Pulmonary Arterial Hypertension Associated With Congenital Heart Disease Research Articles

Triple vasodilator therapy in pulmonary arterial hypertension associated with congenital heart disease

ObjectiveThis study assessed the long-term effects of triple therapy with prostanoids on patients with pulmonary arterial hypertension associated with congenital heart disease (PAH-CHD), as there is limited information on the...

Application of a modified clinical classification for pulmonary arterial hypertension associated with congenital heart disease in children: emphasis on atrial septal defects and transposition of the great arteries. An analysis from the TOPP registry.

A proportion of patients with pulmonary arterial hypertension associated with congenital heart disease (PAH-CHD) do not fit in the current classification. We aimed to analyse the applicability of an adapted clinical classification of PAH-CHD to pediatric patients using the TOPP-1 registry (Tracking Outcomes and Practice in Pediatric Pulmonary Hypertension) and focus on atrial septal defects (ASD) and transposition of the great arteries (TGA). Hemodynamic and clinical data of all patients with PAH-CHD in the TOPP cohort were reviewed. Patients were classified according to predefined ABCDE categories (A: Eisenmenger syndrome, B: left-to-right shunt, C: coincidental defects, including all ASDs, D: corrected CHD, E: TGA), or as complex CHD (group 5), by 2 independent investigators. In case of disagreement, a third reviewer could either settle a final decision, or the patient was deemed not classifiable. Survival curves were calculated for each group and compared to idiopathic PAH patients of the registry. A total of 223 out of 531 patients in the registry had PAH-CHD, and 193 were categorized to the following groups: A 39(20%), B 27(14%), C 62(32%) including 43 ASDs, D 58(30%), E 7(4%), whereas 6 patients were categorized as group 5, and 10 patients were unable to be classified. No survival difference could be demonstrated between the groups. This modified classification seems to be more applicable to pediatric PAH-CHD patients than the previous classification, but some patients with PAH-CHD who never had a shunt remain unclassifiable. The role of ASD in pediatric PH should be reconsidered.

Artificial intelligence-assisted diagnosis of congenital heart disease and associated pulmonary arterial hypertension from chest radiographs: A multi-reader multi-case study

ObjectivesTo explore the possibility of automatic diagnosis of congenital heart disease (CHD) and pulmonary arterial hypertension associated with CHD (PAH-CHD) from chest radiographs using artificial intelligence (AI) technology and to evaluate whether AI assistance could improve clinical diagnostic accuracy. Materials and MethodsA total of 3255 frontal preoperative chest radiographs (1174 CHD of any type and 2081 non-CHD) were retrospectively obtained. In this study, we adopted ResNet18 pretrained with the ImageNet database to establish diagnostic models. Radiologists diagnosed CHD/PAH-CHD from 330/165 chest radiographs twice: the first time, 50% of the images were accompanied by AI-based classification; after a month, the remaining 50% were accompanied by AI-based classification. Diagnostic results were compared between the radiologists and AI models, and between radiologists with and without AI assistance. ResultsThe AI model achieved an average area under the receiver operating characteristic curve (AUC) of 0.948 (sensitivity: 0.970, specificity: 0.982) for CHD diagnoses and an AUC of 0.778 (sensitivity: 0.632, specificity: 0.925) for identifying PAH-CHD. In the 330 balanced (165 CHD and 165 non-CHD) testing set, AI achieved higher AUCs than all 5 radiologists in the identification of CHD (0.670–0.858) and PAH-CHD (0.610–0.688). With AI assistance, the mean ± standard error AUC of radiologists was significantly improved for CHD (ΔAUC + 0.096, 95 % CI: 0.001–0.190; P = 0.048) and PAH-CHD (ΔAUC + 0.066, 95 % CI: 0.010–0.122; P = 0.031) diagnosis. ConclusionChest radiograph-based AI models can detect CHD and PAH-CHD automatically. AI assistance improved radiologists' diagnostic accuracy, which may facilitate a timely initial diagnosis of CHD and PAH-CHD.

