Cyanotic Nephropathy in an Adult Patient with Eisenmenger Syndrome: A Case Report and Literature Review.

INTRODUCTION: Cyanotic nephropathy, a rare disease characterized by proteinuria, decreased estimated glomerular filtration rate, thrombocytopenia, polycythemia, and hyperuricemia, may occasionally be secondary to cyanotic congenital heart disease (CHD). There are currently no detailed diagnostic criteria or treatments for cyanotic nephropathy, owing to its extremely low incidence. Eisenmenger syndrome (ES) was initially defined by Paul Wood in pathophysiologic terms as "pulmonary hypertension (PH) at the systemic level, caused by a high pulmonary vascular resistance, with a reversed or bidirectional shunt at the aorto-pulmonary, ventricular, or atrial level." It typically develops in the presence of large, unrepaired atrial or ventricular septal defects, arterial shunts, or complex forms of CHD and is the most severe hemodynamic phenotype of pulmonary arterial hypertension associated with CHD. This study aimed to outline the case of an ES patient who developed cyanotic nephropathy and successfully achieved clinical remission through primary disease treatment and symptomatic management. Overall, this case expands our understanding of cyanotic nephropathy and lays a theoretical reference for the treatment of ES. CASE PRESENTATION: A 33-year-old Chinese female attended the outpatient department with abnormal urine test results over the past two and a half years. Following a comprehensive medical history collection, she underwent the necessary tests. Cardiac color ultrasound displayed a significant widening of the pulmonary artery and PH (severe), as well as mild tricuspid regurgitation and patent ductus arteriosus. The results of the kidney biopsy, combined with clinical findings, suggested a high risk of polycythemia-related kidney disease. She was eventually diagnosed with cyanotic nephropathy and ES. Her symptoms were relieved following symptomatic treatment, such as the administration of ambrisentan, febuxostat, and home oxygen therapy. Her follow-up visit at 6 months demonstrated improvements in hyperuricemia and a significant increase in physical strength. CONCLUSION: Cyanotic nephropathy is a rare condition in adults. Kidney biopsy remains the gold standard of diagnosis for various nephropathies. Active treatment of CHD and alleviating hypoxia may be pivotal for the treatment of cyanotic nephropathy.

Bronchial Atresia with Eisenmenger Syndrome in a Complex Congenital Heart Disease-A Rare Coexistence: A Case Report.

BACKGROUND: Congenital bronchial atresia (CBA) is a relatively benign and uncommon pulmonary anomaly that is usually an incidental radiological finding. Bronchial atresia may also be acquired. Its association with pulmonary vascular anomalies and congenital heart disease (CHD) has been described in literature as a handful of case reports only. CASE DESCRIPTION: We report a case of a 26-year-old female having a rare coexistence of bronchial atresia with a large patent ductus arteriosus (PDA) and a small atrial septal defect (ASD), and had Eisenmenger syndrome (ES) at the time of presentation. PDA itself causes pulmonary arterial hypertension (PAH) if not corrected early within a few months of infancy. On the contrary, CBA can also lead to PAH and along with PDA may have contributed to the development of ES in our case. CONCLUSION: Timely diagnosis and treatment of CBA and its associated CHD may prevent or delay the complications occurring later on.

Acquired Cardiovascular Diseases in Patients with Pulmonary Hypertension Due to Congenital Heart Disease: A Case Report.

Background: Advances in the diagnosis and treatment of congenital heart diseases (CHDs) have resulted in improved survival rates for CHD patients. Up to 90% of individuals with mild CHD and 40% with complex CHD now reach the age of 60. Previous studies have indicated an elevated risk of atherosclerotic cardiovascular disease (ASCVD) and associated risk factors, morbidity, and mortality in adults with congenital heart disease (ACHD). However, there were no comprehensive guidelines for the prevention and management of acquired cardiovascular diseases (CVDs) in ACHD populations until recently. Case presentation: A 55-year-old man with Eisenmenger syndrome and comorbidities (arterial hypertension, heart failure, dyslipidemia, hyperuricemia, and a history of pulmonary embolism (PE)) presented with progressive breathlessness. The electrocardiogram (ECG) revealed signs of right ventricle (RV) hypertrophy and overload, while echocardiography showed reduced RV function, RV overload, and severe pulmonary hypertension (PH) signs, and preserved left ventricle (LV) function. After ruling out a new PE episode, acute coronary syndrome (ACS) was diagnosed, and percutaneous intervention was performed within 24-48 h of admission. Conclusions: This case highlights the importance of increased awareness of acquired heart diseases in patients with pulmonary hypertension due to CHD.

