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We report a case of pulmonary arterial hypertension (PAH) occurring in a patient with Cowden syndrome with a mutation in the phosphatase and tensin (PTEN) tumor suppressor gene, in the context of exposure to the appetite suppressant dexfenfluramine. Anorexigen exposure is known to be a risk factor for PAH. However, the role of PTEN in cell function and the development of pulmonary vascular remodeling and histopathologic signs of PAH in mice with a Pten depletion in smooth muscle cells suggest that the association of PAH and Cowden syndrome may be relevant. In this case report, we hypothesize that PTEN mutations may be a predisposing factor for the development of PAH, with anorexigen exposure as a potential trigger. [ABSTRACT FROM AUTHOR]

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 (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 developed PAH. Patients who developed 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: The results of this study indicate that 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., Competing Interests: Financial/Nonfinancial Disclosures The authors have reported to CHEST the following: C. G. has received compensation for scientific symposia from AstraZeneca, AOPHealth, Cordis, Janssen, and MSD; speaker fees from AOPHealth, AstraZeneca, Janssen, and Ferrer; and an educational grant from OrphaCare. A. Beurnier has received speaker fees from AstraZeneca and Sanofi Aventis. X. J. has received speaker fees from Janssen and MSD and research grants from Acceleron, Bayer, Janssen, and MSD. E. M. T. L. has received speaker fees from Janssen and GlaxoSmithKline and research grants from Janssen and has served as an advisory board member for Janssen. M. J. has received speaker fees from Janssen. A. Boucly has received compensation for scientific symposia from Janssen and MSD, speaker fees from Janssen, MSD, AOPHealth and Ferrer, and research grants from Acceleron, Janssen and MSD. H. J. B. has received speaker fees and research grants from Janssen, MSD, and Ferrer and consultancy fees from Novartis and was supported by the Dutch Cardiovascular Alliance [Grant 01-001-2017-B010, DOLPHIN-GENESIS]. G. S. has received speaker and consultancy fees from Janssen, Bayer, GlaxoSmithKline, MSD, and Pfizer and research grants from Janssen and has served as a steering committee member for Janssen. O. S. has received speaker fees from AOPHealth, Janssen, Ferrer, and MSD; consultancy fees from Acceleron, Altavant, AOPHealth, Ferrer, Gossamer Bio, Janssen, and MSD; and research grants from Acceleron, AOPHealth, Janssen, and MSD; and has served as an advisory board member for Altavant, Gossamer Bio, Janssen, and MSD. L. S. has received compensation for scientific symposia from Janssen and MSD and speaker fees from Janssen and has served as an advisory board member for Janssen. M. H. has received speaker fees from Janssen and MSD; consultancy fees from Acceleron, Aerovate, Altavant, AOPHealth, Bayer, Chiesi, Ferrer, Janssen, MSD, MorphogenIX, Shou Ti, Tiakis, and United Therapeutics; and research grants from Acceleron, AOPHealth, Janssen, MSD, and Shou Ti; and has served as an advisory board member for Acceleron, Altavant, Janssen, MSD, and United Therapeutics. D. M. has received speaker fees from Bayer, Janssen, and MSD; consultancy fees from Acceleron, Janssen, and MSD; and research grants from Acceleron, Janssen, and MSD. None declared (P. H., B. G., S. G., A. Bouchachi, D. C.)., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Pulmonary venoocclusive disease (PVOD) is an uncommon form of pulmonary hypertension (PH) predominantly characterized by pulmonary vein and capillary involvement. An association between chemotherapy, in particular mitomycin C (MMC), and PVOD has been reported., Research Question: What are the characteristics of MMC-induced PVOD, and what is the prognosis for patients with MMC-induced PVOD?, Study Design and Methods: We report the clinical, functional, radiologic, and hemodynamic characteristics at diagnosis and outcomes of patients with PVOD from the French PH Registry after exposure to MMC. The results are expressed as the median (minimum-maximum)., Results: From June 2011 to December 2018, 17 incident cases of MMC-induced PVOD were identified. At diagnosis, these patients had severe clinical and functional impairment, with 12 patients having a New York Heart Association (NYHA) functional class of III or IV and a 6-min walk distance of 220 (0-465) m. Right heart catheterization confirmed severe precapillary PH with a mean pulmonary artery pressure of 38 (30-52) mm Hg, a cardiac index of 2.2 (1.5-4) L/(min × m 2 ), and pulmonary vascular resistance of 8.3 (5.1-14.5) Wood units. The diffusing capacity of the lungs