Pulmonary artery aneurysm in pulmonary arterial hypertension associated with congenital heart disease

Abstract Introduction Pulmonary artery aneurysms are a common finding in patients with congenital heart disease, often asymptomatic and with a described low complication rate. The aim of this study is to assess the prevalence of PAA in a population with pulmonary arterial hypertension associated with congenital heart disease (PAH-CHD) and associated complications. Methods All adult patients with PAH-CHD at our institution with angiography of the pulmonary tree by computed tomography (CT) or magnetic resonance imaging (MRI) were included in a retrospective analysis. PAA was defined as a main PA diameter > 40 mm. Results In this study, the frequency of PAA was as high as 76%. Simple pre-tricuspid lesions had larger diameters than post-tricuspid lesions (p=0.004), but there were no significant differences with complex lesions. Also, no differences were found between the median diameters of the different PAH-CHD groups. No relationship was seen between the development of aneurysms or larger diameters and haemodynamic severity, even a majority of patients had severe pulmonary arterial hypertension. 15 patients (25% of total with PAA) had complications related to PAA: 4 patients with PA dissection (isolated or with associated thrombosis), 7 patients with chronic pulmonary thrombosis and 5 patients with left main coronary artery compression (figure 2). There were no complications in patients with diameters less than 40 mm. During a median follow-up of 3.8 years (IQR 1.6 to 6.4 years) 24 patients (30%) died or needed lung/cardiopulmonary transplantation (17 and 7 respectively). Only two (8.3%) of the patients with final events did not have PAA. Survival analysis (figure 1) showed a higher rate of death or need for transplantation in patients with pulmonary artery aneurysm, especially if there was an added complication (log-rank test, P=0.017). Conclusions Pulmonary artery aneurysms in patients with pulmonary arterial hypertension associated with congenital heart disease are common. The rate of related complications is also high in this population and may have prognostic implications.Survival analysisComplications related to PA

Evaluating the role of serum uric acid in the risk stratification and therapeutic response of patients with pulmonary arterial hypertension associated with congenital heart disease (PAH-CHD).

Background: Pulmonary arterial hypertension (PAH) is a malignant pulmonary vascular disease that negatively impacts quality of life, exercise capacity, and mortality. This study sought to investigate the relationship between serum uric acid (UA) level and the disease severity and treatment response of patients with PAH and congenital heart disease (PAH-CHD). Methods: This study included 225 CHD patients and 40 healthy subjects. Serum UA was measured in all patients, and UA levels and haemodynamic parameters were re-evaluated in 20 patients who had received PAH-specific drug treatment for at least 7 ± 1month. Results: Serum UA levels were significantly higher in PAH-CHD patients than in CHD patients with a normal pulmonary artery pressure and normal subjects (347.7 ± 105.7μmol/L vs. 278.3 ± 84.6μmol/L; 347.7 ± 105.7μmol/L vs. 255.7 ± 44.5μmol/L, p < 0.05). UA levels in the intermediate and high risk groups were significantly higher than those in the low-risk group (365.6 ± 107.8μmol/L vs. 311.2 ± 82.8μmol/L; 451.6 ± 117.6μmol/L vs. 311.2 ± 82.8μmol/L, p < 0.05). Serum UA levels positively correlated with mean pulmonary arterial pressure, WHO functional class, pulmonary vascular resistance, and NT-proBNP (r = 0.343, 0.357, 0.406, 0.398; p < 0.001), and negatively with mixed venous oxygen saturation (SvO2) and arterial oxygen saturation (SaO2) (r = -0.293, -0.329; p < 0.001). UA significantly decreased from 352.7 ± 97.5 to 294.4 ± 56.8μmol/L (p = 0.001) after PAH-specific drug treatment for at least 6months, along with significant decreases in mean pulmonary arterial pressure and pulmonary vascular resistance and increases in cardiac index and mixed SvO2. Conclusion: Serum UA can be used as a practical and economic biomarker for risk stratification and the evaluation of PAH-specific drug treatment effects for patients with PAH-CHD.