Management and outcomes of pulmonary artery hypertension and Eisenmenger syndrome during pregnancy: a prospective observational cohort study.

OBJECTIVES: Maternal-fetal morbidity and mortality among pregnant women with pulmonary artery hypertension (PAH) and Eisenmenger syndrome are unacceptable, and management decision-making in these clinical scenarios remains debatable. This study aimed to compare and analyse clinical characteristics, management and pregnancy outcomes in PAH and Eisenmenger syndrome. DESIGN: Prospective observational cohort study. SETTINGS: A large tertiary care university hospital. PATIENTS: Thirty patients with pulmonary artery hypertension and 20 patients with Eisenmenger syndrome. METHODS: Data pertaining to clinical characteristics, anaesthetic, medical and obstetric management, and outcomes in pregnancy complicated by PAH and Eisenmenger syndrome were collected between July 2020 and June 2022. Each treating unit followed its management protocol in consultation with the multidisciplinary team. MAIN OUTCOME MEASURES: Maternal mortality and morbidity. RESULTS: Maternal mortality was lower in the PAH group (6.6% versus 15%; p = 0.33). All mortalities were in the postpartum period. The incidence of new-onset or exacerbation of heart failure (23.3% versus 60%; p = 0.009) and hypoxaemia (13.3% versus 50%; p = 0.005) were significantly lower in the PAH group. In the Eisenmenger syndrome group, a significantly higher number of women received pulmonary hypertension and heart failure medications. Prematurity and neonatal intensive care unit admission were frequently noticed in Eisenmenger syndrome, whereas perinatal mortality, birthweight and APGAR score were comparable. CONCLUSIONS: Fetomaternal outcomes are inferior in Eisenmenger syndrome compared with PAH and are either lower or comparable to those reported from contemporary cohorts of developed nations.

Undiagnosed ventricular septal defect with resultant Eisenmenger syndrome presenting with diplopia.

Ventricular septal defect (VSD) is the most common congenital heart lesion among children. In most cases, however, it is identified and corrected in childhood, before long-term sequelae such as pulmonary hypertension develop. In this case report, we present a young man with an undiagnosed VSD with consequent Eisenmenger syndrome who initially presented to medical attention with diplopia found to be caused by cerebral infarcts.

Pregnancy in Eisenmenger syndrome: a case series from a tertiary care hospital of Northern India.

BACKGROUND: Despite advances in medical care, we still come across pregnancy in Eisenmenger syndrome. Eisenmenger syndrome represents the severe end of the spectrum for disease in pulmonary artery hypertension associated with CHD. Due to very high maternal and perinatal morbidity and mortality, pregnancy is contraindicated among these women. Current guidelines also recommend that the women who become pregnant should opt for early termination of pregnancy. Here, we present a case series of 11 women of Eisenmenger syndrome and their pregnancy outcome. METHODS: It was a retrospective analysis of 12 pregnancies among 11 women with Eisenmenger syndrome who were managed in a tertiary care referral centre of Northern India. RESULTS: The mean age of these women was 28 ± 4 years (range 22 to 36 years). Almost 80% of them (9/11) were diagnosed with Eisenmenger syndrome during pregnancy. The commonest cardiac lesion was Ventricular Septal defect (54.5%) followed by Atrial Septal defect (27.3%) and Patent Ductus arteriosus (9.1%). Only three women opted for medical termination of pregnancy, rest eight continued the pregnancy or presented late. Pregnancy complications found include pre-eclampsia (50%), abruption (22%), and fetal growth retardation (62.5%). There were three maternal deaths (mortality rate 27%) in postpartum period. CONCLUSION: This case series highlights the delay in diagnosis and treatment of CHD despite improvement in medical care. Women with Eisenmenger syndrome require effective contraception, preconceptional counselling, early termination of pregnancy, and multidisciplinary care.

Use of venous-venous extracorporeal membrane oxygenation in the treatment of postpartum pulmonary hypertension crisis.

