Clinical Effects of Syncope on Disease Severity and Adverse Outcomes in Children with Idiopathic and Heritable Pulmonary Arterial Hypertension.

Syncope is more common in children with idiopathic pulmonary arterial hypertension (PAH) than in adults with PAH. Although syncope is associated with a poor prognosis in adult PAH, the clinical effects of syncopal events on disease severity and outcome in children have not been carefully investigated. This study assessed the prevalence of syncope in pediatric PAH and examined its clinical, hemodynamic, and prognostic importance. This retrospective study assessed clinical data, including syncope status, from 78 children (37 girls) with idiopathic and heritable PAH (median age at diagnosis, 11 years). Patients were classified as syncopal or non-syncopal, and clinical data from the two groups were compared. The primary outcome was a composite of lung transplantation and cardiac mortality. Overall, 31 (38%) children had a history of syncope at presentation. Median age at diagnosis, sex ratio, brain natriuretic peptide level, and 6-min walk distance at diagnosis did not differ between groups. The hemodynamic parameters of initial right heart catheterization were similar between the syncope and non-syncope group (mean pulmonary artery pressure, 67 versus 71 mm Hg; cardiac index, 2.9 versus 2.9 l/min/m2, respectively). There was not significantly difference in event-free survival rate between two groups. Although syncopal events are common in children with PAH, our findings suggest that syncope may not be correlated with disease severity or outcome in pediatric PAH.

Reverse Remodeling of Pulmonary Arterioles After Pulmonary Artery Banding in Patients ≥ 2 Years Old with Severe Pulmonary Arterial Hypertension and Congenital Heart Disease.

The purpose of this study was to evaluate the pathological changes of the pulmonary arterioles in patients ≥ 2 years of age who first underwent a pulmonary artery banding (PAB) procedure, followed by bidirectional Glenn or Fontan according to their specific conditions. This was a prospective study of 15 children diagnosed and treated with PAB at the Department of Cardiothoracic Surgery of Anzhen Hospital between January 2009 and December 2012. The percentage of media area (%MS) of pulmonary arteriole, the percentage of media thickness (%MT), and pulmonary arterial density (APSC) were calculated from lung tissue sections. Pulmonary artery pressure decreased significantly after PAB surgery (P < 0.01). Postoperative mean pulmonary artery pressure declined significantly (P < 0.01), the cardiothoracic ratio was reduced (P < 0.05), and percutaneous oxygen saturation (inhaled air) decreased to 80-85% (P < 0.01). %MT (from 35.1 ± 5.6% to 26.9 ± 4.3%, P < 0.01), %MS (from 51.4 ± 6.7% to 32.2 ± 7.4%, P < 0.01), and APSC (from 108.3 ± 38.5 to 83.6 ± 19.6, P < 0.01) were decreased significantly after PAB. Five patients underwent the bidirectional Glenn procedure and four underwent Fontan. In conclusion, the results suggest that PAB can reduce pulmonary artery pressure and that pulmonary arterial lesions can be reversed after PAB.

Idiopathic pulmonary arterial hypertension - a unrecognized cause of high-shear high-flow haemostatic defects (otherwise referred to as acquired von Willebrand syndrome) in children.

Acquired von Willebrand syndrome (AVWS) is reported in high-flow high-shear congenital cardiac disorders. We hypothesized that the narrowed pulmonary vasculature in idiopathic pulmonary arterial hypertension (IPAH) may induce AVWS. We conducted a cross-sectional evaluation of children with IPAH. Patients with bleeding symptoms and/or laboratory abnormalities (thrombocytopenia, anomalies in coagulation screening tests) were tested in-depth for haemostatic defects. Fourteen children were followed with IPAH of which 8 were eligible. Four children exhibited abnormal bleeding scores (International Society on Thrombosis and Haemostasis Bleeding Assessment Tool: 3-5). All 8 patients showed very prolonged platelet function analyser (PFA)-100 closure times. Six children demonstrated either mild thrombocytopenia or low-normal von Willebrand factor (VWF) antigen (VWF:Ag) or VWF activity [mean (range), in iu/dl: VWF:Ag: 70 (61-91); VWF activity: 57 (34-70)]. Average VWF collagen binding capacity (VWF:CB) was 64 iu/dl (range: 53-123 iu/dl), with low-normal VWF activity/VWF:Ag or VWF:CB/VWF:Ag ratios occurring in five patients. All children had normal multimers distribution patterns. One patient underwent a lung transplantation, with normalization of haemostatic abnormalities post-surgery. Overall, 8 out of 14 children with IPAH had mild to moderate bleeding symptoms and/or laboratory abnormalities in keeping with AVWS. Normalization of the haemostatic defects following lung transplantation and lack of family history of bleeding attests to the acquired nature of their defects.