Factors associated with the uncorrectable congenital heart disease in children with pulmonary arterial hypertension

BACKGROUND Pulmonary arterial hypertension associated with congenital heart disease (PAH-CHD) is a common complication of uncorrected left-to-right shunt defects in acyanotic CHD and a frequent type of pulmonary hypertension in youth. The standards for operability in left-to-right shunts with increased pulmonary vascular resistance are not universally agreed upon. This study aimed to identify variables associated with uncorrectable lesion in children with PAH-CHD.&#x0D; METHODS This retrospective study used a database of all children who underwent cardiac catheterization at Sanglah Hospital, Bali, from May 2009 to April 2021. Pulmonary hypertension was defined as pulmonary artery pressure of &gt;25 mmHg, while correctability was a fall of &gt;20% in the pulmonary arterial resistance index (PARI) with final value of &lt;6 WU/m2 when doing an acute vasoreactivity test using 100% oxygen. The analyses were carried out using SPSS software version 22.0 (IBM Corp., USA).&#x0D; RESULTS A total of 104 children were included. Cardiac catheterization showed that the uncorrectable group had a higher PARI (14.4 [8.88] WU/m2 versus 8.43 [3.85] WU/m2) and lower flow ratio (1.27 [0.83] versus 1.47 [0.77]) at baseline. In terms of correctability, pre-tricuspid lesions (OR = 0.05; 95% CI = 0.01–0.47; p = 0.01) and younger age group (OR = 0.32; 95% CI = 0.12–0.85; p = 0.01) were protective variables, whilst high baseline PARI (OR = 4.54; 95% CI = 1.64–12.57; p = 0.01) was unfavorable.&#x0D; CONCLUSIONS High baseline PARI was the most significant variable in predicting uncorrectable left-to-right shunt defects in PAH-CHD.

One-minute sit-to-stand test in patients with pulmonary arterial hypertension associated with congenital heart disease: A single-center prospective study

BackgroundPatients with pulmonary arterial hypertension associated with congenital heart disease (PAH-CHD) have reduced exercise capacity. Recently, the 1-minute sit-to-stand test (1MSTST), which measures the number of repetitions from sitting to standing position in 1 minute, has been proposed as an alternative test to the 6-minute walking test (6MWT). The aim of our study was to assess the safety and results of the 1MSTST in comparison to the 6MWT in patients with PAH-CHD. MethodsConsecutive adult patients with PAH-CHD underwent the 6MWT and the 1MSTST on the same day. The 6-minute walking distance in meters and the number of repetitions on the 1MSTST were measured. Heart rate, peripheral oxygen saturations, Borg dyspnea score, and lower limb fatigue were recorded before and immediately after testing. Correlations between both tests and clinical, laboratory, and imaging parameters were statistically analyzed. ResultsThe study included 40 patients (50% female, mean age 43 ± 15 years), of whom 29 (72%) had Eisenmenger syndrome and 14 (35%) had Down syndrome. The number of 1MSTST repetitions correlated significantly with 6MWT distance (r = 0.807, p = 0.000). There were no adverse events, and the 1MSTST results correlated with the WHO functional class. Heart rate increase and oxygen desaturation after both tests correlated significantly, but less desaturation was observed after 1MSTST. ConclusionsOur study showed that the 1MSTST is a safe and easily applicable test in adult patients with PAH-CHD, including patients with Down syndrome. The results of the 1MSTST correlate significantly with the 6MWT, providing an alternative tool for exercise capacity assessment in patients with PAH-CHD.