The incidence of heart disease in pregnancy ranges from 0.5% to 3.0% and is regarded as one of the top three causes of maternal death. The mortality rate of patients with pulmonary hypertension and Eisenmenger syndrome is as high as 16.7%-50%. Changes in haemodynamics during pregnancy and childbirth increase the burden on the heart, and induced pulmonary hypertension crisis is one of the main causes of maternal death. Extracorporeal Membrane Oxygenation (ECMO) is the last-resort treatment strategy to treat patients with pulmonary hypertension crisis. We report a ventricular septal defect in a pregnant woman with pulmonary hypertension and Eisenmenger's syndrome, which is a postpartum pulmonary hypertension crisis that leads to respiratory and circulatory disorders. The patient was successfully treated with venous-venous extracorporeal membrane oxygenation.

Eisenmenger Syndrome: A Revisit of a Hidden but Catastrophic Disease.

BACKGROUND: Eisenmenger syndrome (ES) is a rare condition seen in children with congenital heart disease (CHD). It is characterized by raised pulmonary vascular resistance (PVR) arising from a shunt reversal with the presence of desaturated blood in the systemic circulation. Proper timing and early intervention in children with congenital heart disease have made the syndrome a rare occurrence. However, this cannot be said in developing countries where facilities for the diagnosis and management of children with congenital heart disease are not optimal. OBJECTIVES: The aim of this narrative review is to highlight the importance of early diagnosis and to review the new techniques in the evaluation of children with ES. It also highlights in a snapshot the state of management of ES in a developing country. METHODS: A search for published data on ES was done through several search engines such as Pubmed, google scholar citation, systematic reviews, and meta-analysis. This involves research done over the past 30 years. Keywords such as Eisenmenger'syndrome, 'congenital heart defect', 'Pulmonary hypertension', 'catherterization', 'echocardiography', and children' were used. RESULTS: This review shows the new technique in the diagnosis, aetio-pathogenesis, management and treatment of children with ES in-depth descriptive analysis and new advances in the management of children with ES. CONCLUSION: Eisenmenger syndrome is a preventable disease that can be curbed by early diagnosis and treatment of children with congenital heart disease, especially in the developing world.

CONTEXTE: Le syndrome d'Eisenmenger (SE) est une affection rare observée chez les enfants atteints de cardiopathie congénitale. Il se caractérise par une augmentation de la résistance vasculaire pulmonaire (RVP) due à l'inversion d'un shunt et à la présence de sang désaturé dans la circulation systémique. Le syndrome est devenu rare chez les enfants atteints de cardiopathie congénitale grâce à un choix judicieux du moment et à une intervention précoce. Toutefois, il n'en va pas de même dans les pays en développement où les moyens de diagnostic et de prise en charge des enfants atteints de cardiopathies congénitales ne sont pas optimaux. OBJECTIFS: L'objectif de cette revue narrative est de souligner l'importance d'un diagnostic précoce et de passer en revue les nouvelles techniques d'évaluation des enfants atteints de SE. Elle met également en lumière, sous forme d'un instantané, l'état de la prise en charge de l'ES dans un pays en développement. MÉTHODES: Une recherche de données publiées sur l'ES a été effectuée à l'aide de plusieurs moteurs de recherche tels que Pubmed, google scholar citation, revues systématiques et méta-analyses. Il s'agit de recherches effectuées au cours des 30 dernières années. Des mots clés tels que "syndrome d'Eisenmenger", "malformation cardiaque congénitale", "hypertension pulmonaire", "cathétérisme", "échocardiographie" et "enfants" ont été utilisés. RÉSULTATS: Cette revue présente les nouvelles techniques de diagnostic, d'étio-pathogénie, de prise en charge et de traitement des enfants atteints de SE, ainsi qu'une analyse descriptive approfondie et les nouvelles avancées dans la prise en charge des enfants atteints de SE. CONCLUSION: Le syndrome d'Eisenmenger est une maladie évitable qui peut être enrayée par un diagnostic et un traitement précoces des enfants atteints de cardiopathies congénitales, en particulier dans les pays en développement. Mots-clés: Syndrome d'Eisenmenger; Enfants; Cardiopathie congénitale; Hhypertension pulmonaire; Prise en charge.

