Pulmonary hypertension

According to WHO classification there are 5 groups of PH, where Group I (pulmonary arterial hypertension) is further subdivided into Group I' and Group I'' classes. The WHO classification system in 2022 (with adaptations from the more recent ESC/ERS guidelines shown in italics) can be summarized as follows:

WHO Group I – Pulmonary arterial hypertension (PAH)

• Caused by narrowing and thickening of tiny arteries of the lung{{cite web | title = Learn About Pulmonary Arterial Hypertension | work = PAH | publisher = American Lung Association | url = https://www.lung.org/lung-health-diseases/lung-disease-lookup/pulmonary-arterial-hypertension/learn-about-pulmonary-arterial-hypertension | access-date = 2023-08-01}}
• Idiopathic in most cases (heritable in some cases)
• Heritable (BMPR2, ALK1, SMAD9, caveolin 1, KCNK3 mutations)
• Drug- and toxin-induced (e.g., methamphetamine, amphetamine, or cocaine use{{cite journal | vauthors = Kolaitis NA, Zamanian RT, de Jesus Perez VA, Badesch DB, Benza RL, Burger CD, Chakinala MM, Elwing JM, Feldman J, Lammi MR, Mathai SC, McConnell JW, Presberg KW, Robinson JC, Sager J, Shlobin OA, Simon MA, Kawut SM, Glidden DV, Singer JP, De Marco T | display-authors = 6 | title = Clinical Differences and Outcomes between Methamphetamine-associated and Idiopathic Pulmonary Arterial Hypertension in the Pulmonary Hypertension Association Registry | journal = Annals of the American Thoracic Society | volume = 18 | issue = 4 | pages = 613–622 | date = April 2021 | pmid = 33064950 | pmc = 8174020 | doi = 10.1513/AnnalsATS.202007-774OC | doi-access = free }} )
• Associated conditions:Connective tissue disease, HIV infection, Portal hypertension, Congenital heart diseases, Schistosomiasis

WHO Group I' – Pulmonary veno-occlusive disease (PVOD), pulmonary capillary hemangiomatosis (PCH)

• Idiopathic
• Heritable (EIF2AK4 mutations)
• Drugs, toxins and radiation-induced
• Associated conditions:connective tissue disease, HIV infection

WHO Group I" – Persistent pulmonary hypertension of the newborn

WHO Group II – Pulmonary hypertension secondary to left heart disease

• Left ventricular systolic dysfunction
• Left ventricular diastolic dysfunction
• Valvular heart disease
• Congenital/acquired left heart inflow/outflow tract obstruction and congenital cardiomyopathy
• Congenital/acquired pulmonary venous stenosis

WHO Group III – Pulmonary hypertension due to lung disease, chronic hypoxia

• Chronic obstructive pulmonary disease (COPD)
• Interstitial lung disease
• Mixed restrictive and obstructive pattern pulmonary diseases
• Sleep-disordered breathing
• Alveolar hypoventilation disorders
• Chronic exposure to high altitude
• Developmental abnormalities

WHO Group IV – Chronic arterial obstruction

• Chronic thromboembolic pulmonary hypertension (CTEPH)
• Other pulmonary artery obstructions
• Angiosarcoma or other tumor within the blood vessels
• Arteritis
• Congenital pulmonary artery stenosis
• Parasitic infection (hydatidosis)

WHO Group V – Pulmonary hypertension with unclear or multifactorial mechanisms

• Hematologic diseases: chronic hemolytic anemia (including sickle cell disease)
• Systemic diseases: sarcoidosis, pulmonary Langerhans cell histiocytosis: lymphangioleiomyomatosis, neurofibromatosis, vasculitis
• Metabolic disorders: glycogen storage disease, Gaucher disease, thyroid diseases
• Others: pulmonary tumoral thrombotic microangiopathy, fibrosing mediastinitis, chronic kidney failure, segmental pulmonary hypertension (pulmonary hypertension restricted to one or more lobes of the lungs)

The symptoms of pulmonary hypertension include the following:{{Cite web|title = What Are the Signs and Symptoms of Pulmonary Hypertension? – NHLBI, NIH|url = http://www.nhlbi.nih.gov/health/health-topics/topics/pah/signs|website = www.nhlbi.nih.gov|access-date = 2015-12-30|url-status = live|archive-url = https://web.archive.org/web/20160105180434/http://www.nhlbi.nih.gov/health/health-topics/topics/pah/signs|archive-date = 2016-01-05}}{{cite journal | vauthors = Galiè N, Humbert M, Vachiery JL, Gibbs S, Lang I, Torbicki A, Simonneau G, Peacock A, Vonk Noordegraaf A, Beghetti M, Ghofrani A, Gomez Sanchez MA, Hansmann G, Klepetko W, Lancellotti P, Matucci M, McDonagh T, Pierard LA, Trindade PT, Zompatori M, Hoeper M | display-authors = 6 | title = 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT) | journal = European Heart Journal | volume = 37 | issue = 1 | pages = 67–119 | date = January 2016 | pmid = 26320113 | doi = 10.1093/eurheartj/ehv317 | collaboration = ESC Scientific Document Group | doi-access = free }}{{cite journal | vauthors = McLaughlin VV, Archer SL, Badesch DB, Barst RJ, Farber HW, Lindner JR, Mathier MA, McGoon MD, Park MH, Rosenson RS, Rubin LJ, Tapson VF, Varga J | display-authors = 6 | title = ACCF/AHA 2009 expert consensus document on pulmonary hypertension a report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents and the American Heart Association developed in collaboration with the American College of Chest Physicians; American Thoracic Society, Inc.; and the Pulmonary Hypertension Association | journal = Journal of the American College of Cardiology | volume = 53 | issue = 17 | pages = 1573–1619 | date = April 2009 | pmid = 19389575 | doi = 10.1016/j.jacc.2009.01.004 | doi-access = free }}