Cardiac Magnetic Resonance Derived Left Ventricular Eccentricity Index and Right Ventricular Mass Measurements Predict Outcome in Children with Pulmonary Arterial Hypertension

Pulmonary arterial hypertension (PAH) is associated with increased right ventricular (RV) afterload, affecting RV remodeling and RV performance, a major determinant of outcome in PAH-patients. In children with PAH, treatment strategy is guided by risk stratification where noninvasive prognosticators are highly needed. The prognostic value of RV characteristics derived by cardiac magnetic resonance (CMR) has been scarcely studied in pediatric PAH. We aimed to identify CMR-derived morphometric and functional RV characteristics prognostic for outcome in children with PAH. From the Dutch National cohort, thirty-eight children with either idiopathic/heritable PAH (IPAH/HPAH) or PAH associated with congenital heart disease (PAH-CHD), who underwent CMR, were included (median (interquartile range) [IQR] age 13.0 years (10.8-15.0), 66% females). Patients had severe PAH, characterized by their World Health Organization Functional Class, increased N-terminal pro-B-type natriuretic peptide and high pulmonary arterial pressure and pulmonary vascular resistance index at time of CMR. RV-ejection fraction (RVEF), indexed RV-mass (RVMi), the ratio between RV and LV mass (RVM/LVM-ratio) and left ventricular eccentricity index (LVEI) all correlated with transplant-free survival from time of CMR. These correlations could not be confirmed in the PAH-CHD group. This study shows that CMR-derived measures reflecting RV function and remodeling (LVEI, RVMi, RVM/LVM-ratio, RVEF) predict transplant-free survival in children with IPAH/HPAH and may be included in risk stratification scores in pediatric PAH.

Identification of potential serum biomarkers for congenital heart disease children with pulmonary arterial hypertension by metabonomics

BackgroundPulmonary arterial hypertension is a common complication in patients with congenital heart disease. In the absence of early diagnosis and treatment, pediatric patients with PAH has a poor survival rate. Here, we explore serum biomarkers for distinguishing children with pulmonary arterial hypertension associated with congenital heart disease (PAH-CHD) from CHD.MethodsSamples were analyzed by nuclear magnetic resonance spectroscopy-based metabolomics and 22 metabolites were further quantified by ultra-high-performance liquid chromatography–tandem mass spectroscopy.ResultsSerum levels of betaine, choline, S-Adenosyl methionine (SAM), acetylcholine, xanthosine, guanosine, inosine and guanine were significantly altered between CHD and PAH-CHD. Logistic regression analysis showed that combination of serum SAM, guanine and N-terminal pro-brain natriuretic peptide (NT-proBNP), yielded the predictive accuracy of 157 cases was 92.70% with area under the curve of the receiver operating characteristic curve value of 0.9455.ConclusionWe demonstrated that a panel of serum SAM, guanine and NT-proBNP is potential serum biomarkers for screening PAH-CHD from CHD.

Pulmonary arterial hypertension associated with congenital heart disease: An omics study.

Pulmonary arterial hypertension associated with congenital heart disease (PAH-CHD) is a severely progressive condition with uncertain physiological course. Hence, it has become increasingly relevant to clarify the specific mechanisms of molecular modification, which is crucial to identify more treatment strategies. With the rapid development of high-throughput sequencing, omics technology gives access to massive experimental data and advanced techniques for systems biology, permitting comprehensive assessment of disease occurrence and progression. In recent years, significant progress has been made in the study of PAH-CHD and omics. To provide a comprehensive description and promote further in-depth investigation of PAH-CHD, this review attempts to summarize the latest developments in genomics, transcriptomics, epigenomics, proteomics, metabolomics, and multi-omics integration.

Differences in right ventricular function and response to targeted therapy between patients with IPAH and PAH-CHD.

