Pulmonary arterial hypertension: from the kingdom of the near-dead to multiple clinical trial meta-analyses
Open accessAbstract
Pulmonary arterial hypertension (PAH) is a rare and severe clinical condition characterized by a progressive increase of pulmonary vascular resistance leading to right ventricular failure and premature death (Figure 1).1 Its prevalence ranges from 15 to 50 patients per million population2,3 and it affects a relatively young patient population (average age of 50 years) when compared with the more common thoracic organ diseases such as coronary artery disease and chronic obstructive lung disease. PAH in adults includes at least nine clinical subgroups with virtually identical obstructive pathologic changes (Figures 1 and 2) in the distal pulmonary arteries: idiopathic, heritable, drug- and toxin-induced, associated with, connective tissue diseases, HIV infection, portal hypertension, congenital heart disease, schistosomiasis, and chronic haemolytic anaemia.1 The exact processes that initiate the pathological changes seen in PAH are largely unknown. It is hypothesized that the interaction between genetic predisposition and environmental risk factors (Figure 1) may be involved in the initial stages of the disease. However, even the exact role of the auto-antibodies in connective tissue diseases or the viral involvement in HIV infection is unclear. It appears that a specific injury on the vessel wall of distal pulmonary arteries may initiate, in predisposed individuals, a pathobiological cascade of events which leads to a common final pathological obstructive condition (Figures 1B and C and 2). In the initial phases of these processes, the disease is asymptomatic, and detectable pathophysiological changes and symptoms limiting exercise capacity appear usually when the pathological lesions are fully developed (Figure 1). Pathological lesions in PAH patients affect the distal pulmonary arteries (<500 µm), in particular. The lesions are characterized by medial hypertrophy, intimal proliferative and fibrotic changes (concentric and/or eccentric), adventitial thickening with moderate peri-vascular inflammatory infiltrates (Figures 1B and C and 2), complex lesions (plexiform, dilated), and thrombotic lesion. The pathobiology of the distal pulmonary arteries in PAH patients is multifactorial and involves various biochemical pathways and cell types (Figure 2). Excessive vasoconstriction has been related to abnormal function or expression of potassium channels in the smooth muscle cells and to endothelial dysfunction. Endothelial dysfunction leads to chronically impaired production of vasodilator and antiproliferative agents such as nitric oxide and prostacyclin, along with over-expression of vasoconstrictor and proliferative substances such as thromboxane A2 and endothelin. Many of these abnormalities both elevate vascular tone and promote vascular remodelling by proliferative changes that involve several cell types, including endothelial and smooth muscle cells as well as fibroblasts. In addition, in the adventitia, there is increased production of extracellular matrix including collagen, elastin, and fibronectin and of matrix-bound smooth muscle cell mitogens, such as basic fibroblast growth factor. Other matrix metalloproteases can stimulate the production of tenascin, a smooth muscle cell mitogenic cofactor. Several additional growth factors including vascular endothelial growth factor, platelet-derived growth factor, insulin-like growth factor-1, and epidermal growth factor have been implicated in the development of remodelling and all have been reported to be increased (the molecule and/or the specific receptors) in the lung and/or in the blood of PAH patients. Reduced plasma levels of other vasodilator and antiproliferative substances such as vasoactive intestinal peptide have also been demonstrated. Angiopoietin-1, an angiogenic factor essential for vascular lung development, seems to be up-regulated in cases of PAH correlating directly with the severity of the disease. Receptors of the bone morphogenetic protein pathway, involved in cellular proliferation and apoptosis, are down-regulated and/or malfunctioning in the lung vasculature of both heritable and acquired PAH. Inflammatory cells, cyto- and chemokines, and platelets (through the serotonin pathway) may also play a significant role in PAH. Prothrombotic abnormalities have been demonstrated in PAH patients and thrombi are present in both the small distal pulmonary arteries and in proximal elastic pulmonary arteries. Schematic representation of pathogenesis, pathology, pathophysiology, and symptoms in pulmonary arterial hypertension. (A) Normal small distal pulmonary artery: the thin wall is constituted by a single elastic lamina and a thin layer of smooth muscle cells; a large lumen with red blood cells is also shown. (B) Distal pulmonary artery in pulmonary arterial hypertension: increased thickness of the media due to hypertrophy and hyperplasia of smooth muscle cells and moderate lumen reduction are present. This picture may represent an initial phase o
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
All types of PH develop via an early, common vasculopathy driven by disproportionate pulmonary vasoconstriction and dramatic remodeling of the endothelium and vessel wall.
