Disrupted BMP-9 Signaling Impairs Pulmonary Vascular Integrity in Hepatopulmonary Syndrome.

RATIONALE: Hepatopulmonary syndrome (HPS) is a severe complication of liver diseases characterized by abnormal dilatation of pulmonary vessels, resulting in impaired oxygenation. Recent research highlights the pivotal role of liver-produced bone morphogenetic protein (BMP)-9 in maintaining pulmonary vascular integrity. OBJECTIVES: This study aimed to investigate the involvement of BMP-9 in human and experimental HPS. METHODS: Circulating BMP-9 levels were measured in 63 healthy controls and 203 cirrhotic patients, with or without HPS. Two animal models of portal hypertension were employed: common bile duct ligation (CBDL) with cirrhosis and long-term partial portal vein ligation (PPVL) without cirrhosis. Additionally, the therapeutic effect of low-dose BMP activator FK506 was investigated, and the pulmonary vascular phenotype of BMP-9 knockout rats was analyzed. MEASUREMENTS AND MAIN RESULTS: Patients with HPS related to compensated cirrhosis demonstrated lower levels of circulating BMP-9 compared to patients without HPS. Severe cirrhosis patients exhibited consistently low levels of BMP-9. In animal models, HPS characteristics, including intrapulmonary vascular dilations (IPVDs) and alveolo-arterial gradient enlargement, were observed. HPS development in both rat models correlated with reduced intrahepatic BMP-9 expression, decreased circulating BMP-9 level and activity, and impaired pulmonary BMP-9 endothelial pathway. Daily treatment with FK506 for 2-weeks restored BMP pathway in the lungs, alleviating IPVDs, and improving gas exchange impairment. Furthermore, BMP-9 knockout rats displayed a pulmonary HPS phenotype, supporting its role in disease progression. CONCLUSION: The study findings suggest that portal hypertension-induced loss of BMP-9 signaling contributes to HPS development.

Pulmonary vascular phenotype identified in patients with GDF2 (BMP9) or BMP10 variants: an international multicentre study.

BACKGROUND: Bone morphogenetic proteins 9 and 10 (BMP9 and BMP10), encoded by GDF2 and BMP10, respectively, play a pivotal role in pulmonary vascular regulation. GDF2 variants have been reported in pulmonary arterial hypertension (PAH) and hereditary haemorrhagic telangiectasia (HHT). However, the phenotype of GDF2 and BMP10 carriers remains largely unexplored. METHODS: We report the characteristics and outcomes of PAH patients in GDF2 and BMP10 carriers from the French and Dutch pulmonary hypertension registries. A literature review explored the phenotypic spectrum of these patients. RESULTS: 26 PAH patients were identified: 20 harbouring heterozygous GDF2 variants, one homozygous GDF2 variant, four heterozygous BMP10 variants, and one with both GDF2 and BMP10 variants. The prevalence of GDF2 and BMP10 variants was 1.3% and 0.4%, respectively. Median age at PAH diagnosis was 30 years, with a female/male ratio of 1.9. Congenital heart disease (CHD) was present in 15.4% of the patients. At diagnosis, most of the patients (61.5%) were in New York Heart Association Functional Class III or IV with severe haemodynamic compromise (median (range) pulmonary vascular resistance 9.0 (3.3-40.6) WU). Haemoptysis was reported in four patients; none met the HHT criteria. Two patients carrying BMP10 variants underwent lung transplantation, revealing typical PAH histopathology. The literature analysis showed that 7.6% of GDF2 carriers developed isolated HHT, and identified cardiomyopathy and developmental disorders in BMP10 carriers. CONCLUSIONS: GDF2 and BMP10 pathogenic variants are rare among PAH patients, and occasionally associated with CHD. HHT cases among GDF2 carriers are limited according to the literature. BMP10 full phenotypic ramifications warrant further investigation.

Corrigendum to "Expert management of congenital portosystemic shunts and their complications" [JHEP Reports 6 (2024)].

[This corrects the article DOI: 10.1016/j.jhepr.2023.100933.].

4D flow cardiac MRI to assess pulmonary blood flow in patients with pulmonary arterial hypertension associated with congenital heart disease.