Diverse Right Ventricular Remodeling Evaluated by MRI and Prognosis in Eisenmenger Syndrome With Different Shunt Locations.

BACKGROUND: Congenital shunt location is related to Eisenmenger syndrome (ES) survival. Moreover, right ventricular (RV) remodeling is associated with poor survival in pulmonary hypertension. PURPOSE: To investigate RV remodeling using comprehensive magnetic resonance imaging (MRI) techniques and identify its relationship with prognosis in ES subgroups classified by shunt location. STUDY TYPE: Prospective observational study. POPULATION: Fifty-four adults with ES (16 with pre-tricuspid shunt and 38 with post-tricuspid shunt). FIELD STRENGTH/SEQUENCE: 3.0 T/cine MRI with balanced steady-state free precession sequence, late gadolinium enhancement with inversion recovery segmented gradient echo sequence and phase-sensitive reconstruction, and T1 mapping with modified Look-Locker inversion recovery sequence. ASSESSMENT: Demographics, clinical characteristics, hemodynamics, RV remodeling features (morphology, systolic function, RV-pulmonary artery (PA) coupling and myocardial fibrosis), and prognosis were compared between ES subgroups. The adverse endpoint was all-cause mortality or readmission for heart failure. STATISTICAL TESTS: The independent samples t-test, Fisher's exact test or Chi-squared test, and the Kaplan-Meier method were used. P < 0.05 was considered significant. RESULTS: Compared to patients with post-tricuspid shunt, patients with pre-tricuspid shunt were significantly older and had higher N-terminal pro-B-type natriuretic peptide concentrations and poorer exercise tolerance. Pre-tricuspid shunt showed significantly larger RV dimensions (end-diastolic volume index: 185.81 ± 37.49 vs. 98.20 ± 36.26 mL/m2 ), worse RV ejection fraction (23.54% ± 12.35% vs. 40.82% ± 10.77%), and RV-PA decoupling (0.35 ± 0.31 vs. 0.72 ± 0.29). Biventricular myocardial fibrosis was significantly more severe in pre-tricuspid shunt than post-tricuspid shunt (extracellular volume, left ventricle: 35.85% ± 2.58% vs. 29.10% ± 5.20%; RV free wall: 30.93% ± 5.65% vs. 26.75% ± 5.15%). In addition, pre-tricuspid shunt demonstrated a significantly increased risk of adverse endpoint (hazard ratio: 2.938, 95% confidence interval: 1.204-7.172). DATA CONCLUSION: ES with pre-tricuspid shunt might be a unique subtype with worse clinically decompensated RV remodeling and poor prognosis. LEVEL OF EVIDENCE: 2 Technical Efficacy Stage: 5.

Detection and evaluation of myocardial fibrosis in Eisenmenger syndrome using cardiovascular magnetic resonance late gadolinium enhancement and T1 mapping.

BACKGROUND: Myocardial fibrosis is a common pathophysiological process involved in many cardiovascular diseases. However, limited prior studies suggested no association between focal myocardial fibrosis detected by cardiovascular magnetic resonance (CMR) late gadolinium enhancement (LGE) and disease severity in Eisenmenger syndrome (ES). This study aimed to explore potential associations between myocardial fibrosis evaluated by the CMR LGE and T1 mapping and risk stratification profiles including exercise tolerance, serum biomarkers, hemodynamics, and right ventricular (RV) function in these patients. METHODS: Forty-five adults with ES and 30 healthy subjects were included. All subjects underwent a contrast-enhanced 3T CMR. Focal replacement fibrosis was visualized on LGE images. The locations of LGE were recorded. After excluding LGE in ventricular insertion point (VIP), ES patients were divided into myocardial LGE-positive (LGE+) and LGE-negative (LGE-) subgroups. Regions of interest in the septal myocardium were manually contoured in the T1 mapping images to determine the diffuse myocardial fibrosis. The relationships between myocardial fibrosis and 6-min walk test (6MWT), N-terminal pro-brain natriuretic peptide (NT-pro BNP), hematocrit, mean pulmonary arterial pressure (mPAP), pulmonary vascular resistance index (PVRI), RV/left ventricular end-systolic volume (RV/LV ESV), RV ejection fraction (RVEF), and risk stratification were analyzed. RESULTS: Myocardial LGE (excluding VIP) was common in ES (16/45, 35.6%), and often located in the septum (12/45, 26.7%). The clinical characteristics, hemodynamics, CMR morphology and function, and extracellular volume fraction (ECV) were similar in the LGE+ and LGE- groups (all P > 0.05). ECV was significantly higher in ES patients (28.6 ± 5.9% vs. 25.6 ± 2.2%, P < 0.05) and those with LGE- ES (28.3 ± 5.9% vs. 25.6 ± 2.2%, P < 0.05) than healthy controls. We found significant correlations between ECV and log NT-pro BNP, hematocrit, mPAP, PVRI, RV/LV ESV, and RVEF (all P < 0.05), and correlations trends between ECV and 6MWT (P = 0.06) in ES patients. An ECV threshold of 29.0% performed well in differentiating patients with high-risk ES from those with intermediate or low risk (area under curve 0.857, P < 0.001). CONCLUSIONS: Myocardial fibrosis is a common feature of ES. ECV may serve as an important imaging marker for ES disease severity.

