Characteristics and outcomes of patients developing pulmonary hypertension associated with proteasome inhibitors.

BACKGROUND: Pulmonary arterial hypertension (PAH) has been described in patients treated with proteasome inhibitors (PIs). Our objective was to evaluate the association between PIs and PAH. METHODS: Characteristics of incident PAH cases previously treated with carfilzomib or bortezomib were analysed from the French pulmonary hypertension registry and the VIGIAPATH programme from 2004 to 2023, concurrently with a pharmacovigilance disproportionality analysis using the World Health Organization (WHO) global database (VigiBase) and a meta-analysis of randomised controlled trials. RESULTS: 11 incident cases of PI-associated PAH were identified (six with carfilzomib and five with bortezomib) with a female:male ratio of 2.7:1, a median age of 61 years, and a median delay between PI first exposure and PAH of 6 months. Four patients died (two from right heart failure, one from respiratory distress and one from an unknown cause). At diagnosis, six were in New York Heart Association Functional Class III/IV with severe haemodynamic impairment (median mean pulmonary arterial pressure 39 mmHg, cardiac index 2.45 L·min-1·m-2 and pulmonary vascular resistance 7.2 WU). In the WHO pharmacovigilance database, 169 cases of PH associated with PI were reported since 2013 with significant signals of disproportionate reporting (SDR) for carfilzomib, regardless of the definition of cases or control group. However, SDR for bortezomib were inconsistent. The systematic review identified 17 clinical trials, and carfilzomib was associated with a significantly higher risk of dyspnoea, severe dyspnoea and PH compared with bortezomib. CONCLUSION: PIs may induce PAH in patients undergoing treatment, with carfilzomib emitting a stronger signal than bortezomib, and these patients should be monitored closely.

Risk stratification refinements with inclusion of haemodynamic variables at follow-up in patients with pulmonary arterial hypertension.

BACKGROUND AND AIMS: Haemodynamic variables are prognostic factors in pulmonary arterial hypertension (PAH). However, right heart catheterization (RHC) is not systematically recommended to assess the risk-status during follow-up. This study aimed to assess the added value of haemodynamic variables in prevalent patients to predict the risk of death or lung transplantation according to their risk status assessed by the non-invasive 4 strata model as recommended by the European guidelines. METHODS: We evaluated incident patients with PAH enrolled in the French PAH Registry between 2009 and 2020 who had a first follow-up RHC. Cox regression identified, in each follow-up risk status, haemodynamic variables significantly associated with transplant-free survival (TFS). Optimal thresholds were determined by time-dependent Receiver-Operating Characteristics. Several multivariable Cox regression models were performed to identify the haemodynamic variables improving the non-invasive risk stratification model. RESULTS: We analysed 1240 incident patients reassessed within a year by RHC. None of haemodynamic variable were significantly associated with TFS among low-risk (n=386) or high-risk (n=71) patients. Among patients at intermediate (-low, n=483, -high, n=300) risk at first follow-up, multivariable models including either stroke volume index (SVi) or mixed venous oxygen saturation (SvO2) were the best. The prognostic performance of refined 6 strata risk stratification model including the non-invasive 4 strata model and SVi>37 mL·m-2 and/or SvO2>65% for patients at intermediate-risk (Area Under the Curve 0.81, c-index 0.74), was better than that of 4 strata model (0.79, p=0.009; c-index 0.72). CONCLUSIONS: Cardiopulmonary haemodynamics may improve risk stratification at follow-up in patients at intermediate-risk.

Pulmonary veno-occlusive disease: illustrative cases and literature review.

Pulmonary veno-occlusive disease (PVOD), also known as "pulmonary arterial hypertension (PAH) with overt features of venous/capillary involvement", is a rare cause of PAH characterised by substantial small pulmonary vein and capillary involvement, leading to increased pulmonary vascular resistance and right ventricular failure. Environmental risk factors have been associated with the development of PVOD, such as occupational exposure to organic solvents and chemotherapy, notably mitomycin. PVOD may also be associated with a mutation in the EIF2AK4 gene in heritable forms of disease. Distinguishing PVOD from PAH is critical for guiding appropriate management. Chest computed tomography typically displays interlobular septal thickening, ground-glass opacities and mediastinal lymphadenopathy. Life-threatening pulmonary oedema is a complication of pulmonary vasodilator therapy that can occur with any class of PAH drugs in PVOD. Early referral to a lung transplant centre is essential due to the poor response to therapy when compared with other forms of PAH. Histopathological analysis of lung explants reveals microvascular remodelling with typical fibrous veno-occlusive lesions. This review covers the main features distinguishing PVOD from PAH and two clinical cases that illustrate the challenges of PVOD management.