PURPOSE: The purpose of this study was to evaluate the accuracy of four-dimensional flow cardiac magnetic resonance imaging (4D flow MRI) compared to right heart catheterization in measuring pulmonary flow (Qp), systemic flow (Qs) and pulmonary-to-systemic flow ratio (Qp/Qs) in patients with pulmonary arterial hypertension associated with congenital heart disease (PAH-CHD). MATERIALS AND METHODS: The study was registered on Clinical-trial.gov (NCT03928002). Sixty-four patients with PAH-CHD who underwent 4D flow MRI were included. There were 16 men and 48 women with a mean age of 45.3 ± 13.7 (standard deviation [SD]) years (age range: 21-77 years). Fifty patients (50/64; 78%) presented with pre-tricuspid shunt. Qp (L/min), Qs (L/min) and Qp/Qs were measured invasively using direct Fick method during right heart catheterization and compared with measurements assessed by 4D flow MRI within a 24-48-hour window. RESULTS: The average mean pulmonary artery pressure was 51 ± 17 (SD) mm Hg with median pulmonary vascular resistance of 8.8 Wood units (Q1, Q3: 5.3, 11.7). A strong linear correlation was found between Qp measurements obtained with 4D flow MRI and those obtained with the Fick method (r = 0.96; P < 0.001). Bland Altman analysis indicated a mean difference of 0.15 ± 0.48 (SD) L/min between Qp estimated by 4D flow MRI and by right heart catheterization. A strong correlation was found between Qs and Qp/Qs measured by 4D flow MRI and those obtained with the direct Fick method (r = 0.85 and r = 0.92; P < 0.001 for both). CONCLUSION: Qp as measured by 4D flow MRI shows a strong correlation with measurements derived from the direct Fick method. Further investigation is needed to develop less complex and standardized methods for measuring essential PAH parameters, such as pulmonary arterial pressures and pulmonary vascular resistance.

Sarcoidosis-Associated Pulmonary Hypertension.

Pulmonary hypertension is a life-threatening complication of advanced sarcoidosis. Many mechanisms can cause an elevation of pulmonary pressure in sarcoidosis, leading to precapillary or postcapillary pulmonary hypertension. Sarcoidosis-associated pulmonary hypertension contributes to severe exertional dyspnea, reduced exercise capacity, and notably compromised the survival. Despite the critical functional and prognostic implications of pulmonary hypertension in sarcoidosis, there is a scarcity of specific guidelines on the management of these patients due to a lack of evidence. Hence, further research is required to identify subgroups of patients who may benefit from pulmonary arterial hypertension-targeted therapies and/or immunosuppressive therapies.

Outcomes of listing for lung and heart-lung transplantation in pulmonary hypertension: comparative experience in France and the UK.

Background: Lung or heart-lung transplantation (LT/HLT) for severe pulmonary hypertension (PH) as the primary disease indication carries a high risk of waiting list mortality and post-transplant complications. France and the UK both have coordinated PH patient services but with different referral pathways for accessing LT services. Methods: We conducted a comparative analysis of adult PH patients listed for LT/HLT in the UK and France. Results: We included 211 PH patients in France (2006-2018) and 170 in the UK (2010-2019). Cumulative incidence of transplant, delisting and waiting list death within 3 years were 81%, 4% and 11% in France versus 58%, 10% and 15% in the UK (p<0.001 for transplant and delisting; p=0.1 for death). Median non-priority waiting time was 45 days in France versus 165 days in the UK (p<0.001). High-priority listing occurred in 54% and 51% of transplanted patients respectively in France and the UK (p=0.8). Factors associated with achieving transplantation related to recipients' height, male sex, clinical severity and priority listing status. 1-year post-transplant survival was 78% in France and 72% in the UK (p= 0.04). Conclusion: Access to transplantation for PH patients is better in France than in the UK where more patients were delisted due to clinical deterioration because of longer waiting time. High rates of priority listing occurred in both countries. Survival for those achieving transplantation was slightly better in France. Ensuring optimal outcomes after transplant listing for PH patients is challenging and may involve early listing of higher risk patients, increasing donor lung utilisation and improving allocation rules for these specific patients.