“Pathologically, all types of PH develop via an early, common vasculopathy driven by disproportionate pulmonary vasoconstriction and dramatic remodeling of the endothelium and vessel wall[5,26,27].”
From Enterosalivary nitrate metabolism and the microbiome: Intersection of microbial metabolism, nitric oxide and diet in cardiac and pulmonary vascular health (2017) · cites this paper as [26]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Guidelines for the diagnosis and treatment of pulmonary hypertension
Galiè, N., Hoeper, M. M., Humbert, M. J. C., Torbicki, A., Vachiéry, J., Barberà, J. A., Beghetti, M., Corris, P. A., Gaine, S., Gibbs, J. S. R., et al. (2009) · European Heart Journal · doi:10.1093/eurheartj/ehp297 · Cited by 3,841 · see citing works
Survival in Patients with Primary Pulmonary Hypertension
D’Alonzo, G. E., Barst, R. J., Ayres, S. M., Bergofsky, E. H., Brundage, B. H., Detre, K. M., Fishman, A. P., Goldring, R. M., Groves, B. Μ., Kernis, J. T., et al. (1991) · Annals of Internal Medicine · doi:10.7326/0003-4819-115-5-343 · Cited by 3,488 · see citing works
Barst, R. J., Rubin, L. J., Long, W. A., McGoon, M. D., Rich, S., Badesch, D. B., Groves, B. Μ., Tapson, V. F., Bourge, R. C., Brundage, B. H., et al. (1996) · New England Journal of Medicine · doi:10.1056/nejm199602013340504 · Cited by 2,688 · see citing works
Sildenafil Citrate Therapy for Pulmonary Arterial Hypertension
Galiè, N., Ghofrani, H. A., Torbicki, A., Barst, R. J., Rubin, L. J., Badesch, D. B., Fleming, T. R., Parpia, T., Burgess, G., Branzi, A., et al. (2005) · New England Journal of Medicine · doi:10.1056/nejmoa050010 · Cited by 2,466 · see citing works
Pulmonary Arterial Hypertension in France
Humbert, M. J. C., Sitbon, O., Chaouat, A., Bertocchi, M., Habib, G., Gressin, V., Yaïci, A., Weitzenblum, E., Cordier, J.-F., Chabot, F., et al. (2006) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/rccm.200510-1668oc · Cited by 1,994 · see citing works
Inhaled Iloprost for Severe Pulmonary Hypertension
Olschewski, H., Simonneau, G., Galiè, N., HIGENBOTTAM, T. W., Naeije, R., Rubin, L. J., Nikkho, S. M., Speich, R., Hoeper, M. M., Behr, J., et al. (2002) · New England Journal of Medicine · doi:10.1056/nejmoa020204 · Cited by 1,778 · see citing works
Self-citationChannick, R. N., Simonneau, G., Sitbon, O., Robbins, I. M., Frost, A., Tapson, V. F., Badesch, D. B., Roux, S., Rainisio, M., Bodin, F., et al. (2001) · The Lancet · doi:10.1016/s0140-6736(01)06250-x · Cited by 1,529 · see citing works
Tadalafil Therapy for Pulmonary Arterial Hypertension
Galiè, N., Brundage, B. H., Ghofrani, H. A., Oudiz, R. J., Simonneau, G., Safdar, Z., Shapiro, S., White, R. J., Chan, M., Beardsworth, A., et al. (2009) · Circulation · doi:10.1161/circulationaha.108.839274 · Cited by 1,096 · see citing works
Ambrisentan for the Treatment of Pulmonary Arterial Hypertension
Galiè, N., Olschewski, H., Oudiz, R. J., Torres, F., Frost, A., Ghofrani, H. A., Badesch, D. B., McGoon, M. D., McLaughlin, V. V., Roecker, E. B., et al. (2008) · Circulation · doi:10.1161/circulationaha.107.742510 · Cited by 1,077 · see citing works
Galiè, N., Rubin, L., Hoeper, M. M., Jansa, P., Al‐Hiti, H., Meyer, G. M. B., Chiossi, E., Kusic‐Pajic, A., & Simonneau, G. (2008) · The Lancet · doi:10.1016/s0140-6736(08)60919-8 · Cited by 917 · see citing works
Cellular and Molecular Basis of Pulmonary Arterial Hypertension
Morrell, N. W., Adnot, S., Archer, S. L., Dupuis, J., Jones, P. L., MacLean, M. R., McMurtry, I. F., Stenmark, K. R., Thistlethwaite, P. A., Weißmann, N., et al. (2009) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2009.04.018 · Cited by 818 · see citing works
An epidemiological study of pulmonary arterial hypertension
