Purpose Pulmonary Hypertension Research Articles

Smooth muscle Rac1 contributes to pulmonary hypertension.

Background and PurposePulmonary hypertension (PH) is a multifactorial chronic disease characterized by an increase in pulmonary artery (PA) resistance leading to right ventricle (RV) failure. Endothelial dysfunction and alteration of NO/cGMP signalling in PA plays a major role in PH. We recently described the involvement of the Rho protein Rac1 in the control of systemic blood pressure through its involvement in NO‐mediated relaxation of arterial smooth muscle cell (SMC). The aim of this study was to analyse the role of SMC Rac1 in PH.Experimental ApproachPH is induced by exposure of control and SMC Rac1‐deficient (SM‐Rac1‐KO) mice to chronic hypoxia (10% O2, 4 weeks). PH is assessed by the measurement of RV systolic pressure and hypertrophy. PA reactivity is analysed by isometric tension measurements. PA remodelling is quantified by immunofluorescence in lung sections and ROS are detected using the dihydroethidium probe and electronic paramagnetic resonance analysis. Rac1 activity is determined by immunofluorescence.Key ResultsRac1 activation in PA of hypoxic mice and patients with idiopathic PH. Hypoxia‐induced rise in RV systolic pressure, RV hypertrophy and loss of endothelium‐dependent relaxation were significantly decreased in SM‐Rac1‐KO mice compared to control mice. SMC Rac1 deletion also limited hypoxia‐induced PA remodelling and ROS production in pulmonary artery smooth muscle cells (PASMCs).Conclusion and ImplicationsOur results provide evidence for a protective effect of SM Rac1 deletion against hypoxic PH. Rac1 activity in PASMCs plays a causal role in PH by favouring ROS‐dependent PA remodelling and endothelial dysfunction induced by chronic hypoxia.

PTBP1 Targets ILK to Regulate the Hypoxia-Induced Phenotypic Transformation of Pulmonary Artery Smooth Muscle Cells.

PurposePulmonary hypertension (PH) is a pathological process mainly characterized by the progressive increase in pulmonary vascular resistance. The degradation of pulmonary artery smooth muscle cells (PASMCs) from contractile/differentiated phenotype to synthetic/dedifferentiated phenotype is a key factor for hypoxic pulmonary hypertension.Materials and MethodsIn this study, qPCR was performed to evaluate the gene expression of mRNAs. Western blot, immunofluorescence and RNA pull down were used to detect gene expression levels.ResultsWe found that the gene expression of polypyrimidine tract-binding protein1 (PTBP1) was increased significantly in a time-dependent manner in rats PA tissues and PASMCs after hypoxia. PTBP1 knockdown can inhibit the phenotypic transition of PASMCs. PTBP1 inhibits the phenotypic transition of PASMCs. In addition, PTBP1 inhibits the integrin-linked kinase (ILK) expression under hypoxic conditions, thereby down-regulating the expression of downstream proteins. It inhibits the phenotypic transition of PASMCs and alleviates pulmonary hypertension.ConclusionIn conclusion, PTBP1/ILK axis promotes the development of PH via inducing phenotypic transition of PASMCs. This may provide a novel therapy for PH.

Increased pulmonary serotonin transporter in patients with chronic obstructive pulmonary disease who developed pulmonary hypertension