Outcomes and risk assessment in pulmonary veno-occlusive disease.

Introduction: Pulmonary veno-occlusive disease (PVOD) is a rare and severe subtype of pulmonary arterial hypertension (PAH). Although European Society of Cardiology/European Respiratory Society (ESC/ERS) guidelines advise assessing PAH severity at baseline and during follow-up, no existing risk assessment methods have been validated for PVOD. This study aimed to identify prognostic factors, examine the impact of treatment strategies and evaluate risk assessment methods for PVOD patients. Methods: The study analysed all incident PVOD patients included in the French Pulmonary Hypertension Registry between 2006 and 2021. Survival was assessed based on initial treatment strategy and risk status and compared to a matched (age, sex, pulmonary vascular resistance) PAH group. Six risk assessment methods (number of four low-risk and three noninvasive low-risk variables, ESC/ERS guidelines three-strata and four-strata models, REVEAL 2.0 and Lite 2) were applied at baseline and early follow-up, and their accuracy was compared using Harrell's c-statistic. Results: Among the 327 included PVOD patients, survival rates at 1, 3 and 5 years were 86%, 50% and 27%, respectively. Multivariate analysis showed that only 6-min walk distance was associated with survival, with no significant difference based on initial treatment strategy. All six risk assessment methods could discriminate mortality risk, and the ESC/ERS four-strata model was the most accurate at both baseline and follow-up (C-index 0.64 and 0.74). PVOD survival rates were consistently lower than PAH when comparing baseline risk status using the ESC/ERS four-strata model. Conclusion: PVOD is associated with poor outcomes, and initial treatment strategies do not significantly affect survival. Risk assessment methods can be useful in predicting survival for PVOD patients.

Expert management of congenital portosystemic shunts and their complications.

Congenital portosystemic shunts are often associated with systemic complications, the most challenging of which are liver nodules, pulmonary hypertension, endocrine abnormalities, and neurocognitive dysfunction. In the present paper, we offer expert clinical guidance on the management of liver nodules, pulmonary hypertension, and endocrine abnormalities, and we make recommendations regarding shunt closure and follow-up.

Radiological pulmonary sequelae after COVID-19 and correlation with clinical and functional pulmonary evaluation: results of a prospective cohort.

OBJECTIVES: Whether COVID-19 leads to long-term pulmonary sequelae or not remains unknown. The aim of this study was to assess the prevalence of persisting radiological pulmonary fibrotic lesions in patients hospitalized for COVID-19. MATERIALS AND METHODS: We conducted a prospective single-center study among patients hospitalized for COVID-19 between March and May 2020. Patients with residual symptoms or admitted into intensive care units were investigated 4 months after discharge by a chest CT (CCT) and pulmonary function tests (PFTs). The primary endpoint was the rate of persistent radiological fibrotic lesions after 4 months. Secondary endpoints included further CCT evaluation at 9 and 16 months, correlation of fibrotic lesions with clinical and PFT evaluation, and assessment of predictive factors. RESULTS: Among the 1151 patients hospitalized for COVID-19, 169 patients performed a CCT at 4 months. CCTs showed pulmonary fibrotic lesions in 19% of the patients (32/169). These lesions were persistent at 9 months and 16 months in 97% (29/30) and 95% of patients (18/19) respectively. There was no significant clinical difference based on dyspnea scale in patients with pulmonary fibrosis. However, PFT evaluation showed significantly decreased diffusing lung capacity for carbon monoxide (p < 0.001) and total lung capacity (p < 0.001) in patients with radiological lesions. In multivariate analysis, the predictive factors of radiological pulmonary fibrotic lesions were pulmonary embolism (OR = 9.0), high-flow oxygen (OR = 6.37), and mechanical ventilation (OR = 3.49). CONCLUSION: At 4 months, 19% of patients investigated after hospitalization for COVID-19 had radiological pulmonary fibrotic lesions; they persisted up to 16 months. CLINICAL RELEVANCE STATEMENT: Whether COVID-19 leads to long-term pulmonary sequelae or not remains unknown. The aim of this study was to assess the prevalence of persisting radiological pulmonary fibrotic lesions in patients hospitalized for COVID-19. The prevalence of persisting lesions after COVID-19 remains unclear. We assessed this prevalence and predictive factors leading to fibrotic lesions in a large cohort. The respiratory clinical impact of these lesions was also assessed. KEY POINTS: • Nineteen percent of patients hospitalized for COVID-19 had radiological fibrotic lesions at 4 months, remaining stable at 16 months. • COVID-19 fibrotic lesions did not match any infiltrative lung disease pattern. • COVID-19 fibrotic lesions were associated with pulmonary function test abnormalities but did not lead to clinical respiratory manifestation.

