CHD-PAH Patients Research Articles

Machine learning for clustering and postclosure outcome of adult CHD-PAH patients with borderline hemodynamics

Patients with uncorrected isolated simple shunts associated pulmonary arterial hypertension (PAH) had increased mortality. Treatment strategies for borderline hemodynamics remain controversial. This study aims to investigate pre-closure characteristics and its association with post-closure outcome in this group of patients. Adults with uncorrected isolated simple shunts associated PAH were included. Peak tricuspid regurgitation velocity <2.8m/s with normalized cardiac structures was defined as the favorable study outcome. We applied unsupervised and supervised machine learning for clustering analysis and model constructions. Finally, 246 patients were included. During a median follow-up of 414 days, 58.49% (62/106) of patients with pre-tricuspid shunts achieved favorable outcome while 32.22% (46/127) of patients with post-tricuspid shunts. In unsupervised learning, two clusters were identified in both types of shunts. Generally, the oxygen saturation, pulmonary blood flow, cardiac index, dimensions of the right and left atrium, were the major features that characterized the identified clusters. Specifically, mean right atrial pressure, right ventricular dimension and right ventricular outflow tract helped differentiate clusters in pre-tricuspid shunts while age, aorta dimension and systemic vascular resistance helped differentiate clusters for post-tricuspid shunts. Notably, cluster 1 had better post-closure outcome than cluster 2 (70.83% vs. 32.55%, P<0.001 for pre-tricuspid and 48.10% vs. 16.67%, P<0.001 for post-tricuspid). However, models constructed from supervised learning methods did not achieve good accuracy for predicting the post-closure outcome. There were two main clusters in patients with borderline hemodynamics, in which one cluster had better post-closure outcome than the other. The datasets and analyzed codes are available upon reasonable request from the corresponding author.

Atrial strain in patients with pulmonary arterial hypertension associated with congenital heart disease

Pulmonary arterial hypertension (PAH) has a major impact on mortality and morbidity on congenital heart disease (CHD) patients. Atrial strain in PAH patients has been related to clinical severity and adverse outcomes. The aim of this study was therefore to assess the prognostic role and compare bi-atrial function in patients with CHD-PAH, PAH from other causes (nPAH) and healthy controls. We included in this prospective cohort study 65 patients with CHD-PAH, 67 patients with nPAH and 65 healthy volunteers. Transthoracic echocardiography, clinical assessment, BNP measurement and 6MWT were performed at baseline. Classic echocardiographic measurements and atrial function studying the 3 different phases strain were measured in both. Atrial strain parameters are decreased in patients with CHD-PAH as compared to healthy volunteers, especially the right atrial (RA) reservoir (RASR 29,67% vs. 44,15%, P < 0,0001) and conduit phase (RASCD −15,85 vs. −28,52, P < 0,0001), but also left atrial (LA) reservoir and conduit phases. Active contractile phase seems preserved in both PAH group. Atrial function was comparable between CHD-PAH and nPAH patients. On multivariate analysis, BNP, pericardial effusion, RA ejection fraction, RASR and RASCD were independently associated with death or transplantation. RASR ≤ 30% or RASCD > −8% strain identified patients with a more than 3-fold-increased risk of death or transplant. Patients with CHD-PAH do not differ in atrial adaptation in comparison with npah. Impaired RASR and RASCD identify high risk PAH patients. RA conduit or reservoir function impairment represents a severity marker of PAH, including in patients with CHD-PAH suggesting the importance of RV diastolic dysfunction. This might be an early marker of poor prognosis (Fig. 1).

Clinical outcomes of pulmonary hypertension in pregnancy among women with congenital heart disease in China

Absrtact Objective Pulmonary arterial hypertension (PAH) increases the risk for perinatal women and newborns, especially in women with congenital heart disease (CHD). We explored the maternal, perinatal, and postneonatal outcomes of PAH in pregnant women with CHD in China. Methods A total of 95 pregnant women with CHD-PAH in Beijing Anzhen Hospital from 2009 to 2013 were included retrospectively. We described their characteristics and examined the associations between the grade of PAH and maternal, perinatal, and postneonatal outcomes. Results The New York Heart Association (NYHA) classification grade, delivery mode, and infant outcomes in CHD-PAH patients were analyzed. Overall 95 patients with CHD-PAH, there were 17 patients in mild group(17.7%), 27 patients in moderate group (28.1%), and 51 patients in severe group (53.1%)。The CHD patients with mild PAH, were mostly NYHA class I–II and CHD patients with severe PAH were NYHA class II–IVs. Cesarean section (67.7%) was the most common method of delivery. The rate of therapeutic abortion in the severe group (76.9%) was obviously higher than that in other groups (11.5% in mild group and moderate group respectively), whereas there was no term delivery in severe group, with 2 cases in mild group and moderated group respectively . The rates of heart failure and therapeutic abortion in pregnant women were positively associated with the severity of PAH. The rate of term delivery was higher in patients whose CHD had been corrected by cardiac surgery (83.3%) before pregnancy. Conclusion Patients with severe PAH have poor cardiac adaptability, poor maternal and fetal outcomes, and are contraindicated during pregnancy. Patients with mild PAH are not absolutely contraindicated during pregnancy, but their heart burden increases significantly in the third trimester. Patients in mid-gestation should preferentially be delivered by cesarean section. When pregnant patients prefer to continue pregnancy, their close monitoring is essential. We provide useful data for guiding management of pregnancy and delivery in patients with CHD in China.