PurposePulmonary hypertension (PH) is characterized by a progressive remodelling of the pulmonary vasculature resulting in right heart failure and eventually death. The serotonin transporter (SERT) may be involved in the pathogenesis of PH in patients with chronic-obstructive pulmonary disease (COPD). This study investigated for the first time the SERT in vivo availability in the lungs of patients with COPD and PH (COPD+PH).MethodsSERT availability was assessed using SERT-selective [11C]DASB and positron emission tomography/computed tomography (PET/CT) with dynamic acquisition over 30 min in 4 groups of 5 participants each: COPD, COPD+PH, pulmonary arterial hypertension, and a healthy control (HC). Time activity curves were generated based on a volume of interest within the middle lobe. Tissue-to-blood concentration ratios after 25 to 30 min (TTBR25–30) served as receptor parameter for group comparison and were corrected for lung tissue attenuation. Participants underwent comprehensive pulmonary workup. Statistical analysis included group comparisons and correlation analysis.Results[11C]DASB uptake peak values did not differ among the cohorts after adjusting for lung tissue attenuation, suggesting equal radiotracer delivery. Both the COPD and COPD+PH cohort showed significantly lower TTBR25–30 values after correction for lung attenuation than HC. Attenuation corrected TTBR25–30 values were significantly higher in the COPD+PH cohort than those in the COPD cohort and higher in non-smokers than in smokers. They positively correlated with invasively measured severity of PH and inversely with airflow limitation and emphysema. Considering all COPD patients ± PH, they positively correlated with right heart strain (NT-proBNP).ConclusionBy applying [11C]DASB and PET/CT, semiquantitative measures of SERT availability are demonstrated in the lung vasculature of patients with COPD and/or PH. COPD patients who developed PH show increased pulmonary [11C]DASB uptake compared to COPD patients without PH indicating an implication of pulmonary SERT in the development of PH in COPD patients.

Genetic Profiling of Combined Post-Capillary and Pre-Capillary Pulmonary Hypertension in Left Heart Diseases

Pulmonary hypertension (PH) in left heart diseases (LHD) has been redefined as isolated post-capillary PH (IpcPH) and combined post-capillary and pre-capillary PH (CpcPH). CpcPH's pathophysiology is not well understood. Predisposing constitutional factors may play a role in CpcPH development, as suggested by the variability in the adaptation of the pulmonary circulation to the elevation of pulmonary artery wedge pressure (PAWP). We sought to determine whether a genetic predisposition to CpcPH could be identified, suggesting a common pathway with pulmonary arterial hypertension (PAH). Based on Erasme's hospital right heart catheterization database from January 2007 to January 2015, we selected PH-LHD patients to further identify CpcPH patients. Clinical and hemodynamic variables were used to compare IpcPH to CpcPH patients. A small cohort of CpcPH patients underwent genetic testing for genes predisposing to heritable PAH using a gene panel approach and MLPA analysis. 93 patients presented with PH-LHD, of which 32% met the definition of CpcPH. Clinical data was similar in both IpcPH and CpcPH groups except for higher morphometric features in CpcPH patients. Missense variations of the BMPR2 gene (c.1749C>A, p.Asn583Lys) and of the ENG gene (c.1316A>C, p.Lys439Thr) were identified in one CpcPH patient presenting with heart failure due to dilated cardiomyopathy. Based on current knowledge, both variants were classified as variants of unknown significance (VUS). Our study uncovered genomic variations in the BMPR2 and ENG genes of a CpcPH patient, which may support the concept that a predisposing genetic background could modulate the precapillary component in CpcPH, potentially suggesting common genetic pathways between CpcPH and PAH, although this has to be further confirmed by functional testing, studies in bigger cohorts and with IpcPH control populations.

Accuracy of Doppler echocardiography in the hemodynamic assessment of pulmonary circulation in patients with systemic sclerosis