Eisenmenger Syndrome Among Children with Unrepaired Congenital Heart Defects in Yunnan, China.

Eisenmenger syndrome is a life-threatening complication of congenital heart defects (CHD). Since Eisenmenger syndrome among children of repaired CHD is rare, very few studies have had the necessary data to investigate its distribution in children. The current study used data collected in rural China to investigate the prevalence of Eisenmenger syndrome in children with unrepaired CHD. Data were from the 2006 to 2016 patient medical records of China California Heart Watch, which is a traveling cardiology clinic in Yunnan Province, China. Patients were included if they (1) aged 18 or below, (2) had CHD(s), and (3) the defect was not repaired by the time of the clinic visit. The prevalence of Eisenmenger syndrome was calculated in each age and defect group. Using logistic regression models, we tested whether oxygen saturation, Down syndrome, sex, and age were significantly associated with Eisenmenger syndrome. Of the 1301 study participants, ventricular septum defect (VSD), atrial septal defect (ASD), and patent ductus arteriosus (PDA) were the most common CHD. About one-sixth of the patients had pulmonary hypertension and 1.5% had Eisenmenger syndrome. The percentages of Eisenmenger syndrome were 1.8% in VSD patients, 0 in ASD patients, and 0.9% in PDA patients. Patients in the age group between 15 and 18 years had the highest percentages of Eisenmenger syndrome (11.5%). Age and presence of Down syndrome were significantly associated with the presence of Eisenmenger syndrome. Our finding highlights the importance of early detection and correction of CHD.

Pregnancy in Congenital Heart Disease, Complicated by Pulmonary Arterial Hypertension-A Challenging Issue for the Pregnant Woman, the Foetus, and Healthcare Professionals.

Background and Objectives: Pregnancy and delivery in patients with congenital heart disease (CHD) and pulmonary arterial hypertension (PAH) carry a very high risk for maternal and foetal complications and are contraindicated according to the guidelines. In the last decades, when an available modern PAH-targeted medication therapy and a new management concept improved patients' well-being and survival, some PAH-CHD females decided to conceive. Of note, despite advanced treatment and modern healthcare system possibilities, dealing with pregnancy in a diverse PAH-CHD population is still challenging. The study aimed to share our experience with PAH-CHD pregnancies and discuss the risk assessment and current management of these patients with the combination of two rare diseases. Materials and Methods: The retrospective search of pulmonary hypertension and adult CHD registries in our hospital was performed, selecting all patients with CHD and PAH who conceived pregnancy from 2013 to 2021. Baseline demographic, clinical, and functional characteristics and clinical outcomes were collected. Results: Thirteen pregnancies in eight patients with PAH-CHD resulted in seven live births, three miscarriages, and three terminations. Five women were diagnosed with Eisenmenger syndrome (ES) and three with residual PAH after CHD repair. Before pregnancy, half of them were in WHO functional class III. Seven (87.5%) patients received targeted PAH treatment with sildenafil during pregnancy. In addition, the two most severe cases were administered with iloprost during peripartum. Three ES patients delivered preterm by Caesarean section under general anaesthesia. No neonatal mortality was reported. Maternal complications were observed in half of our cases. One patient died 12 days after the delivery in another hospital due to deterioration of heart failure. Conclusions: On the basis of our clinical experience, we conclude that pregnancy and delivery carry a high risk for maternal complications and should be avoided in women with PAH-CHD. The individualised approach of multidisciplinary care and appropriate monitoring are mandatory in reducing the risk of adverse outcomes.