Characteristics, treatments and survival of pulmonary arterial hypertension associated with congenital heart disease in China: Insights from a national multicenter prospective registry

The purpose of this registry was to provide insights into the characteristics, treatments and survival of patients with PAH-CHD in China. Patients diagnosed with PAH-CHD were enrolled in this national multicenter prospective registry. Baseline and follow-up data on clinical characteristics, PAH-targeted treatments and survival were collected. A total of 1060 PAH-CHD patients (mean age 31 years; 67.9% females) were included, with Eisenmenger syndrome (51.5%) being the most common form and atrial septal defects (37.3%) comprising the most frequent underlying defect. Approximately 33.0% of the patients were in World Health Organization functional class III to IV. The overall mean pulmonary arterial pressure and pulmonary vascular resistance were 67.1 (20.1) mm Hg and 1112.4 (705.9) dyn/s/cm5, respectively. PAH-targeted therapy was utilized in 826 patients (77.9%), and 203 patients (19.1%) received combination therapy. The estimated 1-, 3-, 5-, and 10-year survival rates of the overall cohort were 96.9%, 92.9%, 87.6% and 73.0%, respectively. Patients received combination therapy had significantly better survival than those with monotherapy (p=0.016). NT-proBNP >1400 pg/ml, SvO2 ≤ 65% and Borg dyspnea index ≥ 3 and PAH-targeted therapy were independent predictors of mortality. Hemoglobin > 160g/L was a unique predictor for mortality in Eisenmenger syndrome. Chinese PAH-CHD patients predominantly exhibit Eisenmenger syndrome and have significantly impaired exercise tolerance and right ventricular function at diagnosis, which are closely associated with long-term survival. PAH-targeted therapy including combination therapy showed a favorable effect on survival in PAH-CHD. The long-term survival of Chinese CHD-PAH patients remains to be improved.

Relationships between sexual function, mental health, and quality of life of female patients with pulmonary arterial hypertension associated with congenital heart disease.

In recent years, the treatment of pulmonary arterial hypertension (PAH) has gradually increased, including new drugs and surgical methods, the mortality rate of PAH patients has significantly decreased, and the average survival rate has significantly improved. However, there was no obvious improvement in sexual health, mental health, and quality of life (QoL) in patients with PAH.Although an important dimension of QoL, little is known about sexual health and sexual health-related QoLof patients with PAH in China. In this study, the female sexual function index (FSFI)scale, the Symptom Checklist-90 (SCL-90), and emPHasis-10 were used to evaluate PAH associated with congenital heart disease (CHD-PAH) patients' sexual function, mental health, and QoL. The score of sexual function in female CHD-PAH patients ranged from 4.40 to 34.80 points, and the average score was 26.80 (19.00-27.80) points. The detection rate of sexual dysfunction was 48.30%. The FSFIscore of all dimensions of the sexual dysfunction group was significantly lower than that of the nonsexual dysfunction group. In addition, the scores of SCL-90 and emPHasis-10 were significantly higher than that of the nonsexual dysfunction group (p < 0.01). The sexual function was negatively correlated with mental health (r = -0.58,p < 0.01) and QoL (r = -0.62,p < 0.01) in female CHD-PAH patients. The sexual function of female patients with CHD-PAH is not optimistic. Sexual health may impact mental health and overall QoL in female PAH patients. Reasonable intervention measures should be taken to improve their sexual health, so as to improve their overall QoL.

Right Heart Catheterization in Pediatric Pulmonary Arterial Hypertension: Insights and Outcome from a Large Tertiary Center.