Background and aims: Pulmonary arterial hypertension (PAH) is a chronic pulmonary vascular disorder characterized by elevated pulmonary vascular resistance (PVR) and pulmonary arterial pressure (PAP). Right heart failure is a life-threatening complication of PAH and predicts a poor prognosis. PAH associated with congenital heart disease (PAH-CHD) and idiopathic PAH (IPAH) are two prevalent PAH subtypes in China. In this section, we set out to explore baseline right ventricular (RV) function and its response to targeted agents between IPAH and PAH-CHD. Methods and results: Consecutive patients diagnosed with IPAH or PAH-CHD by right heart catheterization (RHC) in the Second Xiangya Hospital from November 2011 to June 2020 were included. All patients received PAH-targeted therapy and the RV function was assessed by echocardiography at baseline and during follow-up. A total of 303 patients (age, 36.23 ± 13.10years; women, 213 (70.3%); mean PAP [mPAP], 63.54 ± 16.12mmHg; PVR, 14.74 ± 7.61WU) with IPAH (n = 121) or PAH-CHD (n = 182) were included in this study. Compared with PAH-CHD, patients with IPAH had worse baseline RV function. As of the latest follow-up, forty-nine patients with IPAH and six patients with PAH-CHD died. Kaplan-Meier analyses showed better survival in PAH-CHD versus IPAH. After PAH-targeted therapy, patients with IPAH had less improvement in 6MWD, World Health Organization functional class, and RV functional parameters compared with patients with PAH-CHD. Conclusion: Compared with patients with PAH-CHD, patients with IPAH had worse baseline RV function, unfavourable prognosis, and inadequate response to targeted treatment.

Characteristics of exercise intolerance in different subgroups of pulmonary arterial hypertension associated with congenital heart disease

BackgroundExercise intolerance is a major manifestation of pulmonary arterial hypertension associated with congenital heart disease (PAH-CHD). We aimed to investigate the characteristics of exercise intolerance in different subgroups of PAH-CHD. MethodsWe retrospectively enrolled 171 adult patients with PAH-CHD and 30 age and sex-matched healthy subjects and performed cardiopulmonary exercise testing. Gas exchange parameters, including peak oxygen uptake (peak V̇o2), anaerobic threshold, and the slope of ventilatory equivalent for carbon dioxide (V̇e/V̇co2 slope), were recorded. ResultsThe median age of patients at enrollment was 27.8 years, and 131 (76.6%) were female. Peak V̇o2 was reduced in patients compared to healthy controls (median, 14.8 ml/kg/min versus 26.9 ml/kg/min, p < 0.001). Of all 171 patients, 60 (35.1%) had Eisenmenger syndrome, 35 (20.5%) had PAH associated with systemic-to-pulmonary shunts (PAH-SP), 39 (22.8%) had PAH with small defects (PAH-SD), and 37 (21.6%) had PAH after cardiac defect correction (PAH-CD). Patients with Eisenmenger syndrome had the lowest peak V̇o2 (p = 0.003) and the highest V̇e/V̇co2 slope (p = 0.012), compared with other patients, representing the worst exercise capacity and ventilatory efficiency. Patients with PAH-SP had the best exercise capacity among the four groups, indicated by the highest peak V̇o2 (p = 0.003) compared with other patients. Peak V̇o2 was negatively correlated with pulmonary vascular resistance (r = −0.411, p < 0.001). ConclusionsExercise capacity was severely reduced in patients with PAH-CHD. Among the four subgroups, patients with Eisenmenger syndrome had the worst exercise capacity and ventilatory efficiency.

Pulmonary arterial hypertension associated with congenital heart disease: real-world analysis of clinical characteristics, treatment patterns and outcomes from EXPOSURE