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.

ERS International Congress 2023: highlights from the Pulmonary Vascular Diseases Assembly.

Pulmonary vascular diseases such as pulmonary embolism and pulmonary hypertension are important and frequently under-recognised conditions. This article provides an overview of key highlights in pulmonary vascular diseases from the European Respiratory Society International Congress 2023. This includes insights into disease modification in pulmonary arterial hypertension and novel therapies such as sotatercept and seralutinib. Exciting developments in our understanding of the mechanisms underpinning pulmonary hypertension associated with interstitial lung disease are also explored. A comprehensive overview of the complex relationship between acute pulmonary embolism and chronic thromboembolic pulmonary hypertension (CTEPH) is provided along with our current understanding of the molecular determinants of CTEPH. The importance of multidisciplinary and holistic care cannot be understated, and this article also addresses advances beyond medication, with a special focus on exercise training and rehabilitation.

Exercise Hemodynamics Predict Pulmonary Arterial Hypertension in BMPR2 Mutation Carriers.

BACKGROUND: Exercise hemodynamics are recommended for early detection of pulmonary arterial hypertension (PAH) and have been suggested to be predictive of future development of PAH in high-risk populations such as BMPR2 mutation carriers. However, the optimal exercise hemodynamic screening parameter remains to be determined. Recent data suggest that pulmonary vascular distensibility coefficient (α) may serve as a useful parameter for early detection of PAH. RESEARCH QUESTION: What is the value of exercise hemodynamics, including α, for predicting the occurrence of PAH during long-term follow-up in BMPR2 mutation carriers? STUDY DESIGN AND METHODS: Fifty-two asymptomatic BMPR2 mutation carriers who underwent symptom-limited exercise hemodynamic assessment were followed up for a median of 10 years. The impact of hemodynamics at rest and exercise, presence of exercise pulmonary hypertension, and α on occurrence of PAH during long-term follow-up were assessed. RESULTS: During long-term follow-up, five patients demonstrated PAH. Patients who demonstrated PAH showed a significantly lower α (0.8 ± 0.4%/mm Hg) than patients without PAH (1.8 ± 0.8%/mm Hg; P = .008). The only hemodynamic parameter that predicted the occurrence of PAH during long-term follow-up at regression analysis was α. Receiver operating characteristic analysis showed that α ≤ 1.5%/mm Hg predicted PAH occurrence with a specificity of 75% and sensitivity of 100%. INTERPRETATION: Before development of PAH in BMPR2 mutation carriers, α is reduced markedly and may serve as a useful parameter in the setting of early disease detection. Given the low event rate, caution is warranted in interpreting these results, highlighting the need for validation studies.

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.

Evidence and unresolved questions in pulmonary hypertension: Insights from the 5th French Pulmonary Hypertension Network Meeting.

Pulmonary hypertension (PH) continues to present significant challenges to the medical community, both in terms of diagnosis and treatment. The advent of the updated 2022 European Society of Cardiology (ESC) and European Respiratory Society (ERS) guidelines has introduced pivotal changes that reflect the rapidly advancing understanding of this complex disease. These changes include a revised definition of PH, updates to the classification system, and treatment algorithm. While these guidelines offer a critical framework for the management of PH, they have also sparked new discussions and questions. The 5th French Pulmonary Hypertension Network Meeting (Le Kremlin-Bicêtre, France, 2023), addressed these emergent questions and fostering a deeper understanding of the disease's multifaceted nature. These discussions were not limited to theoretical advancements but extended into the practical realms of patient management, highlighting the challenges and opportunities in applying the latest guidelines to clinical practice.

Real-world evidence to advance knowledge in pulmonary hypertension: Status, challenges, and opportunities. A consensus statement from the Pulmonary Vascular Research Institute's Innovative Drug Development Initiative's Real-world Evidence Working Group.

This manuscript on real-world evidence (RWE) in pulmonary hypertension (PH) incorporates the broad experience of members of the Pulmonary Vascular Research Institute's Innovative Drug Development Initiative Real-World Evidence Working Group. We aim to strengthen the research community's understanding of RWE in PH to facilitate clinical research advances and ultimately improve patient care. Herein, we review real-world data (RWD) sources, discuss challenges and opportunities when using RWD sources to study PH populations, and identify resources needed to support the generation of meaningful RWE for the global PH community.