Aim: To define the clinical characteristics, hemodynamics, and adverse events for pediatric patients with pulmonary arterial hypertension (PAH) undergoing right heart catheterization (RHC). Methods: The large referral single center data of 591 diagnostic RHC procedures performed between 2005 and 2020 on pediatric PAH patients was retrospectively collected and analyzed. Results: A total of 591 RHC procedures performed on 469 patients with congenital heart disease (CHD)-PAH (median age 8.8 years, 7.9% New York Heart Association (NYHA) class > II, 1.5% with syncope) and 122 patients with idiopathic PAH (median age of 9.0 years, 27.0% NYHA class > II, 27.0% with syncope) were included. Of those, 373 (63.1%) procedures were performed under general anesthesia. Eighteen patients (18/591, 3.0%) suffered adverse events (mainly pulmonary hypertensive crisis, PHC, n = 17) during the RHC procedure, including 14 idiopathic pulmonary arterial hypertension (IPAH) patients and 4 CHD-PAH patients, and one IPAH patient died in hospital 63 hours after RHC. The risk of developing PHC was significantly increased in patients with IPAH (OR = 14.02, 95%CI: 4.49–43.85, p < 0.001), atrial blood gas pH < 7.35 (OR = 12.504, 95%CI: 3.545–44.102, p < 0.001) and RAP > 14 mmHg (OR = 10.636, 95%CI: 3.668–30.847, p < 0.001). Conclusions: RHC is generally a low-risk procedure in pediatric patients with PAH. However, PHC occur in approximately 3% of patients. Therefore, RHC should be performed in a large, experienced referral pediatric cardiology center, especially in pediatric patients with IPAH requiring general anesthesia.

Transgelin exacerbates pulmonary artery smooth muscle cell dysfunction in shunt-related pulmonary arterial hypertension.

Orchestrating the transition from reversible medial hypertrophy to irreversible plexiform lesions is crucial for pulmonary arterial hypertension related to congenital heart disease (CHD-PAH). Transgelin is an actin-binding protein that modulates pulmonary arterial smooth muscle cell (PASMC) dysfunction. In this study, we aimed to probe the molecular mechanism and biological function of transgelin in the pathogenesis of CHD-PAH. Transgelin expression was detected in lung tissues from both CHD-PAH patients and monocrotaline (MCT)-plus aortocaval (AV)-induced PAH rats by immunohistochemistry. In vitro, the effects of transgelin on the proliferation, migration, and apoptosis of human PASMCs (HPASMCs) were evaluated by the cell count and EdU assays, transwell migration assay, and TUNEL assay, respectively. And the effect of transgelin on the expression of HPASMC phenotype markers was assessed by the immunoblotting assay. (i) Compared with the normal control group (n=12), transgelin expression was significantly overexpressed in the pulmonary arterioles of the reversible (n=15) and irreversible CHD-PAH group (n=4) (reversible group vs. control group: 18.2±5.1 vs. 13.6±2.6%, P<0.05; irreversible group vs. control group: 29.9±4.7 vs. 13.6±2.6%, P<0.001; irreversible group vs. reversible group: 29.9±4.7 vs. 18.2±5.1, P<0.001). This result was further confirmed in MCT-AV-induced PAH rats. Besides, the transgelin expression level was positively correlated with the pathological grading of pulmonary arteries in CHD-PAH patients (r=0.48, P=0.03, n=19). (ii) Compared with the normal control group (n=12), TGF-β1 expression was notably overexpressed in the pulmonary arterioles of the reversible (n=15) and irreversible CHD-PAH group (n=4) (reversible group vs. control group: 14.8±4.4 vs. 6.0±2.5%, P<0.001; irreversible group vs. control group: 20.1±4.4 vs. 6.0±2.5%, P<0.001; irreversible group vs. reversible group: 20.1±4.4 vs. 14.8±4.4, P<0.01). The progression-dependent correlation between TGF-β1 and transgelin was demonstrated in CHD-PAH patients (r=0.48, P=0.04, n=19) and MCT-AV-induced PAH rats, which was further confirmed at sub-cellular levels. (iii) Knockdown of transgelin diminished proliferation, migration, apoptosis resistance, and phenotypic transformation of HPASMCs through repressing the TGF-β1 signalling pathway. On the contrary, transgelin overexpression resulted in the opposite effects. These results indicate that transgelin may be an indicator of CHD-PAH development via boosting HPASMC dysfunction through positive regulation of the TGF-β1 signalling pathway, as well as a potential therapeutic target for the treatment of CHD-PAH.