for carbon monoxide was markedly decreased at 31% (20%-51%) of the theoretical values associated with severe hypoxemia. MMC was withdrawn for all patients, and 14 patients received specific pulmonary arterial hypertension (PAH) therapies. Among these patients, mild but statistically insignificant improvements were observed in NYHA functional class (P = .10), 6-min walk distance (P = .09), and pulmonary vascular resistance (-4.7 Wood units; P = .052) at reassessment (median delay of 4.8 months). Three patients experienced pulmonary edema requiring the cessation or reduction of PAH treatment. The median overall survival was 20 months, and the 6-, 12-, and 24-month survival rates were 76%, 58%, and 18%, respectively., Interpretation: PVOD after MMC treatment is a rare but life-threatening complication associated with a poor prognosis despite MMC withdrawal and PAH-specific therapy., (Copyright © 2020 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Background: The role of decreased pulmonary arterial (PA) compliance (C), equivalent to increased PA stiffness (1/C), as a critical determinant of right ventricular dysfunction and prognosis has been emphasized in pulmonary arterial hypertension (PAH)., Methods: This study retrospectively reviewed all incident patients diagnosed with idiopathic PAH according to right heart catheterization who were enrolled in the French Pulmonary Arterial Hypertension Network registry between 2006 and 2016 and who had complete baseline data allowing calculation of stiffness (PA pulse pressure/stroke volume index)., Results: In the 719 patients included (median age: 66 years; 53.7% female), PA stiffness was 1.49 mm Hg × m 2 /mL (interquartile ratio: 1.08-2.04 mm Hg × m 2 /mL). Stiffness was related to mean pulmonary artery pressure (mPAP) (r 2  = 0.33) and heart rate (r 2  = 0.15) but not to age or sex. Higher PA stiffness and higher pulmonary vascular resistance (PVR) were documented in high-risk vs low-risk patients, as defined according to the European Society of Cardiology/European Respiratory Society guidelines. The dispersion of the PVR × C product was as variable as patient age and mPAP, and C could not be estimated on the basis of PVR alone (95% limits of agreement of the bias: -50% to 54%). Although transplant-free survival differed across PA stiffness quartiles (P = .04), stiffness was not an independent predictor of long-term outcome (median follow-up duration: 2.43 years)., Conclusions: In incident idiopathic PAH, PA stiffness was related to mPAP and heart rate, and this finding outperformed the potential influences of age and sex. Baseline PA stiffness did not independently predict outcome. The great dispersion of the PVR × C product implied that PVR and PA stiffness were differently affected by the disease process., (Copyright © 2018 American College of Chest Physicians. All rights reserved.)

Background: Inflammation may contribute to the pathobiology of pulmonary arterial hypertension (PAH). Deciphering the PAH fingerprint on the inflammation orchestrated by dendritic cells (DCs) and T cells, key driver and effector cells, respectively, of the immune system, may allow the identification of immunopathologic approaches to PAH management., Methods: Using flow cytometry, we performed immunophenotyping of monocyte-derived DCs (MoDCs) and circulating lymphocytes from patients with idiopathic PAH and control subjects. With the same technique, we performed cytokine profiling of both populations following stimulation, coculture, or both. We tested the immunomodulatory effects of a glucocorticoid (dexamethasone [Dex]) on this immunophenotype and cytokine profile. Using an epigenetic approach, we confirmed the immune polarization in blood DNA of patients with PAH., Results: The profile of membrane costimulatory molecules of PAH MoDCs was similar to that of control subjects. However, PAH MoDCs retained higher levels of the T-cell activating molecules CD86 and CD40 after Dex pretreatment than did control MoDCs. This was associated with an increased expression of IL-12p40 and a reduced migration toward chemokine (C-C motif) ligand 21. Moreover, both with and without Dex, PAH MoDCs induced a higher activation and proliferation of CD4+ T cells, associated with a reduced expression of IL-4 (T helper 2 response) and a higher expression of IL-17 (T helper 17 response). Purified PAH CD4+ T cells expressed a higher level of IL-17 after activation than did those of control subjects. Lastly, there was significant hypomethylation of the IL-17 promoter in the PAH blood DNA as compared with the control blood., Conclusions: We have highlighted T helper 17 cell immune polarization in patients with PAH, as has been previously demonstrated in other chronic inflammatory and autoimmune conditions.