Survival of adults with systemic autoimmune rheumatic diseases and pulmonary arterial hypertension after lung transplantation.

Objectives: Pulmonary arterial hypertension (PAH) is a major cause of morbidity and mortality in adults with systemic autoimmune rheumatic diseases (ARDs). The aim of this study was to determine whether adults with ARDs and PAH on right-sided heart catheterization (ARD-PAH) have increased mortality following lung transplantation compared with those with PAH not due to an ARD. Methods: We conducted a retrospective cohort study of 93 adults with ARD-PAH and 222 adults with PAH who underwent lung transplantation in the USA between 4 May 2005 and 9 March 2015 using data from the United Network for Organ Sharing. We examined associations between diagnosis and survival after lung transplantation using stratified Cox models adjusted for potential confounding recipient factors. Results: Among adults undergoing lung transplantation in the USA, we did not detect a difference in the multivariable-adjusted mortality rate between those with ARD-PAH and those with PAH [hazard ratio 0.75 (95% CI 0.47, 1.19)]. Conclusion: The presence of an ARD was not associated with increased mortality after lung transplantation in adults with PAH.

Cardiac catheterization in children with pulmonary arterial hypertension.

Cardiac catheterization of childhood pulmonary arterial hypertension (PAH) is used to assess the severity of the disease as well as prognosis, selection of the most adequate pulmonary vasodilators, and evaluation of effectiveness. Sudden deterioration of cardiovascular hemodynamics, however, can be easily induced by pain, patient agitation, catheter manipulation, and by vasodilator provocation tests; these could trigger a pulmonary hypertension crisis, vagotony, respiratory distress, and hemoptysis resulting in critical complications, including death. Those patients with New York Heart Association functional class IV are at an especially high risk. It is noteworthy that pulmonary arteriography is a contraindication in patients with PAH. In a review of 7218 adult patients, 76 (1.1%) serious complications, including four deaths, were reported; with regard to the pediatric patients, 29 (10.7%) out of 270 patients with complications, including one with cardiogenic shock requiring cardiopulmonary resuscitation in addition to minor complications, were reported. To prevent serious complications, basic and routine precautions, such as oxygen and concomitant transcutaneous oxygen saturation and electrocardiogram monitoring during transportation to and from the catheter laboratory, are mandatory. Furthermore, the cooperation of experienced physicians and well informed medical staff in addition to meticulous preparation, for example, calculation of prior doses of catecholamine and confirmation of the presence of emergency equipment, is required.

O-linked ß-N-acetylglucosamine transferase directs cell proliferation in idiopathic pulmonary arterial hypertension.

BACKGROUND: Idiopathic pulmonary arterial hypertension (IPAH) is a cardiopulmonary disease characterized by cellular proliferation and vascular remodeling. A more recently recognized characteristic of the disease is the dysregulation of glucose metabolism. The primary link between altered glucose metabolism and cell proliferation in IPAH has not been elucidated. We aimed to determine the relationship between glucose metabolism and smooth muscle cell proliferation in IPAH. METHODS AND RESULTS: Human IPAH and control patient lung tissues and pulmonary artery smooth muscle cells (PASMCs) were used to analyze a specific pathway of glucose metabolism, the hexosamine biosynthetic pathway. We measured the levels of O-linked ß-N-acetylglucosamine modification, O-linked ß-N-acetylglucosamine transferase (OGT), and O-linked ß-N-acetylglucosamine hydrolase in control and IPAH cells and tissues. Our data suggest that the activation of the hexosamine biosynthetic pathway directly increased OGT levels and activity, triggering changes in glycosylation and PASMC proliferation. Partial knockdown of OGT in IPAH PASMCs resulted in reduced global O-linked ß-N-acetylglucosamine modification levels and abrogated PASMC proliferation. The increased proliferation observed in IPAH PASMCs was directly impacted by proteolytic activation of the cell cycle regulator, host cell factor-1. CONCLUSIONS: Our data demonstrate that hexosamine biosynthetic pathway flux is increased in IPAH and drives OGT-facilitated PASMC proliferation through specific proteolysis and direct activation of host cell factor-1. These findings establish a novel regulatory role for OGT in IPAH, shed a new light on our understanding of the disease pathobiology, and provide opportunities to design novel therapeutic strategies for IPAH.