High and intermediate risk pulmonary embolism in the ICU.

Pulmonary embolism (PE) is a common and important medical emergency, encountered by clinicians across all acute care specialties. PE is a relatively uncommon cause of direct admission to the intensive care unit (ICU), but these patients are at high risk of death. More commonly, patients admitted to ICU develop PE as a complication of an unrelated acute illness. This paper reviews the epidemiology, diagnosis, risk stratification, and particularly the management of PE from a critical care perspective. Issues around prevention, anticoagulation, fibrinolysis, catheter-based techniques, surgical embolectomy, and extracorporeal support are discussed.

Thirty years of surgical management of pediatric pulmonary hypertension: Mid-term outcomes following reverse Potts shunt and transplantation.

BACKGROUND: Reverse Potts shunt (RPS) and lung or heart-lung transplantation are life-extending surgical interventions for pediatric patients with severe pulmonary arterial hypertension (PAH). Robust criteria for identifying patients who will benefit from these procedures remain elusive. Based on 30 years of experience, we sought to refine the surgical indications. METHODS: This single-center retrospective cohort study included 61 consecutive pediatric patients with PAH managed by RPS (2004-2020) or transplantation (1988-2020). Their mid-term outcomes were assessed. RESULTS: Compared with the 20 patients managed by RPS, the 41 transplant waitlist patients, of whom 28 were transplanted, were older (14.9 vs 8.0 years, P = .0001), had worse right ventricular impairment (tricuspid annular plane systolic excursion, 12.5 mm vs 18.0 mm, P = .03), and were managed later in the evolution of the disease (6.0 vs 1.7 years, P = .002). After implementation of a high-priority allocation program in 2007, waitlist mortality decreased from 52.6% to 13.6% (P = .02) and 5-year survival increased from 57.1% to 74.7% after RPS and 55.6% to 77.2% after transplantation. At a median follow-up of 8.6 years after RPS and 5.9 years after transplantation, functional capacity had improved significantly, and PAH-specific drug requirements had diminished markedly in the RPS group. Two patients successfully underwent double-lung transplant 6 and 9 years after RPS. CONCLUSIONS: In selected children with suprasystemic PAH, RPS is associated with functional capacity improvements and decreased pharmacotherapy needs over the midterm. RPS deserves consideration earlier in the course of pediatric PAH, with transplantation being performed in the event of refractory RV failure.

More rapid blood interferon α2 decline in fatal versus surviving COVID-19 patients.

Background: The clinical outcome of COVID-19 pneumonia is highly variable. Few biological predictive factors have been identified. Genetic and immunological studies suggest that type 1 interferons (IFN) are essential to control SARS-CoV-2 infection. Objective: To study the link between change in blood IFN-α2 level and plasma SARS-Cov2 viral load over time and subsequent death in patients with severe and critical COVID-19. Methods: One hundred and forty patients from the CORIMUNO-19 cohort hospitalized with severe or critical COVID-19 pneumonia, all requiring oxygen or ventilation, were prospectively studied. Blood IFN-α2 was evaluated using the Single Molecule Array technology. Anti-IFN-α2 auto-Abs were determined with a reporter luciferase activity. Plasma SARS-Cov2 viral load was measured using droplet digital PCR targeting the Nucleocapsid gene of the SARS-CoV-2 positive-strand RNA genome. Results: Although the percentage of plasmacytoid dendritic cells was low, the blood IFN-α2 level was higher in patients than in healthy controls and was correlated to SARS-CoV-2 plasma viral load at entry. Neutralizing anti-IFN-α2 auto-antibodies were detected in 5% of patients, associated with a lower baseline level of blood IFN-α2. A longitudinal analysis found that a more rapid decline of blood IFN-α2 was observed in fatal versus surviving patients: mortality HR=3.15 (95% CI 1.14-8.66) in rapid versus slow decliners. Likewise, a high level of plasma SARS-CoV-2 RNA was associated with death risk in patients with severe COVID-19. Conclusion: These findings could suggest an interest in evaluating type 1 IFN treatment in patients with severe COVID-19 and type 1 IFN decline, eventually combined with anti-inflammatory drugs. Clinical trial registration: https://clinicaltrials.gov, identifiers NCT04324073, NCT04331808, NCT04341584.