Background: Mutations in BMPR2 encoding bone morphogenetic protein receptor type 2 (BMPRII) is the main genetic risk factor for heritable pulmonary arterial hypertension (PAH). The suspected mechanism is considered to be a defect of BMP signaling. The BMPRII receptor exists in a short isoform without a cytoplasmic tail, which has preserved BMP signaling., Methods: This cohort study compared age at PAH diagnosis and severity between patients carrying a BMPR2 mutation affecting the cytoplasmic tail of BMPRII and affected carriers of a mutation upstream of this domain., Results: We identified 171 carriers affected with PAH with a mutated BMPR2. Twenty-three were carriers of a point mutation located on the cytoplasmic tail of BMPRII. This population was characterized by having an older age at diagnosis compared with other BMPR2 mutation carriers (43.2 ± 12.1 years and 35.7 ± 14.6 years, P = .040), a lower pulmonary vascular resistance (13.3 ± 3.5 and 17.4 ± 6.7, P = .023), and a higher proportion of acute vasodilator responders with a long-term response to calcium channel blockers (8.7% and 0%, P = .02). No statistically significant differences were observed in survival. An in vitro assay showed that mutations located in the cytoplasmic tail led to normal activation of the Smad pathway, whereas activation was abolished in the presence of mutations located in the kinase domain., Conclusions: Patients carrying a mutation affecting the cytoplasmic tail of BMPRII were characterized by an older age at diagnosis compared with other BMPR2 mutation carriers, less severe hemodynamic characteristics, and a greater chance of being a long-term responder to calcium channel blockers. Further investigations are needed to better understand the consequences of these BMPR2 mutations in BMPRII signaling pathways and their possible role in pulmonary arterial remodeling.

Pulmonary arterial hypertension (PAH) is a disorder in which mechanical obstruction of the pulmonary vascular bed is largely responsible for the rise in mean pulmonary arterial pressure, resulting in a progressive functional decline despite current available therapeutic options. The fundamental pathogenetic mechanisms underlying this disorder include pulmonary vasoconstriction, in situ thrombosis, medial hypertrophy, and intimal proliferation, leading to occlusion of the small to mid-sized pulmonary arterioles and the formation of plexiform lesions. Several predisposing or promoting mechanisms that contribute to excessive pulmonary vascular remodeling in PAH have emerged, such as altered crosstalk between cells within the vascular wall, sustained inflammation and dysimmunity, inhibition of cell death, and excessive activation of signaling pathways, in addition to the impact of systemic hormones, local growth factors, cytokines, transcription factors, and germline mutations. Although the spectrum of therapeutic options for PAH has expanded in the last 20 years, available therapies remain essentially palliative. However, over the past decade, a better understanding of new key regulators of this irreversible pulmonary vascular remodeling has been obtained. This review examines the state-of-the-art potential new targets for innovative research in PAH, focusing on (1) the crosstalk between cells within the pulmonary vascular wall, with particular attention to the role played by dysfunctional endothelial cells; (2) aberrant inflammatory and immune responses; (3) the abnormal extracellular matrix function; and (4) altered BMPRII/KCNK3 signaling systems. A better understanding of novel pathways and therapeutic targets will help in the designing of new and more effective approaches for PAH treatment.