PurposePulmonary hypertension (PH) is an ominous complication in systemic sclerosis patients (SSc) and echocardiography is a screening tool for its detection. The goal of this study was to assess the reliability of resting and exercise echo Doppler parameters with data obtained by right heart catheterization (RHC). Material and methodsWe included 91 patients (84 F, 53.3 ± 15.2 years) with SSc. Transthoracic echocardiography followed by exercise Doppler-echocardiography (EDE) were performed. A positive EDE was defined as a ≥20 mmHg increase in tricuspid regurgitation peak gradient (TRPG). RHC with exercise was performed in positive EDE patients and/or in subjects with resting TRPG > 31 mmHg. ResultsFinally, RHC was performed in 20 patients. The correlation for the echocardiography and invasive measurement of systolic (sPAP) and mean (mPAP) pulmonary artery pressure was r = 0.66 (p = 0.001) and r = 0.7 (p = 0.001), respectively. We also found significant correlation between echocardiography and invasive measurement of exercise sPAP r = 0.68 (p = 0.001) and exercise mPAP r = 0.67 (p = 0.002). There was a correlation between pulmonary vascular resistance (PVR) assessed by echocardiography and measured by RHC r = 0.49, p = 0.027. The equation derived within our population was: PVR by echocardiography = 9.6*TRV/TVIRVOT+0.068. We also performed ROC analysis to predict PVR > 2 WU. Our results highlight that sPAP has the highest AUC (0.802, 95% CI 0.585–1). ConclusionDoppler resting and exercise echocardiography may provide a reliable, noninvasive method for determining resting and exercise sPAP, mPAP, and PVR in SSc patients, although it may underestimate or overestimate these values in some individuals. Doppler echocardiography does not replace RHC for definite hemodynamic assessment of suspected PH.

PH in Heart Transplant (HT) Candidates: Don't Look at Ghosts, Search the Evil in the Details

Purpose Pulmonary hypertension (PH) is frequent in HT candidates; identifying patients (pts) with urgent need of HT is challenging. Guidelines suggest diastolic transpulmonary gradient (DPG) ≥ 7 mmHg to differentiate combined (CpC) and isolated (IpC) post-capillary PH, but its clinical relevance in this setting is unknown. The aim of our study is to analyze the prognostic impact of PH classification in pts referred for HT, and the interplay of CpC and IpC with markers of ventricular function. Methods We included all pts evaluated for HT in our Center (2002-17) undergoing to a right heart cath, collecting data at first evaluation. We created 3 groups: no- PH, IpC-PH (mean PAP > 25 mmHg, PVR 25 mmHg, PVR ≥3 WU and/or DPG≥7 mmHg). Pulmonary artery pulsatility index (PAPi) was analyzed as marker of RV function. The endpoint was the combined incidence of death on the waiting list or urgent HT (1-and 2-yrs survival rates). Results Among the overall cohort of 566 pts (53± 11y, 83% M, 45% DCM, 40% CAD), 59.5% had PH: 31.8% IpC-PH, 27.7% CpC-PH. The endpoint was more frequent in the PH subgroups at 1 and 2 yrs (p Conclusion Our study shows that current definition of CpC and IpC in type 2 PH stratifies prognosis in HT candidates, but DPG is epidemiologically irrelevant and doesn't increase diagnostic accuracy. Adding an indirect marker of RV function (PAPi) to PVR assessment could predict better the need for HT.

The Role of Transpulmonary Gradient and Mean Pulmonary Artery Pressure in Risk Stratification of Heart Transplant Candidates with Pulmonary Hypertension

Purpose Pulmonary hypertension (PH) is common in patients with heart failure and portends a poor prognosis in heart transplant (HT) recipients. The clinical relevance of discordant PH indices remains unclear. We assessed the post-HT outcomes of patients with elevated pulmonary vascular resistance (PVR) in patients with and without elevated pulmonary artery (PA) pressures. Methods The UNOS database was queried to identify HT recipients with PH (PVR >3) from 1997 - 2017. Patients were then stratified based upon mPA 15mmHg to assess the additional discrimination of these two variables on post-HT outcomes. Results In medically managed HT recipients with PH (n=3760)The mean PVR in this patient group was 4.3 ± 1.2 WU with a mean PA pressure of 35.8 ± 9.0 mmHg, a mean PCWP of 21.0 ± 8.1 mmHg, and mean TPG of 14.8 ± 4.8 mmHg. Both mPA pressure 15 mmHg (HR: 1.28, p=0.025) were associated with worse post-transplant mortality in univariable and multivariable analysis (Figure 1). Secondary analysis was performed in patients BTT with LVAD (n=6664). Compared to medically managed patients with similar PVRs, LVAD patients experienced higher mortality regardless of PVR. Neither mPA pressure nor TPG were associated with 1-year mortality in this population. Conclusion In medically managed patients with PH, both mPA and TPG refine risk stratification for post-HT mortality. mPA