Management of Eisenmenger syndrome by cardiac defect closure combined bilateral lung transplantation with intraoperative venoarterial ECMO support.

BACKGROUND: Optimal surgical treatment for Eisenmenger syndrome in adult congenital heart disease remains in debate. CASE REPORT: We report a case of a 22-year-old female with Eisenmenger syndrome secondary to ventricular septum defect (VSD), who underwent cardiac defect closure combined with bilateral lung transplantation in our center. The patient had an uncorrected peri-membranous VSD and subsequently developed severe pulmonary hypertension. We patched the defect under cardiopulmonary bypass. Then a sequential bilateral lung transplantation was performed with venoarterial extracorporeal membrane oxygenation support. The patient had a good postoperative recovery and remained well at follow-up at 1 year. To conclude, cardiac defect repair combined bilateral lung transplantation may be a feasible option for selected patients with Eisenmenger Syndrome.

Fatal Association of Mirror and Eisenmenger Syndrome during the COVID-19 Pandemic.

Mirror syndrome (MS) or Ballantyne's syndrome is a rare maternal condition that can be life-threatening for both mother and fetus. The condition is characterized by maternal signs and symptoms similar to those seen in preeclampsia in the setting of fetal hydrops. Despite recent advances in the field of maternal-fetal medicine, the etiopathogenesis of MS remains elusive. For patients and doctors, the COVID-19 pandemic has become an extra hurdle to overcome. The following case illustrates how patients' non-compliance associated with mirror syndrome and SARS-CoV-2 infection led to the tragic end of a 19-year-old patient. Therefore, knowledge of the signs and symptoms of mirror syndrome should always be part of the armamentarium of every obstetrician.

[Evidence base for specific pulmonary vasodilators in adults with congenital heart disease].

After reviewing the current definitions and classification of pulmonary hypertension (PH) associated with congenital heart disease (CHD), based on an analysis of 59 clinical trials (of which 14 are randomized controlled trials) drugs registered in the Russian Federation, the evidence base for PH therapy in adults with CHD is provided. The presence of a randomized controlled trial of bosentan BREATHE-5 and uncontrolled trials of other drugs became the basis for a higher class and level of evidence of bosentan (IB) compared to other drugs (IIaC) for Eisenmenger syndrome in the current European (ERS/ESC 2015) and updated Russian (2020) guidelines. According to the updated European (ESC 2020) guidelines for congenital heart disease in adults, in Eisenmenger patients with reduced exercise capacity (6MWT distance 450 m), a treatment strategy with initial endothelin receptor antagonist monotherapy should be considered followed by combination therapy if patients fail to improve (IIaB), in low- and intermediate-risk patients with repaired simple lesions and pre-capillary PH, initial oral combination therapy or sequential combination therapy is recommended and high-risk patients should be treated with initial combination therapy including parenteral prostanoids (IA) and endothelin receptor antagonists and phosphodiesterase 5 inhibitors may be considered in selected patients with elevated pulmonary pressure/resistance in the absence of elevated ventricular end diastolic pressure (IIbC). Only three (bosentan, macitentan and selexipag) out of seven specific pulmonary vasodilators registered in the Russian Federation have indications for pulmonary arterial hypertension associated with congenital heart disease and Eisenmenger syndrome or pulmonary arterial hypertension associated with corrected simple congenital heart disease in the instructions for use.

Evaluation of Macitentan in Patients With Eisenmenger Syndrome.