BMPR2 mutation status influences bronchial vascular changes in pulmonary arterial hypertension.

The impact of bone morphogenetic protein receptor 2 (BMPR2) gene mutations on vascular remodelling in pulmonary arterial hypertension (PAH) is unknown. We sought to identify a histological profile of BMPR2 mutation carriers.Clinical data and lung histology from 44 PAH patients were subjected to systematic analysis and morphometry.Bronchial artery hypertrophy/dilatation and bronchial angiogenesis, as well as muscular remodelling of septal veins were significantly increased in PAH lungs carrying BMPR2 mutations. We found that patients displaying increased bronchial artery remodelling and bronchial microvessel density, irrespective of the mutation status, were more likely to suffer from severe haemoptysis. History of substantial haemoptysis (>50 mL) was significantly more frequent in BMPR2 mutation carriers. 43.5% of BMPR2 mutation carriers, as opposed to 9.5% of noncarriers, displayed singular large fibrovascular lesions, which appear to be closely related to the systemic lung vasculature.Our analysis provides evidence for the involvement of the pulmonary systemic circulation in BMPR2 mutation-related PAH. We show that BMPR2 mutation carriers are more prone to haemoptysis and that haemoptysis is closely correlated to bronchial arterial remodelling and angiogenesis; in turn, pronounced changes in the systemic vasculature correlate with increased pulmonary venous remodelling, creating a distinctive profile in PAH patients harbouring a BMPR2 mutation.

Heart-lung vs. double-lung transplantation for idiopathic pulmonary arterial hypertension.

Patients with idiopathic pulmonary arterial hypertension (IPAH) have improved survival after heart-lung transplantation (HLT) and double-lung transplantation (DLT). However, the optimal procedure for patients with IPAH undergoing transplantation remains unclear. We hypothesized that critically ill IPAH patients, defined by admission to the intensive care units (ICU), would demonstrate improved survival with HLT vs. DLT. All adult IPAH patients (>18 yr) in the Scientific Registry of Transplant Recipients (SRTR) database, who underwent either HLT or DLT between 1987 and 2012, were included. Baseline characteristics, survival, and adjusted survival were compared between the HLT and DLT groups. Similar analyses were performed for the subgroups as defined by the recipients' hospitalization status. A total of 928 IPAH patients (667 DLT, 261 HLT) were included in this analysis. The HLT recipients were younger, more likely to be admitted to the ICU, and have had their transplant in previous eras. Overall, the adjusted survivals after HLT or DLT were similar. For recipients who were hospitalized in the ICU, DLT was associated with worse outcomes (HR 1.827; 95% CI 1.018-3.279). In IPAH patients, the overall survival after HLT or DLT is comparable. HLT may provide improved outcomes in critically ill IPAH patients admitted to the ICU at time of transplantation.

Successful bilateral lung transplantation after 16 h of lung preservation with EP-TU solution: report of a case.

We report a case of bilateral lung transplantation (BLT) after preservation of the donor graft for 16 h 5 min with EP-TU, an extracellular phosphate-buffered lung preservation solution. The recipient was a 26-year-old woman with idiopathic pulmonary arterial hypertension and the graft ischemic time was prolonged significantly because of the time required to induce peripheral veno-arterial extracorporeal membrane oxygenation (V-A ECMO) under local anesthesia, and address the severe intrathoracic and pericardial adhesions from past surgery for partial anomalous pulmonary venous return, with concurrent annular plication of the tricuspid valve. After the operation, ECMO and continuous hemodiafiltration were started preemptively to protect the grafts against excessive edema. Postoperative chest X-ray showed diffuse bilateral infiltrates, which improved within a few days and she was weaned off ECMO on day 9. Successful BLT after a graft ischemic time of over 16 h has rarely been described in clinical lung transplantation.