Non-invasive methods for estimating mPAP in COPD using cardiovascular magnetic resonance imaging

PurposePulmonary hypertension (PH) is associated with a poor outcome in chronic obstructive pulmonary disease (COPD) and is diagnosed invasively. We aimed to assess the diagnostic accuracy and prognostic value of non-invasive cardiovascular magnetic resonance (CMR) models.MethodsPatients with COPD and suspected PH, who underwent CMR and right heart catheter (RHC) were identified. Three candidate models were assessed: 1, CMR-RV model, based on right ventricular (RV) mass and interventricular septal angle; 2, CMR PA/RV includes RV mass, septal angle and pulmonary artery (PA) measurements; 3, the Alpha index, based on RV ejection fraction and PA size.ResultsOf 102 COPD patients, 87 had PH. The CMR-PA/RV model had the strongest diagnostic accuracy (sensitivity 92%, specificity 80%, positive predictive value 96% and negative predictive value 63%, AUC 0.93, p<0.0001). Splitting RHC-mPAP, CMR-RV and CMR-PA/RV models by 35mmHg gave a significant difference in survival, with log-rank chi-squared 5.03, 5.47 and 7.10. RV mass and PA relative area change were the independent predictors of mortality at multivariate Cox regression (p=0.002 and 0.030).ConclusionCMR provides diagnostic and prognostic information in PH-COPD. The CMR-PA/RV model is useful for diagnosis, the RV mass index and PA relative area change are useful to assess prognosis.Key Points• Pulmonary hypertension is a marker of poor outcome in COPD.• MRI can predict invasively measured mean pulmonary artery pressure.• Cardiac MRI allows for estimation of survival in COPD.• Cardiac MRI may be useful for follow up or future trials.• MRI is potentially useful to assess pulmonary hypertension in patients with COPD.

Downregulation of KCNQ5 expression in the rat pulmonary vasculature of nitrofen-induced congenital diaphragmatic hernia

PurposePulmonary hypertension (PH) is a common complication of congenital diaphragmatic hernia (CDH). Voltage-gated potassium channels KCNQ1, KCNQ4, and KCNQ5 are expressed by rodent pulmonary artery smooth muscle cells, contributing to their vascular tone. We hypothesized that KCNQ1, KCNQ4, and KCNQ5 expression is altered in the pulmonary vasculature of nitrofen-induced CDH rats. MethodsAfter ethical approval (REC913b), time-pregnant rats received nitrofen or vehicle on gestational day (D)9. D21 fetuses were divided into CDH and control group (n=22). QRT-PCR and western blotting were performed to determine gene and protein expression of KCNQ1, KCNQ4, and KCNQ5. Confocal microscopy was used to detect these proteins in the pulmonary vasculature. ResultsRelative mRNA level of KCNQ5 (p=0.025) was significantly downregulated in CDH lungs compared to controls. KCNQ1 (p=0.052) and KCNQ4 (p=0.574) expression was not altered. Western blotting confirmed the decreased pulmonary KCNQ5 protein expression in CDH lungs. Confocal-microscopy detected a markedly diminished KCNQ5 expression in pulmonary vasculature of CDH fetuses. ConclusionsDownregulated pulmonary expression of KCNQ5 in CDH lungs suggests that this potassium channel may play an important role in the development of PH in this model. KCNQ5 channel activator drugs may be a potential therapeutic target for the treatment of PH in CDH. Level of evidence2b (Centre for Evidence-Based Medicine, Oxford)

The strengths and weaknesses of non-invasive parameters obtained by echocardiography and cardiopulmonary exercise testing in comparison with the hemodynamic assessment by the right heart catheterization in patients with pulmonary hypertension