Abstract Background Treatment patterns for patients with pulmonary arterial hypertension associated with congenital heart disease (PAH-CHD) are currently not well described. Purpose To use real-world data from the EXPOSURE study to describe clinical characteristics, treatment patterns and outcomes of PAH-CHD patients in current clinical practice. Methods EXPOSURE (EUPAS19085) is an ongoing, multicentre, prospective, observational study of PAH patients initiating a PAH-specific therapy in Europe and Canada. Clinical characteristics, treatment patterns, hospitalisation and mortality are described for PAH-CHD patients classified into four clinical subgroups. Baseline was considered to be within 30 days of PAH-specific treatment initiation. Results Between September 2017 and November 2021, there were 1588 PAH patients with follow-up data in EXPOSURE, of whom 168 (11%) had PAH-CHD. Of these, 40% (N=67) had Eisenmenger's Syndrome (ES), 25% (N=42) had PAH with coincidental CHD, 21% (N=35) had PAH with left-to-right shunts, and 14% (N=24) had PAH after CHD corrective surgery. Baseline characteristics are summarised in the Table. Across the subgroups, the median age was 46–53 years. Compared to the other subgroups, at baseline, ES patients had a substantially longer time from diagnosis (median [Q1, Q3]: 12.6 [3.3, 31.5] years), a lower 6MWD (median [Q1, Q3]: 400 [309, 480] m) and were more likely to be in WHO FC III/IV (Table). The majority of patients across all subgroups initiated a new PAH-specific therapy as part of combination therapy at enrolment (Table). Treatment patterns over time for ES patients are shown in the Figure. The majority of ES patients received double or triple combination therapy at baseline. Overall, most ES patients remained on the same treatment regimen 6 months after baseline, with limited treatment escalation (Figure). The median observation period ranged between 15.0 and 23.0 months for all subgroups (Table). Incidence of all-cause hospitalisation during this time was generally comparable across subgroups (Table). All-cause mortality incidence rates (95% CI) were higher in patients with ES (6.3 [2.3, 13.7]) and PAH after CHD corrective surgery (8.1 [1.7, 23.8]) compared to the other two subgroups (Table). Conclusions In EXPOSURE, 11% of patients were PAH-CHD patients, with ES being the most common PAH-CHD aetiology. The majority of PAH-CHD patients were enrolled on combination therapy. ES patients had a longer time from diagnosis compared to other subgroups and their treatment patterns followed a stepwise approach. At 6 months post-baseline, the majority of ES patients were on double or triple combination therapy. Hospitalisation was comparable between subgroups and mortality was higher in ES and PAH after CHD corrective surgery patients. Funding Acknowledgement Type of funding sources: Other. Main funding source(s): Actelion Pharmaceuticals Ltd, a Janssen Pharmaceutical Company of Johnson &amp; Johnson

Maternal and fetal outcomes of pregnant women with pulmonary arterial hypertension associated with congenital heart disease in Beijing, China: A retrospective study.

As pulmonary arterial hypertension associated with congenital heart disease (PAH‐CHD) may increase maternal and fetal risk, this study explored the pregnancy outcomes of Chinese women with PAH‐CHD. The clinical data of pregnant women with PAH‐CHD admitted to the Beijing Anzhen Hospital from 2010 to 2019 were retrospectively analyzed; these patients and their offspring were followed up, with a mean period of 5.9 ± 2.7 years. Overall, 260 patients with PAH‐CHD were included. The mean maternal age was 27.7 ± 4.1 years, and 205 (78.8%) patients were nulliparous. The estimated systolic pulmonary artery pressure was 40–50 mmHg in 34.6% of the patients, 50–70 mmHg in 23.1%, and >70 mmHg in 42.3%. More than 96% of patients were diagnosed with PAH‐CHD before pregnancy. During pregnancy, heart failure occurred in 19.2% of the patients. Cesarean delivery was performed in 88.1% (15.0% emergency) of the patients. Complications included fetal distress (5.8%), preterm delivery (34.2%), and low birth weight (33.8%). A total of 15 mothers (5.8%) died, with the highest mortality rate in those with Eisenmenger syndrome (10/43, 23.3%), and 10 offspring died (3.8%), two (0.8%) following hospital discharge and eight (3.1%) while in hospital. Although most pregnant women with PAH‐CHD were able to have children, PAH increased the maternal and fetal risk. Thus, an individualized risk‐based approach with shared decision‐making may be more appropriate in pregnant women with PAH‐CHD.