Impact of composite clinical worsening events on outcome of patients with pulmonary arterial hypertension associated with congenital heart disease

Objective: To explore the impact of composite clinical worsening (cCW) events and its components on the prognosis of patients with pulmonary arterial hypertension associated with congenital heart disease (CHD-PAH). Methods: This is a retrospective study. Patients who were diagnosed with CHD-PAH in Beijing Anzhen Hospital between January 2007 and July 2018, were included, and their baseline clinical data including demographic, clinical manifestations and New York Heart Association (NYHA) classification were collected retrospectively. All-cause deaths and clinical worsening events were recorded, which included syncope, PAH related hospitalization, NYHA classification deterioration and ≥ 2 PAH related clinical symptoms (dyspnea, hemoptysis, edema, chest pain, palpitations, cyanosis) appearance/progress. Three kinds of cCW events were defined: cCW1 (included PAH related hospitalization, NYHA classification deterioration), cCW2 (increased syncope on the basis of cCW1) and cCW3 (increased ≥ 2 PAH related clinical symptoms appearance/progress on the basis of cCW2). The Kaplan-Meier survival curve was used to analyze the long-term survival of the included patients. Univariate and multivariate Cox regression models were used to evaluate the impact of cCW events and their components on the risk of all-cause mortality. Results: A total of 525 patients with CHD-PAH were included in this study. The median age at diagnosis was 20.7 (11.2, 30.3) years. There were 43.8% children (<18 years), and 68.8% female patients. There were 431 patients (82.1%) with NYHA classification II. A total of 180 patients had PAH symptoms at diagnosis. The median follow-up time was 4.5 (2.6, 6.7) years. Forty-seven patients (9.0%) died during the follow-up period. Survival rates at 1, 5 and 10 years after diagnosis of PAH were 98.0%, 89.9% and 84.4%, respectively. Cox multivariate analysis showed that NYHA classification deterioration (HR=3.901, 95%CI 1.863-8.169, P<0.001), ≥2 PAH symptoms appearance/progress (HR=4.458, 95%CI 1.870-10.625, P<0.001), PAH-related hospitalization (HR=4.058, 95%CI 1.851-8.896, P<0.001) and syncope (HR=11.313, 95%CI 4.860-26.332, P<0.001) were independent predictors of increased risk of death. All 3 kinds of cCW events were significantly associated with the significantly increased risk of death, and cCW2 was highly predictive to increased risk of death (HR=15.476, 95%CI 4.346-37.576, P<0.001). Conclusions: The overall long-term prognosis of CHD-PAH patients in this study is relatively good. cCW events and its components (NYHA classification deterioration, ≥2 PAH symptoms occurrence/worsening, PAH-related hospitalization and syncope) have adverse influence on all-cause death in this patient cohort.

NOTCH3 Mutations and CADASIL Phenotype in Pulmonary Arterial Hypertension Associated with Congenital Heart Disease

Background: The etiology of pulmonary arterial hypertension associated with congenital heart disease (PAHCHD) is complicated and the phenotype is heterogeneous. Genetic defects of NOTCH3 were associated with cerebral disease and pulmonary hypertension. However, the relationship between NOTCH3 mutations and the clinical phenotype has not been reported in CHD-PAH. Methods: We eventually enrolled 142 PAH-CHD patients from Fuwai Hospital. Whole exome sequencing (WES) was performed to screen the rare deleterious variants of NOTCH3 gene. Results: This PAH-CHD cohort included 43 (30.3%) men and 99 (69.7%) women with the mean age 29.8 ± 10.9 years old. The pathogenic or likely pathogenic mutations of NOTCH3 were identified in five cases. Patients 2, 5, 8 and 11 carried the same NOTCH3 mutation c.1630C > T (pArg544Cys), which is the hot-spot mutation for cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Patient 3 carried the NOTCH3 mutation p.Arg75Gln that has also been reported to be associated with the CADASIL. Patients 2, 5, 8, 11 took the examination of the cerebral magnetic resonance imaging (MRI) and confirmed the phenotype of CADASIL. Conclusions: We first reported the NOTCH3 rare mutations and CADASIL phenotypes in CHD-PAH patients. The NOTCH3 rare variants were with a relatively high positive rate and CADASIL phenotypes were likely enriched in PAH-CHD patients. The preoperative neurological examination might be recommended for PAH-CHD patients to determine the surgical contraindications and reduce intraoperative neurological complications.

Differential serum lipid distribution in IPAH and CHD-PAH patients

Lipid homeostasis is dysregulated in pulmonary arterial hypertension (PAH). A decrease in serum high- and low-density lipoprotein cholesterol (HDL-C and LDL-C) is significantly associated with the worse prognosis of PAH. However, no study has investigated the differential distribution of lipids in various PAH subtypes. We enrolled 190 patients in this retrospective study, which includes 20 patients with congenital heart disease without PAH (CHD-nonPAH), 101 patients with PAH associated with congenital heart disease (CHD-PAH), 69 patients with idiopathic PAH (IPAH) and 81 healthy controls. Laboratory parameters such as liver and renal function, serum lipids, C-reactive protein, N-terminal pro-brain natriuretic peptide (NT-proBNP), echocardiography, right heart catheterization and 6-min walk distance (6MWD) were performed. All types of cholesterol including HDL-C, LDL-C and total cholesterol (CHOL) were significantly lower in IPAH patients in association with right heart function. Although LDL-C and CHOL were lower in CHD-PAH, they were not associated with disease severity or heart failure. Thus, we conclude that IPAH and CHD-PAH patients exhibited a differential distribution pattern of serum lipids.