PurposePulmonary hypertension (PH) diagnosis requires invasive assessment by right heart catheterization (RHC), but screening and monitoring are performed using non-invasive methods: echocardiography and cardiopulmonary exercise testing (CPET). The aim of the study was to assess correlations between the parameters obtained in non-invasive testing and RHC in patients with PH of different etiologies. Material/methodsThe study included 53 medical records of PH patients (32 women) aged 29–81 years. We analyzed correlations between RHC (systolic pulmonary artery pressure (sPAP), diastolic pulmonary artery pressure (dPAP), pulmonary vascular resistance (PVR), cardiac output (CO)) and echocardiographic (tricuspid annular plane systolic excursion (TAPSE), sPAP) and CPET parameters (end-tidal oxygen and carbon dioxide pressures (PetO2, PetCO2), ventilation efficiency (VE/VCO2) slope). ResultsEchocardiographic estimation correlated well with RHC measurement of sPAP (r=0.65, P<0.001). TAPSE correlated with PVR assessed with thermodilution method (r=−0.5, P=0.005), dPAP (r=−0.53, P=0.002) and CO (r=0.53, P=0.002). PVR assessed with thermodilution and Fick methods showed positive correlation with PetO2 (r=0.74, P<0.001 and r=0.72, P<0.001) and negative correlation with PetCO2 (r=−0.59, P=0.004 and r=−0.64, P=0.002) at the anaerobic threshold. VE/VCO2 slope correlated with dPAP (r=0.43, P=0.04) and PVR calculated with both methods (r=0.52, P=0.01 and r=0.52, P=0.02). ConclusionsSimple cardiac function indicators obtained by commonly used non-invasive methods allow only approximate estimation of the main hemodynamic RHC-derived parameters: sPAP, CO and PVR. Obtained results suggest the relationship between RV dysfunction and ventilation abnormalities in PH patients.

Ambrisentan May Improve Exercise Tolerance and Cardiac Function in Patients With Pulmonary Hypertension

PurposePulmonary hypertension (PH) is characterized by a significant increase in pulmonary vascular resistance, which results in ventricular failure and death. Ambrisentan appears to be an effective treatment in the pathogenesis and progression of ambrisentan, but some researchers disagree. Therefore, this meta-analysis aims to examine the clinical efficacy of ambrisentan in the treatment of PH. MethodsA search of the scientific literature using the Embase, Cochrane, and CHINAHL databases retrieved published studies related to our topic of interest. Eight cohort studies related to ambrisentan and PH treatment were selected on the basis of our strict inclusion and exclusion criteria for a systematic meta-analysis. Statistical analyses were conducted using STATA version 12.0 statistical software (StataCorp LP, College Station, Texas). FindingsOur meta-analysis retrieved 124 studies using our search criteria (90 studies in English and 34 studies in Chinese), and 8 studies (4 studies in English and 4 studies in Chinese) were eventually selected for this meta-analysis. The 8 studies contained data on a total of 172 PH patients. Pooled data in our meta-analysis revealed that 6-minute walking distance in PH patients significantly improved after ambrisentan treatment compared with before treatment. The mean pulmonary arterial pressure, brain natriuretic peptide level, and systolic pulmonary artery pressure in PH patients decreased measurably after ambrisentan treatment compared with before treatment. Sensitivity analysis results confirmed that the included studies had no publication bias (all P > 0.05). ImplicationsOur meta-analysis results demonstrated that ambrisentan is highly effective in improving exercise tolerance and cardiac function in PH patients, and the mean pulmonary arterial pressure, systolic pulmonary artery pressure, and brain natriuretic peptide level levels in PH patients significantly decreased. However, with the limitations of small sample size, insufficient data, and ethnic difference in the study, further studies with larger sample sizes and sufficient information are essential to validate our findings of the high safety profile and efficacy of ambrisentan in treatment of PH.