Peacock, A., Murphy, N. F., McMurray, J. J. V., Caballero, L., & Stewart, S. (2007) · European Respiratory Journal · doi:10.1183/09031936.00092306 · Cited by 793 · see citing works
Inflammation, Growth Factors, and Pulmonary Vascular Remodeling
Hassoun, P. M., Mouthon, L., Barberà, J. A., Eddahibi, S., Flores, S. C., Grimminger, F., Jones, P. L., Maitland, M. L., Michelakis, E. D., Morrell, N. W., et al. (2009) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2009.04.006 · Cited by 711 · see citing works
Pathologic assessment of vasculopathies in pulmonary hypertension
Pietra, G. G., Capron, F., Stewart, S., et al. (2004) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2004.02.033 · Cited by 710 · see citing works
A meta-analysis of randomized controlled trials in pulmonary arterial hypertension
Galiè, N., Mañes, A., Negro, L., Palazzini, M., Reggiani, M. L. B., & Branzi, A. (2008) · European Heart Journal · doi:10.1093/eurheartj/ehp022 · Cited by 648 · see citing works
Self-citationCombination of bosentan with epoprostenol in pulmonary arterial hypertension: BREATHE-2
Humbert, M. J. C., Barst, R. J., Robbins, I. M., Channick, R. N., Galiè, N., Boonstra, A., Rubin, L. J., Horn, E. M., Manes, A., & Simonneau, G. (2004) · European Respiratory Journal · doi:10.1183/09031936.04.00028404 · Cited by 638 · see citing works
Self-citationRandomized Study of Adding Inhaled Iloprost to Existing Bosentan in Pulmonary Arterial Hypertension
McLaughlin, V. V., Oudiz, R. J., Frost, A., Tapson, V. F., Murali, S., Channick, R. N., Badesch, D. B., Barst, R. J., Hsu, H. H., & Rubin, L. J. (2006) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/rccm.200603-358oc · Cited by 624 · see citing works
Genetics and Genomics of Pulmonary Arterial Hypertension
Soubrier, F., Chung, W. K., Machado, R. D., Grünig, E., Aldred, M. A., Geraci, M. W., Loyd, J. E., Elliott, C. G., Trembath, R. C., Newman, J. H., et al. (2013) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2013.10.035 · Cited by 614 · see citing works
Simonneau, G., Rubin, L. J., Galiè, N., Barst, R. J., Fleming, T. R., Frost, A. E., Engel, P. J., Kramer, M. R., Burgess, G., Collings, L., et al. (2008) · Annals of Internal Medicine · doi:10.7326/0003-4819-149-8-200810210-00004 · Cited by 613 · see citing works
Addition of Inhaled Treprostinil to Oral Therapy for Pulmonary Arterial Hypertension
McLaughlin, V. V., Benza, R. L., Rubin, L. J., Channick, R. N., Voswinckel, R., Tapson, V. F., Robbins, I. M., Olschewski, H., Rubenfire, M., & Seeger, W. (2010) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2010.01.027 · Cited by 564 · see citing works
Genetics and Genomics of Pulmonary Arterial Hypertension
Machado, R. D., Eickelberg, O., Elliott, C. G., et al. (2009) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2009.04.015 · Cited by 371 · see citing works
Development and Pathology of Pulmonary Hypertension
Tuder, R. M., Abman, S. H., Braun, T. W., et al. (2009) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2009.04.009 · Cited by 271 · see citing works
End Points and Clinical Trial Design in Pulmonary Arterial Hypertension
McLaughlin, V. V., Badesch, D. B., Delcroix, M., Fleming, T. R., Gaine, S., Galiè, N., Gibbs, J. S. R., Kim, N. H., Oudiz, R. J., Peacock, A. J., et al. (2009) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2009.04.007 · Cited by 249 · see citing works
Macchia, A., Marchioli, R., Marfisi, R., et al. (2007) · American Heart Journal · doi:10.1016/j.ahj.2007.02.037 · Cited by 233 · see citing works
Macchia, A., Marchioli, R., Tognoni, G., et al. (2010) · American Heart Journal · doi:10.1016/j.ahj.2009.11.028 · Cited by 114 · see citing works
End-points and clinical trial design in pulmonary arterial hypertension: have we made progress?
