Echo parameters of LAD,RVD and Tei of right ventricle were significantly enlarged in Cpc-PH group.At the end of the follow-up,worse left ventricular failure occurred in 28 patients(39.4%)in Cpc-PH group,higher than the Ipc-PH group and the normal group(P=0.012).Cardiac readmission occurred for 56 times in Cpc-PH group,higher than the Ipc-PH group and the normal group(P=0.013).The re-hospitalization occurred for 74 times in Cpc-PH group,higher than the Ipc-PH group and the normal group(P=0.009).There were 9 all-cause deaths in Cpc-PH group,with 6 in Ipc-PH group and 0 in the normal group(P=0.034).Multiple linear regression analysis revealed that only NT-proBNP and SOD3 were independent predictors of pulmonary vascular resistance.Compared with the normal group and Ipc-PH group,the Cpc-PH group had the lowest survival rate(87.3%)and the highest composite clinical endpoint events rate(82.3%).Cox regression analysis revealed that only the value of PVR(?3.36 WUs)and the level of SOD3 in pulmonary plasma(?320.81ng/ml)were independent predictors of death in patients with PH-LVD.ConclusionsThe survival rate in Cpc-PH group is low,with complex clinical events rate high.The pulmonary plasma level of SOD3 in patients of PH-LVD decreased significantly and negatively correlated with PVR.The pulmonary plasma concentration of SOD3 and the value of PVR are the independent predictors of death in patients with left ventricular dysfuncation associated with pulmonary hypertension.Part 3:Pulmonary Artery Denervation to Treat Pulmonary Arterial Hypertension Secondary to Left Ventricular Failure,The Single-Center,Prospective StudyObjectivesIt was proved that PADN was beneficial on hemodynamics and functional capacity in patients with idiopathic PA hypertension(IPAH).This study aimed to test the efficacy and safety of PADN for patients with combined post-and pre-capillary pulmonary hypertension(Cpc-PH).MethodsThe total of 82 patients with Cpc-PH enrolled this study.28 patients received the PADN therapy.The other 54 patients were labled as the control group,who accepted PDE5i was decided by his(her)cardiologist.Pulmonary denervation was done at the bifurcation of the main PA and the ostial left PA.Echocardiography,hemodynamic parameters and the 6-MWD were recorded.The primary endpoint was 6-MWD at 6 months follow-up.The secondary endpoints were mPAP,PVR and Tei of RV.The safety endpoint was pulmonary embolism.ResultsCompared to the control group,PADN group showed significant improvement of the 6MWT(431.9±94.7 m vs.370.9±86.7 m,P=0.009),and significant reduction of mPAP(31.4±10.1mmHg vs.36.7±7.1mmHg,P=0.009)and improvement of the cardiac output(4.4±1.8 L/min vs.3.6±1.3 L/min,P<0.015)at 6 months follow-up.After 6 months of treatment,compared with the baseline,PADN improved LV Tei(P=0.001)and RV Tei(P<0.001),and decreased the pericardial effusion(P=0.015).Compared with the baseline,the control group showed that LV Tei index was improved significantly(P=0.017),mPAP,RV Tei and pericardial effusion had no changes at 6 months follow-up.Compared with the control group,after 6 months treatment,the PADN group showed reduction of RV Teiand pericardial effusion(P<0.001,P=0.043 respectively),without any change of LV Tei(P=0.178).There was no pulmonary embolism in both groups.ConclusionsPADN is favourable to patients with Cpc-PH on 6MWD,functional capacity and hemodynamics. |
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