C80. Pulmonary Embolism in Congenital Heart Disease with Pulmonary Arterial Hypertension: a Case Series

Abstract Background Pulmonary arterial hypertension (PAH) is a frequent complication of congenital heart disease (CHD), notably in patients with left-to-right shunts. Patients with severe PAH due to CHD, Eisenmenger syndrome (ES), represent a high-risk group of pulmonary artery (PA) thrombosis patients. We present serial adult cases of CHD with PAH complicated by pulmonary embolism (PE). Case Description We found 3 cases of pulmonary embolism on adult congenital heart disease in our center. All of the patients were female, with an age range of 36 to 61 years old. The presenting symptoms were shortness of breath, WHO classification class II-III. All patients were hemodynamically stable. CHD and estimated RV systolic pressure were evaluated with echocardiography. CT-PA was performed in all patients, which findings were supporting PE. All patients were treated with anticoagulation. After three months, right heart catheterization was conducted in two patients, and one patient was refused. Discussion The prevalence of PE among adult patient with CHD and PAH range from 17 to 21%. PE was frequently found in older patients, women, and patients with lower oxygen saturation. To date, no uniformity regarding routine prophylaxis anticoagulation therapy in ES due to the high bleeding risk in this population despite being at risk of PA thrombosis. We conclude that risk stratification for PA thrombosis in adult CHD-PAH patients is essential, and further research is needed to prevent PE in this population.

C80. Pulmonary Embolism in Congenital Heart Disease with Pulmonary Arterial Hypertension: a Case Series

Abstract Background Pulmonary arterial hypertension (PAH) is a frequent complication of congenital heart disease (CHD), notably in patients with left-to-right shunts. Patients with severe PAH due to CHD, Eisenmenger syndrome (ES), represent a high-risk group of pulmonary artery (PA) thrombosis patients. We present serial adult cases of CHD with PAH complicated by pulmonary embolism (PE). Case Description We found 3 cases of pulmonary embolism on adult congenital heart disease in our center. All of the patients were female, with an age range of 36 to 61 years old. The presenting symptoms were shortness of breath, WHO classification class II-III. All patients were hemodynamically stable. CHD and estimated RV systolic pressure were evaluated with echocardiography. CT-PA was performed in all patients, which findings were supporting PE. All patients were treated with anticoagulation. After three months, right heart catheterization was conducted in two patients, and one patient was refused. Discussion The prevalence of PE among adult patient with CHD and PAH range from 17 to 21%. PE was frequently found in older patients, women, and patients with lower oxygen saturation. To date, no uniformity regarding routine prophylaxis anticoagulation therapy in ES due to the high bleeding risk in this population despite being at risk of PA thrombosis. We conclude that risk stratification for PA thrombosis in adult CHD-PAH patients is essential, and further research is needed to prevent PE in this population.

Plasma metabolomics in perioperative period of defect repair in patients with pulmonary arterial hypertension associated with congenital heart disease

Abstract Background The pathophysiological alterations in response to shunt correction in patients with pulmonary arterial hypertension associated with congenital heart disease (CHD-PAH) is still not clear. Purpose To explore the dynamic plasma metabolite profiling and its relationship with clinical characteristics in patients with CHD-PAH during the perioperative period of defect repair. Methods Plasma samples from 13 patients with CHD-PAH were harvested at four time points: before cardiopulmonary bypass (CPB) after anesthesia (Pre), immediately after CPB (T0), 24 h (T24), and 48 h (T48) after defect repair. The untargeted metabolomics strategy based on UPLC Q-TOF MS was used to detect the metabolites. Clinical measures were recorded at indicated time points. Results The sample distribution at four time points was well separated (Figure 1A, B). 193 metabolites were distinguished at different time points according to Variable Important in Projection (VIP) score (Figure 1C), enriched in pathways such as carnitine synthesis, phospholipid biosynthesis and oxidation of branched chain fatty acids (Figure 2A). 17 metabolites alterations were significantly correlated with gradients in mean pulmonary arterial pressure (mPAP) at T48 versus Pre, indicative of the response to defect correction (Figure 2B). Intriguingly, 4 out of the 17 (23.5%) metabolites including propionylcarnitine, butenylcarnitine, isobutyryl-L-carnitine and hexanoylcarnitine were enriched in oxidation of branched chain fatty acids. They were increased at both T24 and T48 (all P&amp;lt;0.05 except propionylcarnitine with P&amp;lt;0.05 at T24) (Figure 2C). Conclusions This is the first study to show the altered metabolic profiles of CHD-PAH patients in perioperative period of defect repair. Metabolites that respond to shunt correction could be a suitable non-invasive marker and would be of great value in disease monitoring and evaluating future therapeutic interventions. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): 13th Five-Year Plan–Precise Medicine–Key Research and Development Program–Clinical Cohort of Rare Disease; National Natural Science Foundation of China Figure 1. Overall analysis of metabolitesFigure 2. Shunt correction associated metabolites