Peacock, A. J., Naeije, R., Galiè, N., et al. (2009) · European Respiratory Journal · doi:10.1183/09031936.00107108 · Cited by 53 · see citing works
Robin, E. D. (1987) · CHEST Journal · doi:10.1378/chest.92.2.330 · Cited by 31 · see citing works
Pharmacological impact on right ventricular remodelling in pulmonary arterial hypertension
Galiè, N., Manes, A., Palazzini, M., et al. (2007) · European Heart Journal Supplements · doi:10.1093/eurheartj/sum055 · Cited by 17 · see citing works
Self-citation
Flagged first, then by citations
Cited by
Sorted by citations
2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension
Galiè, N., Humbert, M., Vachiery, J.-L., Gibbs, S., Lang, I., Torbicki, A., Simonneau, G., Peacock, A., Vonk Noordegraaf, A., Beghetti, M., et al. (2016) · European Heart Journal · doi:10.1093/eurheartj/ehv317 · Cited by 6,931 · see citing works
Risk stratification and medical therapy of pulmonary arterial hypertension
Galiè, N., Channick, R. N., Frantz, R. P., Grünig, E., Jing, Z. C., Moiseeva, O., Preston, I. R., Pulido, T., Safdar, Z., Tamura, Y., et al. (2019) · European Respiratory Journal · doi:10.1183/13993003.01889-2018 · Cited by 819 · see citing works
Koch, C. D., Gladwin, M. T., Freeman, B. A., Lundberg, J. O., Weitzberg, E., & Morris, A. (2017) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2016.12.015 · Cited by 186 · see citing works
Pathways in pulmonary arterial hypertension: the future is here
Sitbon, O., & Morrell, N. (2012) · European Respiratory Review · doi:10.1183/09059180.00004812 · Cited by 117 · see citing works
- Authors
- Galie, N., Palazzini, M., & Manes, A.
- Affiliations
- University of Bologna (IT)
- Venue
- European Heart Journal
- Publisher
- Oxford University Press (OUP)
- Published
- 2010-05-26
- Volume
- 31
- Issue
- 17
- Pages
- 2080-2086
- ISSN
- 0195-668X (ISSN-L)
- 1522-9645
- PMC
- PMC2930983
- OpenAlex
- W2169337689
- Cited by
- 175
- References
- 28
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 7 · 2023: 5 · 2022: 12 · 2021: 8 · 2020: 12 · 2019: 12 · 2018: 13 · 2017: 25 · 2016: 21 · 2015: 11 · 2014: 9 · 2013: 13 · 2012: 9
- FWCI
- 9.07
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- other-oa
- Locations
- European Heart Journal (publishedVersion, other-oa)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- Archivio istituzionale della ricerca (Alma Mater Studiorum Università di Bologna) (submittedVersion)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Pulmonary Hypertension Research and Treatments
- Health Sciences › Medicine › Genetics › Vascular Anomalies and Treatments
- Health Sciences › Medicine › Pathology and Forensic Medicine › Systemic Sclerosis and Related Diseases
- Keywords
- pulmonary arterial hypertension, pulmonary vascular resistance, right heart failure, idiopathic pulmonary arterial hypertension, connective tissue disease-associated pulmonary arterial hypertension, endothelial dysfunction, vasoconstriction, pulmonary embolism, pulmonary vasodilator therapy, pulmonary vascular remodeling
- MeSH terms
- Antihypertensive Agents, Drug Combinations, Forecasting, Humans, Hypertension, Pulmonary, Meta-Analysis as Topic, Randomized Controlled Trials as Topic, Treatment Outcome
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