0290 : Clinical, epidemiological and etiological characteristics of pulmonary hypertension and its prognostic value in chronic systolic heart failure: a report from the Ibn Rochd-HF Registry

Purpose Pulmonary hypertension (PH) is a predictor of mortality and morbidity in patients with chronic heart failure (HF) but it is poorly described in our population. We sought to study, the prevalence, determinants, and prognostic significance of PH in a large representative population with HF. Methods We retrospectively studied 1613 patients with HF. Systolic pulmonary artery pressure PASP was determined by echocardiography, PH was defined as PAPS> 50 mmHg. Results The proportion of patients with PASP>50mm Hg was: 12,15%(196/1613), with an average age of 69 years, there was 40,30% women and 59,70% men, 96,43% of patients had low LVEF(left ventricular ejection fraction) and only 1,02% had preserved LVEF. The ischemic etiology of HF was predominant (17,86%).Most patients were receiving diuretics (66,33%), beta-blockers (58,16%) and ACE inhibitor (86,22%), whereas 55, 10% were on Spironolactone. The etiology of PH was mostly due to the left heart disease, while 1.02% was due to primary HP and 2.04% patient had COPD (Chronic obstructive pulmonary disease). Patients with PH had a rate of 6.06% of AHFD (acute heart failure decompensation) occurrence. we note that patients with both PH and RV dysfunction had a greater risk of AHFD (14.28%). Conclusion PH is common in HF patients, associated with worse LV function and provide incremental prognostic informations. The combination of PH and RV dysfunction is particularly ominous. Thus, the estimation of PASP should be considered in the standard assessment of ambulatory HF patients and we must study it as a therapeutic way in this population

CT measurement of airway wall thickness and emphysema in COPD: Correlation with pulmonary hypertension

Purpose Pulmonary hypertension (PH) is a common complication of COPD associated with increased mortality. The mechanisms coupling PH and bronchial obstruction are unknown; in particular PH appears unrelated to emphysema. We hypothesized that CT measurement of airway remodeling instead of emphysema may correlate with PH in COPD. Material and Method Data were retrieved from 60 COPD patients who had both right heart catheterization (RHC) and CT in a period of stability, and no other disease known to cause PH. CT measurement of airway wall thickness (WT) was assessed from the third to the fifth bronchial generation in 4 bronchial paths. Low lung area percentage (LAA %) was used to quantify emphysema extent. Results Thirty-four out of 60 COPD patients had PH (mean pulmonary arterial pressure [PAP m ] ≥ 25 mmHg). There was no difference between the two groups regarding age, sex, and spirometric results, whereas there was more profound hypoxemia in the PH group. WT measured at the fourth (WT4) and fifth generation (WT5) was increased in COPD with PH and correlated with PAP m ( r = 0.40; P = 0.01 and r = 0.63; P m and LAA % ( r = 0.13; P = 0.28). Conclusion This study demonstrates for the first time an association between structural alteration of bronchi and PH in COPD. Unlike quantification of emphysema, CT measurement of bronchial wall thickness correlates with PAP m and could estimate the severity of PH in COPD. Airway remodeling burden is not limited to airflow limitation to explain COPD severity and mortality ( Figure 1 ).

Pulmonary Hypertension in Sickle Cell Disease: Correlation With Echocardiographic Assessment and Serum Brain Natriuretic Peptide Concentration