CYLD mediates human pulmonary artery smooth muscle cell dysfunction in congenital heart disease-associated pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is a common complication of congenital heart disease (CHD). Deubiquitinase cylindromatosis (CYLD) has been reported to significantly aggravate vascular smooth muscle cell (VSMC) phenotypic transformation, proliferation, and migration. Here, we aimed to further investigate its roles and underlying mechanisms in the CHD-PAH development. The expression of CYLD in the lung tissues from CHD-PAH patients and monocrotaline (MCT) plus aortocaval (AV)-induced PAH rats, pulmonary artery smooth muscle cells (PASMCs) from MCT-AV-induced PAH rats, and human PASMCs (HPASMCs) was evaluated. After infection with CYLD siRNA or pcNDA3.1-CYLD, the proliferation, migration, and apoptosis of HPASMCs were measured using an EdU assay, transwell and scratch wound healing assays, and flow cytometric assay, respectively. An adeno-associated virus (AAV) vector encoding CYLD was used to suppress CYLD expression by being intratracheally instilled in rats 7 days before MCT-AV treatment. The results showed that CYLD was increased in the lung tissues from CHD-PAH patients and MCT-AV-induced PAH rats, and in PASMCs from MCT-AV-induced PAH rats. The contractile-type HPASMCs expressed low levels of CYLD, while the proliferative synthetic-type HPASMCs expressed high levels of CYLD. In addition, CYLD could mediate HPASMC dysfunction, which regulated HPASMC phenotypic transformation and proliferation via the modulation of p38 and ERK activation, while CYLD regulated HPASMC migration via the modulation of p38 activation. In vivo results demonstrated that the local suppression of CYLD expression could attenuate the increased levels of PAH and its associated pulmonary vascular remodeling in MCT-AV-induced PAH rats. Collectively, these results indicated that CYLD might be a potential novel therapeutic target for the prevention of PAH and pulmonary vascular remodeling in CHD-PAH through the modulation of HPASMC dysfunction.

Treatment with macitentan for pulmonary arterial hypertension (PAH) associated with congenital heart disease (CHD): real-world experience from the combined OPUS and OrPHeUS data sets

Abstract Introduction Restrictive inclusion criteria can exclude some CHD-PAH patients from clinical trials. The OPsumit® USers (OPUS) Registry and the OPsumit® Historical USers (OrPHeUS) data sets provide real-world data in PAH patients newly started on macitentan, including patients with CHD-PAH regardless of defect type. Purpose To describe the characteristics, safety and clinical outcomes of CHD-PAH patients newly treated with macitentan. Methods OPUS is a prospective, US, multicentre, observational drug registry ongoing since April 2014. OrPHeUS was a retrospective, US, multicentre chart review; observation period Oct 2013–Mar 2017. This analysis reports information on CHD-PAH patients in the combined OPUS/OrPHeUS data set, descriptively compared with idiopathic/heritable PAH (I/HPAH) patients. Results As of Sept 2019, there were 4268 PAH patients with follow-up data, of whom 264 (6%) had CHD-PAH and 2396 (56%) had I/HPAH. For CHD-PAH and I/HPAH patients respectively at macitentan initiation: median age (Q1, Q3) was 48 (36, 62) and 65 (53, 73) years; 199 (75%) and 1748 (73%) were female; 67/114 (59%) and 802/1301 (62%) were WHO functional class III/IV; median (Q1, Q3) 6-minute walk distances were 350 (274, 420) and 289 (195, 375) m for the 82 and 840 patients with measurements; median (Q1, Q3) time from PAH diagnosis to macitentan initiation was 37.3 (4.5, 113.1) and 7.4 (1.4, 38.3) months; and 99 (38%) and 1056 (44%) initiated macitentan as monotherapy. The number of patients with ≥1 hepatic adverse event (HAE) was similar for CHD-PAH and I/HPAH (22 [8%] and 184 [8%]), as were the adverse event (AE) profiles (collected from OPUS only). Exposure, discontinuations, outcomes and most common AEs are shown in the table. Conclusions In general, compared with I/HPAH patients, CHD-PAH patients were younger and a greater proportion had prevalent disease than I/HPAH patients. Safety and outcomes were similar between the groups. Funding Acknowledgement Type of funding source: Other. Main funding source(s): Actelion Pharmaceuticals Ltd