[Short-term efficacy of atrial septostomy in the treatment of idiopathic pulmonary arterial hypertension patients complicating with right heart failure].

OBJECTIVE: To evaluate the efficacy of atrial septostomy in idiopathic pulmonary arterial hypertension (IPAH) patients complicating right ventricular failure. METHODS: This retrospective analysis included 5 IPAH patients (3 males, (29.3±15.2) years old) with right ventricular failure which were refractory to conventional and target-specific medication in Shanghai Chest Hospital from March to July 2014. Graded balloon dilation septostomy procedures were performed in all 5 patients. RESULTS: Successful atrial septostomy was achieved in 5 attempts with no procedure-related complications. Immediately post procedure, the mean systemic oxygen saturation decreased from (98.0±1.8)% to (86.4±3.2)% (P = 0.002), while the mean right atrial pressure decreased from (18.9±1.7) mmHg (1 mmHg = 0.133 kPa) to (16.0±1.3) mmHg (P = 0.039) and the mean cardiac index increased from (2.1±0.3) L · min(-1) · m(-2) to (2.7±0.5) L · min(-1) · m(-2) (P = 0.029). Mean follow-up was (6.2 ±1.8) months. Cardiac functional class (WHO) was 3 in 3 patients and 4 in 2 patients before the procedure, and increased 1 class in all patients during follow-up (P = 0.062). Exercise endurance (6-min walk test) also improved from (289.2±16.9) m to (320.4±19.6) m (P = 0.019), while B-type natriuretic peptide (BNP) level declined from (550.0±35.7) ng/L to (218.0±36.2) ng/L (P < 0.001). Except one patient developed spontaneous closure of created defect, right to left shunt at atrial septal level was evidenced by echocardiography during follow-up in the rest 4 patients. CONCLUSIONS: Atrial septostomy is safe and can improve hemodynamics and heart function in selected IPAH patients with right heart failure. Atrial septostomy can be used as a palliative treatment for IPAH and further study is warranted to evaluate the long-term efficacy of this procedure.

[Primary (idiopathic) pulmonary hypertension (Ayerza-Arrillaga syndrome) and pregnancy - intensive care and anesthesia management].

The lecture deals with detailed information about the etiology, pathogenesis and clinical manifestations of primary (idiopathic) pulmonaiy hypertension, intensive treatment and anesthesia in pregnancy.

Reverse Potts for the Treatment of Severe Idiopathic Pulmonary Hypertension in Children.

Idiopathic pulmonary arterial hypertension is a rare and progressive disease with poor prognosis. Many patients progressively worsen even when using combinations of specific drugs for its treatment. Herein, we present our experience in the management of three children with severe pulmonary arterial hypertension refractory to clinical treatment who underwent Potts surgery in addition to clinical treatment.

Early implementation of renal replacement therapy after lung transplantation does not impair long-term kidney function in patients with idiopathic pulmonary arterial hypertension.

OBJECTIVES: In patients with idiopathic pulmonary arterial hypertension, cardiac function can be impaired in the early postoperative phase after lung transplantation because the chronically untrained left ventricle is prone to fail. Thus, restrictive fluid management is pivotal to unload the left heart. In our institution, continuous renal replacement therapy is implemented liberally whenever a patient cannot be balanced negatively. It remains unclear whether such strategy impairs long-term kidney function. METHODS: We retrospectively reviewed our institutional database for patients with idiopathic pulmonary arterial hypertension who underwent transplantation between 2000 and 2018. The impact of postoperative continuous renal replacement therapy on long-term outcomes was investigated using a linear mixed model and multivariable Cox regression. RESULTS: A total of 87 idiopathic pulmonary arterial hypertension lung transplant recipients were included in this analysis. In 38 patients (43%), continuous renal replacement therapy was started in the early postoperative period for a median of 16 days (10-22). In this group, urine production significantly decreased and patients began to acquire a positive fluid balance; however, homeostatic functions of the kidney were still preserved at the time of continuous renal replacement therapy initiation. All patients were successfully weaned from continuous renal replacement therapy and fully recovered their kidney function at the time of hospital discharge. No difference in kidney function was found between continuous renal replacement therapy and noncontinuous renal replacement therapy in patients within 5 years. CONCLUSIONS: Early implementation of continuous renal replacement therapy for perioperative volume management does not impair long-term kidney function in idiopathic pulmonary arterial hypertension lung transplant recipients. Our data suggest that such a strategy leads to excellent long-term outcomes.