BACKGROUND: Eisenmenger syndrome describes congenital heart disease-associated severe pulmonary hypertension accompanied by right-to-left shunting. The multicenter, double-blind, randomized, placebo-controlled, 16-week, phase III MAESTRO study (Macitentan in Eisenmenger Syndrome to Restore Exercise Capacity) evaluated the efficacy and safety of the endothelin receptor antagonist macitentan in patients with Eisenmenger syndrome. METHODS: Patients with Eisenmenger syndrome aged ≥12 years and in World Health Organization functional class II-III were randomized 1:1 to placebo or macitentan 10 mg once daily for 16 weeks. Patients with complex cardiac defects, Down syndrome and background PAH therapy were eligible. The primary end point was change from baseline to week 16 in 6-minute walk distance. Secondary end points included change from baseline to week 16 in World Health Organization functional class. Exploratory end points included NT-proBNP (N-terminal pro-B-type natriuretic peptide) at end of treatment expressed as a percentage of baseline. In a hemodynamic substudy, exploratory end points included pulmonary vascular resistance index (PVRi) at week 16 as a percentage of baseline. RESULTS: Two hundred twenty six patients (macitentan n=114; placebo n=112) were randomized. At baseline, 60% of patients were in World Health Organization functional class II and 27% were receiving phosphodiesterase type-5 inhibitors. At week 16, the mean change from baseline in 6-minute walk distance was 18.3 m and 19.7 m in the macitentan and placebo groups (least-squares mean difference, -4.7 m; 95% confidence limit (CL), -22.8, 13.5; P=0.612). World Health Organization functional class improved from baseline to week 16 in 8.8% and 14.3% of patients in the macitentan and placebo groups (odds ratio, 0.53; 95% CL, 0.23, 1.24). NT-proBNP levels decreased with macitentan versus placebo (ratio of geometric means, 0.80; 95% CL, 0.68, 0.94). In the hemodynamic substudy (n=39 patients), macitentan decreased PVRi compared with placebo (ratio of geometric means, 0.87; 95% CL, 0.73, 1.03). The most common adverse events with macitentan versus placebo were headache (11.4 versus 4.5%) and upper respiratory tract infection (9.6 versus 6.3%); a hemoglobin decrease from baseline of ≥2 g/dL occurred in 36.0% versus 8.9% of patients. Five patients (3 macitentan; 2 placebo) prematurely discontinued treatment and 1 patient died (macitentan group). CONCLUSIONS: Macitentan did not show superiority over placebo on the primary end point of change from baseline to week 16 in exercise capacity in patients with Eisenmenger syndrome. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01743001.

Osteopontin plays important roles in pulmonary arterial hypertension induced by systemic-to-pulmonary shunt.

Recent studies indicated that osteopontin (OPN) was involved in the genesis and progression of pulmonary arterial hypertension (PAH); however, its role in congenital heart disease-associated PAH (CHD/PAH) remains unknown. Our results showed that OPN was increased in lungs and plasma of patients with Eisenmenger syndrome; moreover, OPN and αVß3-integrin expression levels were augmented in rat lungs exposed to systemic-to-pulmonary shunt. Cell culture assay demonstrated that distal pulmonary arterial smooth muscle cells (PASMCs) from rat lungs suffering from volume and pressure overload exhibited enhanced proliferation compared with those from healthy rats. Mechanical stretch (20% at 1 Hz) increased OPN expression and activated ERK1/2 and protein kinase B (Akt) signal pathway in distal PASMCs from healthy rats. Interestingly, OPN enhanced the proliferation and migration of PASMCs while blocking αVß3-integrin with neutralizing antibody LM609 or Arg-Gly-Asp peptidomimetic antagonist cyclo(Ala-Arg-Gly-Asp-3-aminomethylbenzoyl) (XJ735), rectified the proliferative and migratory effects of OPN, which were partially mediated via ERK1/2 and Akt signaling pathways. Furthermore, surgical correction of systemic-to-pulmonary shunt, particularly XJ735 supplementation after surgical correction of systemic-to-pulmonary shunt, significantly alleviated the pulmonary hypertensive status in terms of pulmonary hemodynamic indices, pulmonary vasculopathy, and right ventricular hypertrophy. In summary, OPN alteration in lungs exposed to systemic-to-pulmonary shunt exerts a deteriorative role in pulmonary vascular remodeling through modulating the proliferation and migration of PASMCs, at least in part, via ανß3-ERK1/2 and ανß3-Akt signaling pathways. Antagonizing OPN receptor ανß3-integrin accelerated the regression of pulmonary vasculopathy after surgical correction of systemic-to-pulmonary shunt, indicating a potential therapeutic strategy for patients with CHD/PAH.-Meng, L., Liu, X., Teng, X., Gu, H., Yuan, W., Meng, J., Li, J., Zheng, Z., Wei, Y., Hu, S. Osteopontin plays important roles in pulmonary arterial hypertension induced by systemic-to-pulmonary shunt.