Background &amp; Purpose Pulmonary hypertension (PH) in sickle cell disease (SCD) is an important risk factor for complications including sudden death. In this study, we aimed to determine the prevalence of PH and correlate the echocardiographic parameters and general laboratory data with markers of hemolysis and serum NT pro-brain natriuretic peptide [BNP] concentrations in Omani SCD patients. Methods A cohort of 163 SCD patients [Mean age 25.4±8.4 years], in steady state was prospectively screened for PH with Doppler echocardiography (defined as a tricuspid regurgitation jet flow velocity of ≥ 2.5 m/sec and/or mean pulmonary artery pressure [mPAP] ≥25 mmHg). After a written informed consent, all patients were investigated with a complete blood count, renal chemistry, hemolytic parameters including LDH, haptoglobin, liver function tests, coagulation studies, HPLC studies including HbS and HbF level estimations, X ray Chest, ECG, ABG, Pulmonary function tests, Pulse oximetry, and Serum NT pro-BNP levels. Results In the evaluable patient cohort of 116 subjects [63 females, 53-males], the prevalence of PH was 5.2%. No statistically significant differences were detected in Hb levels, ECG, chest radiography, pulmonary function tests between patients with and without PH. However, plasma NT pro-BNP levels were significantly correlated with PAH [r=0.934, p&lt;0.000], TRV jet [r=.671, p&lt;0.000], Abnormal ECHO [r=0.672, p&lt;0.000], and direct Bilirubin levels [r=0.278,p&lt;0.009] in SCD patients. Furthermore, in SCD patients with PH, there was a statistically significant increase in plasma NT pro-BNP levels [ p&lt;0.001], ALT [p&lt;0.02], S. Creatinine [p=0.045] and Total bilirubin [p&lt;0.0001] and direct Bilirubin levels [p&lt;0.0001][Table]. Conclusions Serum NT pro-BNP is a strong indicator of PH in SCD patients. Doppler ultrasound echocardiography is a useful initial screen for PH in SCD patients. The correlation between PH and hemolytic markers suggests an implication in the pathogenesis of PH. Disclosures: No relevant conflicts of interest to declare.

Antenatal maternally-administered phosphodiesterase type 5 inhibitors normalize eNOS expression in the fetal lamb model of congenital diaphragmatic hernia

PurposePulmonary hypertension (pHTN), a main determinant of survival in congenital diaphragmatic hernia (CDH), results from in utero vascular remodeling. Phosphodiesterase type 5 (PDE5) inhibitors have never been used antenatally to treat pHTN. The purpose of this study is to determine if antenatal PDE5 inhibitors can prevent pHTN in the fetal lamb model of CDH. MethodsCDH was created in pregnant ewes. Postoperatively, pregnant ewes received oral placebo or tadalafil, a PDE5 inhibitor, until delivery. Near term gestation, lambs underwent resuscitations, and lung tissue was snap frozen for protein analysis. ResultsMean cGMP levels were 0.53±0.11 in placebo-treated fetal lambs and 1.73±0.21 in tadalafil-treated fetal lambs (p=0.002). Normalized expression of eNOS was 82%±12% in Normal-Placebo, 61%±5% in CDH-Placebo, 116%±6% in Normal-Tadalafil, and 86%±8% in CDH-Tadalafil lambs. Normalized expression of β-sGC was 105%±15% in Normal-Placebo, 82%±3% in CDH-Placebo, 158%±16% in Normal-Tadalafil, and 86%±8% in CDH-Tadalafil lambs. Endothelial NOS and β-sGC were significantly decreased in CDH (p=0.0007 and 0.01 for eNOS and β-sGC, respectively), and tadalafil significantly increased eNOS expression (p=0.0002). ConclusionsPDE5 inhibitors can cross the placental barrier. β-sGC and eNOS are downregulated in fetal lambs with CDH. Antenatal PDE5 inhibitors normalize eNOS and may prevent in utero vascular remodeling in CDH.