BLTx Combined With Cardiac Correction in Treatment of PAH in Puerpera: Is It a Feasible Strategy?

Though pregnancy is not recommended under current guidelines in pulmonary arterial hypertension, some women insist on parturition. The related surgical treatments are controversial, especially to those complicated with Eisenmenger syndrome. In this report, 2 cases of severe pulmonary arterial hypertension complicated with Eisenmenger syndrome were reviewed. Owing to a lifesaving tenet, bilateral lung transplantation combined with surgical atrioventricular defect correction were performed after careful assessments. Both patients were followed up at 1 year and displayed no obvious complication. It showed that the strategy of bilateral lung transplantation combined with a cardiac correction may be feasible and worthy of further investigation.

Lung transplantation as an intervention for pediatric pulmonary hypertension.

Lung transplantation is a treatment option for selected children with end-stage lung disease and pulmonary vascular disorders. Overall, pulmonary hypertension (PH) is the second most frequent indication for infants and children requiring lung transplants. In pediatric PH patients, timing for listing remains a difficult decision due to patient heterogeneity and varying allocation policies across different countries. Furthermore, perioperative management can be challenging, making interdisciplinary collaboration among surgical, anesthesiology, critical care, and lung transplant teams essential. Because pediatric PH patients typically have preserved cardiac index and exercise tolerance even with advanced disease, they should be referred early even if they do not meet the criteria for listing of primarily adults by International Society for Heart and Lung Transplantation (ISHLT) published in 2015: New York Heart Association (NYHA) functional class III or IV without improvement, cardiac index < 2 L/min/m2 , mean right atrial pressure of >15 mmHg. Bridging strategies with extracorporeal support should be determined at the time of listing in anticipation of possible clinical deterioration. Bilateral lung transplantation using cardiopulmonary bypass to provide hemodynamic stability is nowadays the standard surgical approach in pediatric centers. The immediate post-transplant period is characterized by dramatic changes in the right ventricle (RV) and and left ventricle (LV) anatomy and physiology, which can be life-threatening. Induction, immunosuppression, prophylaxis, and surveillance are not different from patients without PH. Overall, outcomes in pediatric lung and heart-lung transplant patients for PH are not different from those children undergoing transplantation for other indications. In fact, long-term survival is superior in children with idiopathic PH compared to other diseases, providing most recipients with improved quality of life.

Heart-lung transplantation for idiopathic pulmonary arterial hypertension and giant pulmonary artery aneurysm - case report.

BACKGOUND: Idiopathic pulmonary arterial hypertension (IPAH) is a rare condition that requires lung transplantation in patients' refractory to medical therapy. Pulmonary artery aneurysm (PAA) is a documented complication of IPAH however, optimal management and timing of intervention for this rare entity is not well understood. CASE REPORT: We report a case of a 51-year-old female who underwent heart-lung transplantation for IPAH and giant PAA. The extreme size of the PAA and underlying pathology encountered in this case precluded both lung transplantation and conventional aneurysm repair. CONCLUSION: This case demonstrates that heart-lung transplantation is a good surgical option for IPAH complicated by giant sized PAA and right heart failure.

Pediatric lung transplantation in the largest lung transplantation center of China: embarking on a long road.