Nestin represents a potential marker of pulmonary vascular remodeling in pulmonary arterial hypertension associated with congenital heart disease

ObjectiveReportedly, nestin was re-expressed in proliferative synthetic-type pulmonary artery smooth muscle cells (PASMCs) and obligatory for PASMC proliferation in pulmonary arterial hypertension (PAH). Accordingly, nestin is increased in pulmonary vascular lesions of congenital heart disease (CHD)-associated PAH patients. We tested the hypothesis whether nestin was re-expressed in proliferative synthetic-type PASMCs and associated with pulmonary vascular remodeling in CHD-PAH. Materials and methodsNestin expression was tested using lung tissues from CHD-PAH patients and monocrotaline (MCT) plus aortocaval (AV) shunt-induced PAH rats, human PASMCs (HPASMCs), and pulmonary artery endothelial cells (PAECs) and PASMCs from MCT-AV-induced PAH rats. The role and possible mechanism of nestin on HPASMC proliferation, apoptosis, cell cycle and migration were investigated by assays of CCK-8, EdU, TUNEL, flow cytometry, transwell chamber and immunoblotting assays. ResultsNestin was solely expressed in proliferative synthetic-type PASMCs, but rarely detected in PAECs. Nestin was barely detected in normal pulmonary arterioles and occlusive pulmonary vascular lesions. Its expression was robustly increased in developing pulmonary vasculature, but returned to normal levels at the late stage of pulmonary vascular remodeling in lung tissues from CHD-PAH patients and MCT-AV-induced PAH rats. Besides, nestin peaks were consistent with the histological features in lung tissues of MCT-AV-induced PAH rats. Moreover, nestin overexpression effectively promoted HPASMC phenotypic transformation, proliferation, apoptosis resistance and migration via enhancing Wnt/β-catenin activation. ConclusionsThese data indicated that nestin was re-expressed in proliferative synthetic-type PASMCs and might represent a potential marker of pulmonary vascular remodeling in CHD-PAH.

Right ventricular remodelling in CHD-PAH patients using 3D speckle tracking

Survival in pulmonary arterial hypertension (PAH) relates to right ventricular (RV) function. Whereas prognosis differs widely between PAH associated with congenital heart disease (CHD) and other causes of PAH, only little is known about differences in RV function. We aimed at comparing RV function assessed by 3D-speckle-tracking in patients with CHD-PAH, other PAH aetiologies and healthy controls; and assess the relationship between ventricular function and prognostic parameters. We performed a prospective multi-centric study between June 2015 and June 2017 recruiting 27 patients with CHD-PAH (3 had closed shunts, 24 had Eisenmenger syndrome; among these, 11 had a pre-tricuspid shunt, 13 had a post-tricuspid shunt), to compare with 27 group 1 non-CHD related-PAH patients (nPAH) and 27 controls matched on age and sex with the CHD-PAH group. Patients with complex CHD were excluded. All patients underwent 2D and 3D transthoracic echocardiography at baseline. 3D RV echocardiographic sequences were analysed by a commercial RV-specific software and output meshes were post-processed to extract deformation data. There was no significant age difference between the subgroups. In CHD-PAH patients, RV global area and longitudinal strain did not significantly differ as compared to nPAH but RV global circumferential strain was significantly better ( P = 0.006). All strain components were impaired as compared to controls ( P < 0.0001). In the whole patient population, over a mean follow-up of 27.6 ± 13.3 months, 10 patients (17.5%) died from PAH or were transplanted (including 2 patients with CHD-PAH). Global RV circumferential strain was significantly associated to death or transplant ( P = 0.004, AUC 0.823; HR 1.41[1.09–1.81]) ( Fig. 1 ). RV remodelling differs between adults with CHD-PAH and PAH from other aetiologies: 3D RV global circumferential strain is better in CHD-PAH patients and associated with survival free from transplant.

P6013Evidence for ANTXR2 as a therapeutic target on systemic-to-pulmonary shunt induced pulmonary arterial hypertension