Pulmonary arterial hypertension: closing the gap in congenital heart disease.

PURPOSE OF REVIEW: Pulmonary arterial hypertension associated with congenital heart disease (PAH-CHD) is a common association adversely affecting quality of life and survival in these patients. We provide herewith recent advances in the understanding and management of PAH-CHD. RECENT FINDINGS: Significant progress has been made in disease-targeting therapy with pulmonary vasodilators for the treatment of Eisenmenger syndrome, the most severe form of PAH-CHD. Important gaps, however, still exist in the assessment and management of patients with PAH-CHD with systemic to pulmonary shunts. The choice of therapy, either interventional, medical, or both is an on-going dilemma that requires more long-term data. PAH after defect closure represents the most concerning subgroup of patients with the worst prognosis, requiring close follow-up and proactive disease-targeting therapy treatment. Small defects are not considered responsible for patients who have severe PAH and therefore, present different subgroup of patients similar to idiopathic PAH. SUMMARY: Even with advances in diagnosis and treatment PAH-CHD remains a challenging field requiring lifelong follow-up and meticulous treatment in centres specialized in both CHD and PAH.

Image diagnosis: Eisenmenger's syndrome in patients with simple congenital heart disease.

BACKGROUND: Early identification of congenital heart disease (CHD) allows detection of the pulmonary arteriopathy in an early stage, and timely shunt closure can permanently reverse pulmonary arterial hypertension (PAH). However, surgical correction is not recommended in patients with irreversible PAH. Herein we report our experience about Eisenmenger's syndrome in simple CHD. CASE PRESENTATION: From January 2017 to November 2018, a total of 8 CHD patients (3 ventricular septal defects (VSD), 2 atrial septal defects (ASD), and 3 patent ductus arteriosus (PDA), median age, 15.5 years [range, 3-18 years]) with PAH were detected by chest X-ray, electrocardiogram, transthoracic echocardiography (TTE), computed tomographic angiography (CTA) and cardiac catheterization. The median defect diameter, pulmonary artery pressure (PAP), pulmonary vascular resistance (PVR) were 16.5 mm (range, 3-30 mm), 75 mmHg (range, 60-86 mmHg), and 16 Woods units (range, 12-19 Woods units), respectively. Here, we report the representative cases of three types of simple CHD with irreversible PAH. The surgical correction was not performed in all patients who had fixed PAH and were referred to medical treatment. CONCLUSIONS: PAH in CHD can be reversed by early shunt closure, but this potential is lost beyond a certain point of no return. This article highlights the essence of enhancing the level of healthcare and services in Chinese rural areas. Failure to accurately and timely assess PAH will delay effective treatment past optimal treatment time, and even lead to death.

Focused Update on Pulmonary Hypertension in Children-Selected Topics of Interest for the Adult Cardiologist.

Pulmonary hypertensive vascular disease (PHVD), and pulmonary hypertension (PH), which is a broader term, are severe conditions associated with high morbidity and mortality at all ages. Treatment guidelines in childhood are widely adopted from adult data and experience, though big differences may exist regarding aetiology, concomitant conditions and presentation. Over the past few years, paediatric aspects have been incorporated into the common guidelines, which currently address both children and adults with pulmonary hypertension (PH). There are multiple facets of PH in the context of cardiac conditions in childhood. Apart from Eisenmenger syndrome (ES), the broad spectrum of congenital heart disease (CHD) comprises PH in failing Fontan physiology, as well as segmental PH. In this review we provide current data and novel aspects on the pathophysiological background and individual management concepts of these conditions. Moreover, we focus on paediatric left heart failure with PH and its challenging issues, including end stage treatment options, such as mechanical support and paediatric transplantation. PH in the context of rare congenital disorders, such as Scimitar Syndrome and sickle cell disease is discussed. Based on current data, we provide an overview on multiple underlying mechanisms of PH involved in these conditions, and different management strategies in children and adulthood. In addition, we summarize the paediatric aspects and the pros and cons of the recently updated definitions of PH. This review provides deeper insights into some challenging conditions of paediatric PH in order to improve current knowledge and care for children and young adults.