Platelet Activation Markers in Children with Pulmonary Arterial Hypertension Associated with Congenital Heart Disease

The study aimed to evaluate mean platelet volume (MPV), platelet distribution width (PDW), and platecrit in children with pulmonary arterial hypertension associated with congenital heart disease (PAH-CHD), to assess the predictive value of these platelet activation markers for adverse outcomes, and to correlate their levels with various data in these patients. This prospective cohort study included 60 children with PAH-CHD as group I and 60 children with CHD and no PAH as group II. Another 60 healthy children of matched age and sex served as the control group. All included children were evaluated by echocardiography. MPV, PDW, and platecrit were also measured using an automated blood counter. All patients were followed up for death or readmission for 6 months. MPV, PDW, and platecrit were significantly higher in group I compared to group II and the control group and they correlated well with increasing severity of PAH. MPV, PDW, and platecrit positively correlated with right ventricular diameter and mean pulmonary artery pressure, however they correlated negatively with right ventricular systolic and diastolic function. The best cut-off of platelet activation markers levels to predict poor prognosis in group I was > 11.2 FL with 75% sensitivity and 96.6% specificity for MPV, > 12.7 FL with 75% sensitivity and 61.5% specificity for PDW, and > 0.505% with 75% sensitivity and 93.2% specificity for platecrit. MPV, PDW, and platecrit were elevated in children with PAH-CHD and found to be good predictive markers for poor prognosis in these children.

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.

Medical treatment of pulmonary hypertension in adults with congenital heart disease: updated and extended results from the International COMPERA-CHD Registry.

Pulmonary arterial hypertension (PAH) is common in congenital heart disease (CHD). Because clinical-trial data on PAH associated with CHD (PAH-CHD) remain limited, registry data on the long-term course are essential. This analysis aimed to update information from the COMPERA-CHD registry on management strategies based on real-world data. The prospective international pulmonary hypertension registry COMPERA has since 2007 enrolled more than 10,000 patients. COMPERA-CHD is a sub-registry for patients with PAH-CHD. A total of 769 patients with PAH-CHD from 62 specialized centers in 12 countries were included into COMPERA-CHD from January 2007 through September 2020. At the last follow-up in 09/2020, patients [mean age 45.3±16.8 years; 512 (66%) female] had either post-tricuspid shunts (n=359; 46.7%), pre-tricuspid shunts (n=249; 32.4%), complex CHD (n=132; 17.2%), congenital left heart or aortic valve or aortic disease (n=9; 1.3%), or miscellaneous CHD (n=20; 2.6%). The mean 6-minute walking distance was 369±121 m, and 28.2%, 56.0%, and 3.8% were in WHO functional class I/II, III or IV, respectively (12.0% unknown). Compared with the previously published COMPERA-CHD data, after 21 months of follow-up, the number of included PAH-CHD patients increased by 91 (13.4%). Within this group the number of Eisenmenger patients rose by 39 (16.3%), the number of "Non-Eisenmenger PAH" patients by 45 (26.9%). Currently, among the 674 patients from the PAH-CHD group with at least one follow-up, 450 (66.8%) received endothelin receptor antagonists (ERA), 416 (61.7%) PDE-5 inhibitors, 85 (12.6%) prostacyclin analogues, and 36 (5.3%) the sGC stimulator riociguat. While at first inclusion in the COMPERA-CHD registry, treatment was predominantly monotherapy (69.3%), this has shifted to favoring combination therapy in the current group (53%). For the first time, the nature, frequency, and treatment of significant comorbidities requiring supportive care and medication are described. Analyzing "real life data" from the international COMPERA-CHD registry, we present a comprehensive overview about current management modalities and treatment concepts in PAH-CHD. There was an trend towards more aggressive treatment strategies and combination therapies. In the future, particular attention must be directed to the "Non-Eisenmenger PAH" group and to patients with complex CHD, including Fontan patients. www.clinicaltrials.gov, study identifier: Clinicaltrials.gov NCT01347216.

Computational simulation-derived hemodynamic and biomechanical properties of the pulmonary arterial tree early in the course of ventricular septal defects.