Lung transplantation (LT) has been an effective treatment for carefully selected children with end-stage lung diseases. The aim of this retrospective study is to introduce our experience at the largest LT center in Wuxi, China and to compare the outcomes of pediatric LT between children with idiopathic pulmonary arterial hypertension (IPAH) and other end-stage lung diseases. Ten pediatric patients undergoing LT from 2007 to 2019 were included. Sequential bilateral lung transplantation (BLT) with bilateral anterior thoracotomies was performed in all patients, seven of whom also underwent reduced size LT. Eight children survived until the end of our follow-up period on July 31st, 2019, with the longest survival of 11 years. Extracorporeal membrane oxygenation (ECMO) was intraoperatively used in all IPAH children and one non-IPAH child. Left heart function of IPAH children, though initially compromised, recovered after surgery. Statistically significant differences in operation time and post-operative mechanical ventilation between IPAH group and non-IPAH group were observed without discernible impact on post-LT survival. Pediatric LT appears to be a safe treatment for IPAH children to improve longevity and quality of life and ECMO may help reduce the risk of surgery and the postoperative complications.

Single Lung Transplant vs Double Lung Transplant: A Single-Center Experience With Particular Consideration for Idiopathic Pulmonary Arterial Hypertension.

BACKGROUND: Lung transplant remains the only viable treatment for certain patients with end-stage lung diseases. Such patients can become either single or double lung recipients. The 2 procedures are associated with specific risks and benefits. The aim of the study was to assess the survival of patients after lung transplant in a single center. METHODS: The retrospective study consists of 128 lung transplant recipients. Patients underwent transplant between 2004 and 2017 because of following diseases: chronic obstructive pulmonary disease (28.2%), cystic fibrosis (26.5%), and primary pulmonary hypertension (12.3%), including idiopathic pulmonary arterial hypertension and interstitial lung diseases (33%). Patients with idiopathic pulmonary arterial hypertension were not treated with postoperative extracorporeal membrane oxygenation as left heart conditioning. RESULTS: Regardless of underlying disease, 75% of DLT recipients and 51% of SLT recipients reached 5-year survival (P = .0066). A total of 87% of lung transplant recipients with cystic fibrosis reached 1-year survival. Among lung recipients with primary pulmonary hypertension who underwent DLT and SLT, 5-year survival was reached by 84% and 51%, respectively (P = .025). Among patients with chronic obstructive pulmonary disease, 82% of DLT recipients and 62% of SLT recipients reached 1-year survival (P = .22). Patients who received transplants because of primary pulmonary hypertension presented the worst short-term survival among all SLT recipients. CONCLUSIONS: Patients with CF have the best overall survival among all lung transplant recipients. Double lung transplant provides statistically significantly better outcomes than single lung transplant. This observation is also present among recipients who underwent transplant because of primary pulmonary hypertension, as single lung transplant is not recommended among such patients in particular.

Extracorporeal Membrane Oxygenation as a Postoperative Left Ventricle Conditioning Tool After Lung Transplantation in Patients With Primary Pulmonary Artery Hypertension: First Polish Experience.

BACKGROUND: Primary pulmonary hypertension can lead to hypertrophy of the right ventricle and ultimately to its insufficiency. Lung transplantation remains the only viable treatment for patients with certain forms of this disease. Usage of extracorporeal membrane oxygenation in veno-arterial form (VA-ECMO) after transplantation is both protective for left ventricle (enables adaptation to increased blood flow) and right ventricle (provides time to return to appropriate dimensions and in some cases to correct tricuspid regurgitaion). CASE PRESENTATION: The case study describes 4 patients who were treated with VA-ECMO as a perioperative support. Three patients were diagnosed with idiopathic form of precapillary primary pulmonary hypertension. A fourth patient was a 49-year old woman diagnosed with hypoplastic pulmonary veins representing the postcapillary form of pulmonary hypertension. In all of the cases, VA-ECMO was introduced during the surgery (femoral vein/internal jugular vein and femoral artery) and maintained for several days after the transplantation. Regular echocardiographic and biochemical assessment in postoperative course revealed that cardiac function improved during and after such treatment among all patients. They were successfully weaned off ECMO and finally surgically explanted without any local complications. One patient was treated with awake ECMO protocol. CONCLUSIONS: VA-ECMO was proved to be a useful tool during the transplantation and postoperative period. It helps to restore proper cardiac function, as well as prevent adverse effects of aforementioned pathologic changes of a heart.