Pulmonary hypertension in sickle cell disease.

Sickle cell disease (SCD) is a complex genetic disorder that has long challenged both patients and healthcare professionals. One of its chronic and debilitating complications is pulmonary hypertension (PH). SCD-associated PH is often post-capillary, secondary to left heart disease. It can also sometimes be pre-capillary with multiple and often interrelated mechanisms including obstructive remodeling of the pulmonary vascular bed secondary to hemolysis, endothelial dysfunction, thrombosis, hypoxia, or associated risk factors like portal hypertension. Screening symptomatic patients with echocardiographic signs of PH is crucial to determine those who should undergo right heart catheterization, the cornerstone exam to diagnose and categorize patients with PH. The workup following the diagnosis relies on identifying the cause of PH to personalize treatment. Ongoing efforts are made to treat this complex condition, starting with treating the underlying disease with hydroxyurea or chronic blood exchange transfusion. Robust data on the efficacy of PAH-specific therapies are lacking in this specific population. Initiation of such therapies must be made by an expert center after a case-by-case assessment of the benefit-risk ratio according to the phenotype and the mechanisms involved in the development of PH. Efforts are also poured into studying the interventional and medical therapies used on chronic thromboembolic PH for patients presenting with a thrombotic form. The management of those patients requires a multidisciplinary approach, with conjoint efforts from PH and SCD specialists.

Pharmacological management of connective tissue disease-associated pulmonary arterial hypertension.

INTRODUCTION: Pulmonary arterial hypertension (PAH) is a severe, progressive pulmonary vasculopathy (Group 1 Pulmonary Hypertension (PH)) that complicates the course of many connective tissue diseases (CTD). Detailed testing is required to differentiate PAH from other types of PH caused by CTD such as left heart disease (Group 2 PH), pulmonary parenchymal disease (Group 3 PH), and chronic thromboembolic pulmonary hypertension (Group 4 PH). PAH is most frequently seen in systemic sclerosis but can also be seen with systemic lupus erythematosus, mixed CTD, and primary Sjogren's syndrome. AREAS COVERED: This review discusses the epidemiology of CTD-associated PAH, outlines the complex diagnosis approach, and finishes with an in-depth discussion on the current treatment paradigm. Focus is placed on challenges faced in the treatment of CTD-associated PAH, (decreased efficacy and poorer tolerance of pharmacological therapies) and includes a discussion on the future investigational treatments. EXPERT OPINION: Despite significant advances over the past decades with more aggressive treatment algorithms, CTD-associated PAH patients continue to have poorer survival compared to those with idiopathic PAH. This review highlights factors leading to disparate outcomes compared to other forms of PAH, and discusses on further improvements that may increase quality of life and survival for CTD-associated PAH patients.

Treatment of pulmonary arterial hypertension: recent progress and a look to the future.

Pulmonary arterial hypertension (PAH) is a severe but treatable form of pre-capillary pulmonary hypertension caused by pulmonary vascular remodelling. As a result of basic science discoveries, randomised controlled trials, studies of real-world data, and the development of clinical practice guidelines, considerable progress has been made in the treatment options and outcomes for patients with PAH, underscoring the importance of seamless translation of information from bench to bedside and, ultimately, to patients. However, PAH still carries a high mortality rate, which emphasises the urgent need for transformative innovations in the field. In this Series paper, written by a group of clinicians, researchers, and a patient with PAH, we review therapeutic approaches and treatment options for PAH. We summarise current knowledge of the cellular and molecular mechanisms of PAH, with an emphasis on emerging treatable pathways and optimisation of current management strategies. In considering future directions for the field, our ambition is to identify therapies with the potential to stall or reverse pulmonary vascular remodelling. We highlight novel therapeutic approaches, the important role of patients as partners in research, and innovative approaches to PAH clinical trials.

Pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is a rare and progressive disease characterised by remodelling of the pulmonary arteries and progressive narrowing of the pulmonary vasculature. This leads to a progressive increase in pulmonary vascular resistance and pulmonary arterial pressure and, if left untreated, to right ventricular failure and death. A correct diagnosis requires a complete work-up including right heart catheterisation performed in a specialised centre. Although our knowledge of the epidemiology, pathology and pathophysiology of the disease, as well as the development of innovative therapies, has progressed in recent decades, PAH remains a serious clinical condition. Current treatments for the disease target the three specific pathways of endothelial dysfunction that characterise PAH: the endothelin, nitric oxide and prostacyclin pathways. The current treatment algorithm is based on the assessment of severity using a multiparametric risk stratification approach at the time of diagnosis (baseline) and at regular follow-up visits. It recommends the initiation of combination therapy in PAH patients without cardiopulmonary comorbidities. The choice of therapy (dual or triple) depends on the initial severity of the condition. The main treatment goal is to achieve low-risk status. Further escalation of treatment is required if low-risk status is not achieved at subsequent follow-up assessments. In the most severe patients, who are already on maximal medical therapy, lung transplantation may be indicated. Recent advances in understanding the pathophysiology of the disease have led to the development of promising emerging therapies targeting dysfunctional pathways beyond endothelial dysfunction, including the TGF-ß and PDGF pathways.

[Post-COVID-19 syndrome]. / Syndrome post-COVID-19.

In the aftermath of acute infection with the severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2), a large number of symptoms persist or appear, constituting a real syndrome called "long COVID-19" or "post-COVID- 19" or "post-acute COVID-19 syndrome". Its incidence is very high, half of patients showing at least one symptom at 4-6 months after Coronarovirus infectious disease 2019 (COVID-19). They can affect many organs. The most common symptom is persistent fatigue, similar to that seen after other viral infections. Radiological pulmonary sequelae are relatively rare and not extensive. On the other hand, functional respiratory symptoms, primarily dyspnoea, are much more frequent. Dysfunctional breathing is a significant cause of dyspnoea. Cognitive disorders and psychological symptoms are also very common, with anxiety, depression and post-traumatic stress symptoms being widely described. On the other hand, cardiac, endocrine, cutaneous, digestive or renal sequelae are rarer. The symptoms generally improve after several months, even if their prevalence at two years remains significant. Most of the symptoms are favored by the severity of the initial illness, and the psychic symptoms by the female sex. The pathophysiology of most symptoms is poorly understood. The influence of the treatments used in the acute phase is also important. Vaccination, on the other hand, seems to reduce their incidence. The sheer number of affected patients makes long-term COVID-19 syndrome a public health challenge.

Management of Acutely Decompensated Pulmonary Hypertension.

Pulmonary arterial hypertension is a severe life-threatening condition associated with increased pulmonary vascular resistance and resulting right heart dysfunction. Admission to intensive care unit with acutely decompensated right heart failure is a significant negative prognostic event with a high risk of multisystem organ dysfunction and death. Presentations are heterogenous and may combine signs of both diastolic and systolic dysfunction complicating management. Renal dysfunction is often present, but other organ systems can be involved resulting in findings such as acute hepatic dysfunction or bowel wall congestion and ischemia. The goals of therapy are to rapidly reverse ventriculo-arterial decoupling and reduce right ventricular afterload to prevent progression to refractory or irreversible right heart failure. Triggering events must be investigated for and addressed urgently if identified. Volume status management is critical and both noninvasive and invasive testing can aid in prognostication and guide management, including the use of inotropes and vasopressors. In cases of refractory right heart dysfunction, consideration of urgent lung transplantation and mechanical circulatory support is necessary. These patients should be managed at expert centers in an intensive care setting with a multidisciplinary team of practitioners experienced in the management of right heart dysfunction given the high short- and long-term mortality resulting from acute decompensated right heart failure.