Untreated ventricular septal defects (VSDs) can lead to pulmonary arterial hypertension (PAH) characterized by elevated pulmonary artery (PA) pressure and vascular remodeling, known as PAH associated with congenital heart disease (PAH-CHD). Though previous studies have investigated hemodynamic effects on vascular mechanobiology in late-stage PAH, hemodynamics leading to PAH-CHD initiation have not been fully quantified. We hypothesize that abnormal hemodynamics from left-to-right shunting in early stage VSDs affects PA biomechanical properties leading to PAH initiation. To model PA hemodynamics in healthy, small, moderate, and large VSD conditions prior to the onset of vascular remodeling, computational fluid dynamics simulations were performed using a 3D finite element model of a healthy 1-year-old's proximal PAs and a body-surface-area-scaled 0D distal PA tree. VSD conditions were modeled with increased pulmonary blood flow to represent degrees of left-to-right shunting. In the proximal PAs, pressure, flow, strain, and wall shear stress (WSS) increased with increasing VSD size; oscillatory shear index decreased with increasing VSD size in the larger PA vessels. WSS was higher in smaller diameter vessels and increased with VSD size, with the large VSD condition exhibiting WSS >100 dyn/cm[Formula: see text], well above values typically used to study dysfunctional mechanotransduction pathways in PAH. This study is the first to estimate hemodynamic and biomechanical metrics in the entire pediatric PA tree with VSD severity at the stage leading to PAH initiation and has implications for future studies assessing effects of abnormal mechanical stimuli on endothelial cells and vascular wall mechanics that occur during PAH-CHD initiation and progression.

Pulmonary arterial hypertension in adults with congenital heart disease: markers of disease severity, management of advanced heart failure and transplantation

ABSTRACT Introduction Pulmonary arterial hypertension associated with congenital heart disease (PAH-CHD) is a progressive, life-limiting disease. Areas covered In this paper, we review the classification and pathophysiology of PAH-CHD, including the mechanisms of disease progression and multisystem effects of disease. We evaluate current strategies of risk stratification and the use of biological markers of disease severity, and review principles of management of PAH-CHD. The indications, timing, and the content of advanced heart failure assessment and transplant listing are discussed, along with a review of the types of transplant and other forms of available circulatory support in this group of patients. Finally, the integral role of advance care planning and palliative care is discussed. Expert opinion/commentary All patients with PAH-CHD should be followed up in expert centers, where they can receive appropriate risk assessment, PAH therapy, and supportive care. Referral for transplant assessment should be considered if there continue to be clinical high-risk features, persistent symptoms, or acute heart failure decompensation despite appropriate PAH specific therapy. Expert management of PAH-CHD patients, therefore, requires vigilance for these features, along with a close relationship with local advanced heart failure services and a working knowledge of listing criteria, which may disadvantage congenital heart disease patients.

Role of Plasma Connective Tissue Growth Factor Levels in Assessment of Pulmonary Arterial Hypertension in Children with Congenital Heart Disease

Abstract Background: To investigate plasma Connective Tissue Growth Factor (CTGF) levels in Pulmonary Arterial Hyper-tension (PAH) associated with Congenital Heart Disease (PAH-CHD) in children and the relationships of CTGF with hemodynamic parameters. Plasma CTGF levels were calculated in 30 children with PAH-CHD and 30 health volunteers, using the subtraction method. Aim of Study: To assess plasma Connective Tissue Growth Factor (CTGF) levels in children with CHD and study its role in assessment of PAH that can be promising diagnostic and prognostic biomarkers for PAH in children with CHD. Patients and Methods: Our study was conducted in Pedi-atric Cardiology Clinic and Cardiology Catheter Laboratory of Ain Shams University Pediatric Hospital, in the period from Jan. 2019 to May 2020, including 30 patient and 30 healthy controls of matched age and sex. Results: The patients with PAH, 17 were acyanotic and 13 were cyanotic. The health control group and patient groups did not differ significantly in terms of age, gender and BSA (p>0.05). Height, weight and BMI were significantly lower in PAH-CHD group compared with the HCG (p 0.05). In addition, CTGF levels were higher in PAH-CHD group than health control group. Depicts that, PAH-CHD group had higher PASP, PADP, RVSP, mPAP, Qp, Rp and Rp/Rs (p < 0.01). Conclusion: Plasma CTGF levels could be a promising diagnostic biomarker for PAH-CHD in children.