Abstract Introduction Pulmonary arterial hypertension secondary to congenital heart disease (CHD-PAH) with systemic-to-pulmonary shunt is characterized by proliferative vascular remodeling. Excessive proliferation and resistance to apoptosis of pulmonary artery smooth muscle cells (PASMCs) are the primary cellular bases of vascular remodeling. Anthrax toxin receptor 2 (ANTXR2) exhibits anti-proliferative properties. The effects of ANTXR2 on vascular remodeling and systemic-to-pulmonary shunt induced PAH remain unexplored. Purpose The purpose of this study was to determine the possible roles of ANTXR2 in the pathogenesis of systemic-to-pulmonary shunt induced PAH and explore its possible mechanisms. Methods Lung tissue sections from CHD-PAH patients, systemic-to-pulmonary shunt induced PAH rat model, ANTXR2−/− rats, and PASMCs were used. Immunohistochemistry, real time polymerase chain reaction, Western blot, proliferation, apoptosis, and next generation sequencing (NGS) were performed in this study. Results ANTXR2 expression was reduced in severe CHD-PAH patient lung tissue and pulmonary arterioles, as well as in lung tissues from rats with systemic-to-pulmonary shunt induced PAH. Over-expression of ANTXR2 in cultured PASMCs inhibited cell proliferation and promoted apoptosis, while knockdown of ANTXR2 promoted cell proliferation and inhibited apoptosis. Male ANTXR2−/− rats showed more severe percent medial thickness and muscularization of pulmonary arterioles than wild type (WT) rats in basal conditions, and exhibited heavier PAH following exposure to systemic-to-pulmonary shunt. To further determine the underling mechanism, NGS was performed in ANTXR2−/− rat lungs and that of WT littermates. A total of 1319 genes were found to be dysregulated, and biological processes influenced by these differentially expressed genes include negative regulation of blood vessel diameter,vasoconstriction, regulation of blood vessel diameter, regulation of blood vessel size, vascular process in circulatory system, etc. Conclusion Our work identifies a novel role for ANTXR2 in systemic-to-pulmonary shunt induced PAH based on the findings that ANTXR2 deficiency could exacerbate systemic-to- pulmonary shunt induced vascular remodeling in the development of PAH. ANTXR2 may be a potential target for CHD-PAH treatment. Acknowledgement/Funding Beijing Natural Science Foundation (7172078 and 7172182), the National Major Research Plan Training Program of China (91849111)

The expression of survivin in irreversible pulmonary arterial hypertension rats and its value in evaluating the reversibility of pulmonary arterial hypertension secondary to congenital heart disease.

The reversibility of pulmonary arterial hypertension (PAH) determines the operability of congenital heart disease (CHD) complicating with PAH, but it lacks a method for evaluating the reversibility. The current study aims to investigate the serum survivin level in irreversible PAH rats and to explore its potential as a biomarker for evaluating the reversibility of PAH in CHD patients. Irreversible PAH rats were characterized by prominent obstructive lesions resulting from the intimal formation, which was associated with decreased apoptosis and increased survivin expression, while reversible PAH rats were featured by medial hypertrophy resulting in mild occlusion, with increased apoptosis and unchanged survivin expression. In addition, the serum survivin was significantly increased in irreversible PAH rats when compared to both reversible PAH and control rats, and a positive correlation of serum survivin with survivin expression in the lung was confirmed. Third, the preoperative serum survivin was significantly higher in patients with irreversible CHD-PAH than in these with reversible CHD-PAH, and significant correlations between the serum survivin and BNP, preoperative pulmonary vascular resistance index, and postoperative mean pulmonary arterial pressure were also identified. In conclusion, the increased survivin level is a feature of irreversible PAH and the serum survivin represents a candidate biomarker reflecting the operability of CHD-PAH patients.

Acute Iloprost Inhalation Improves Right Ventricle Function in Pulmonary Artery Hypertension: A Cardiac Magnetic Resonance Study.

Background: Right ventricle (RV) function is among the most important prognostic factors for pulmonary arterial hypertension (PAH) patients. Inhaled iloprost, an inhaled member of the prostacyclin family, is effective for the treatment of severe PAH and acute RV failure. However, the acute effects of iloprost on RV physiology have not been thoroughly explored in the past.Materials and Methods: This prospective study involved 69 incident PAH patients, including 23 idiopathic PAH (IPAH) patients, 26 patients with PAH associated with connective tissue disease (CTD-PAH) and 20 with PAH associated with congenital heart disease (CHD-PAH). All patients underwent both right heart catheterization and cardiac magnetic resonance imaging at baseline and 20 min after 5 μg iloprost inhalation.Results: Acute iloprost inhalation reduced PVR from 13 ± 7 to 10 ± 6 Wood U (P < 0.001), increased RV ejection fraction (RVEF) from 31 ± 11 to 35 ± 12 % (P < 0.001), increased RV stroke volume from 53 ± 21 to 57 ± 22 ml (P < 0.001) and decreased RV end-diastolic volume from 179 ± 67 to 172 ± 69 ml (P < 0.001). Acute iloprost inhalation-induced RVEF improvement was correlated with the degree of PVR reduction (P < 0.001) in IPAH patients, but not in CTD-PAH or CHD-PAH patients.Conclusion: Acute iloprost inhalation improved RVEF, RV stroke volume and decreased RV volume in IPAH and CTD-PAH patients. Iloprost-induced RVEF increase was proportional to PVR reduction in IPAH patients, but not in CTD-PAH or CHD-PAH patients.