Quality of Life of Children with Pulmonary Hypertension

Purpose Pulmonary hypertension (PH) is rare in children and can necessitate complex and invasive treatment protocols. Quality of life (QoL) has not been previously evaluated in children with PH. Methods and Materials Children attending routine outpatient appointments and their parents completed a generic QoL measure (PedsQL), covering the domains of physical, emotional, social and school functioning. Scores range from 0-100, with higher scores denoting better QoL. Parents also completed a measure of their own anxiety and depression. Clinical data were extracted from the medical notes and comparisons made with published norms. Results Data were collected on 115 children (age range: 0–17 years, median 6 years; 60 boys). Fourteen had idiopathic PH, 50 had PH secondary to heart disease, 30 secondary to lung disease and 21 due to other conditions. Nine children were on epoprostenol and the number of medications ranged from 0-10 (median 3). Twenty-seven had definite or probable learning disability (LD). The mean total QoL score for the whole group (parent rating) was 60.52 (S.D. 18.79), which was significantly lower than healthy norms (84.61; t=−13.61; p Conclusions Quality of life is impaired in children with PH compared with healthy norms. Further evaluation is required with a larger sample to determine the salience of medical and other factors for QoL so that interventions can be targeted to improve QoL outcomes for this group of patients.

Targeting Anti-Oxidant and Anti-Proliferative Pathways in Pulmonary Hypertension Secondary to Heart Failure. Is One Better Than the Other?

Purpose Pulmonary hypertension (PH), which develops secondary to left-heart failure (LHF), is a progressive disorder with limited therapeutic options. PN induced smooth muscle cell (SMC) proliferation and pulmonary vascular remodeling by inactivating PTEN, Our findings indicated that PN/PTEN is a potential target in LHF-PH. The goal of this study was to evaluate the efficacy of curcumin derivatives HO-3867, a dual-function antioxidant/ anti-proliferative and H-4073 an anti-proliferative agent in LHF-PH. Methods and Materials In vitro studies established HO-3867 was a potent PN scavenger and inhibited PN-stimulated human pulmonary artery SMC proliferation. PH was induced by permanent ligation of LAD in rats for 4 weeks. Echo, hemo-dynamics, histopathology, and protein analysis were performed. HO-3867 and H-4073 were administered at a dose of 100 ppm in diet for 4 weeks post-ligation. Results HO-3867 did not affect cardiac function. However, H-4073 significantly improved the ejection fraction. Both agents significantly decreased the right ventricular systolic pressure. [ figure 1 ] H&E staining of lungs in both groups showed a marked decrease in medial thickening and luminal narrowing. HO-3867 attenuated PN generation in the lung by 85%, restored PTEN activity from 53±6% to 84±3% of control (p Conclusions Targeting SMC proliferative pathways in the pulmonary vasculature delays progression of LHF-PH. Augmentation of cardiac function has an additive effect.

THE INCIDENCE OF PULMONARY HYPERTENSION AT HIGH-ALTITUDE LIVER TRANSPLANT CENTERS IS SIGNIFICANTLY HIGHER THAN AT LOW-ALTITUDE LIVER TRANSPLANT CENTERS.

Purpose Pulmonary hypertension (PH) occurs in a fraction of patients with cirrhosis. The basic lesion of PH is pulmonary arteriolar vasoconstriction. Because we have noted possible differences in the prevalence of PH in patients evaluated at a high-altitude center (Denver), we performed a formal analysis to compare the prevalence of PH in cirrhotics at high-altitude (Denver) and low-altitude (Chapel Hill) liver transplantation centers. Methods All 721 patients evaluated for liver transplantation at each institution between July 1999 and October 2001 were retrospectively analyzed. Estimates of the maximum systolic pulmonary artery pressure (PAP) were made from the tricuspid regurgitation jet velocity (gradient = 4(jet velocity)2) by echocardiography and confirmed by right heart catheterization in selected patients. PH was defined as systolic PAP > 35 mm Hg, 36 to 45 mm Hg mild, 46 to 60 mm Hg moderate, > 60 mm Hg severe. Results Patients with PH were more likely to have advanced liver disease, restrictive pulmonary function tests, female gender, and evaluation in Denver. The percentage of patients with PH and severe PH in Denver was significantly higher than in Chapel Hill, p Conclusions Patients with cirrhosis who are evaluated at a high-altitude center have a significantly higher prevalence and severity of PH compared with patients at a low-altitude center. The explanation for this observation is not known, but we speculate that one possibility is relative hypoxia experienced at high altitude.