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• Shortness of breath
• Fatigue
• Chest pain
• Palpitations (heartbeat rate increased)
• Right-sided abdominal pain
• Poor appetite
• Lightheadedness
• Fainting
• Swelling (legs/ankles)
• Cyanosis

}}

Less common signs/symptoms include non-productive cough and exercise-induced nausea and vomiting. Coughing up of blood may occur in some patients, particularly those with specific subtypes of pulmonary hypertension such as heritable pulmonary arterial hypertension, Eisenmenger syndrome and chronic thromboembolic pulmonary hypertension.{{cite journal | vauthors = Diller GP, Gatzoulis MA | title = Pulmonary vascular disease in adults with congenital heart disease | journal = Circulation | volume = 115 | issue = 8 | pages = 1039–1050 | date = February 2007 | pmid = 17325254 | doi = 10.1161/CIRCULATIONAHA.105.592386 | doi-access = free }} Pulmonary venous hypertension typically presents with shortness of breath while lying flat or sleeping (orthopnea or paroxysmal nocturnal dyspnea), while pulmonary arterial hypertension (PAH) typically does not.{{cite journal | vauthors = Fang JC, DeMarco T, Givertz MM, Borlaug BA, Lewis GD, Rame JE, Gomberg-Maitland M, Murali S, Frantz RP, McGlothlin D, Horn EM, Benza RL | display-authors = 6 | title = World Health Organization Pulmonary Hypertension group 2: pulmonary hypertension due to left heart disease in the adult--a summary statement from the Pulmonary Hypertension Council of the International Society for Heart and Lung Transplantation | journal = The Journal of Heart and Lung Transplantation | volume = 31 | issue = 9 | pages = 913–933 | date = September 2012 | pmid = 22884380 | doi = 10.1016/j.healun.2012.06.002 | doi-access = free }}

Other typical signs of pulmonary hypertension include an accentuated pulmonary component of the second heart sound, a right ventricular third heart sound, and parasternal heave indicating a hypertrophied right ventricle. Signs of systemic congestion resulting from right-sided heart failure include jugular venous distension, ascites, and hepatojugular reflux.{{Cite book|title = Evidence-Based Cardiology|url = https://books.google.com/books?id=tjgJzBWDneYC|publisher = John Wiley & Sons|date = 2011|page = 70.3 (figure)|isbn = 978-1-4443-5945-9| vauthors = Yusuf S, Cairns J, Camm J, Fallen EL, Gersh BJ |url-status = live|archive-url = https://web.archive.org/web/20160430061345/https://books.google.com/books?id=tjgJzBWDneYC|archive-date = 2016-04-30}} Evidence of tricuspid insufficiency and pulmonic regurgitation is also sought and, if present, is consistent with the presence of pulmonary hypertension.{{Cite web|title = Primary Pulmonary Hypertension Clinical Presentation: History, Physical Examination, Complications|url = http://emedicine.medscape.com/article/301450-clinical#b2|website = emedicine.medscape.com|access-date = 2015-12-30|url-status = live|archive-url = https://web.archive.org/web/20151101111008/http://emedicine.medscape.com/article/301450-clinical#b2|archive-date = 2015-11-01}}

Pulmonary hypertension is a pathophysiologic condition with many possible causes. Indeed, this condition frequently accompanies severe heart or lung conditions. A 1973 World Health Organization meeting was the first attempt to classify pulmonary hypertension by its cause, and a distinction was made between primary PH (resulting from a disease of the pulmonary arteries) and secondary PH (resulting secondary to other, non-vascular causes). Further, primary PH was divided into the "arterial plexiform", "veno-occlusive" and "thromboembolic" forms.{{cite book |vauthors=Hatano S, Strasser R | title=Primary pulmonary hypertension | publisher=World Health Organization | location=Geneva | year=1975}} In 1998, a second conference at Évian-les-Bains addressed the causes of secondary PH.{{cite book |vauthors=Rich S, Rubin LJ, Abenhail L, etal | title=Executive summary from the World Symposium on Primary Pulmonary Hypertension (Evian, France, September 6–10, 1998) | publisher=The World Health Organization | location=Geneva | year=1998 |url=https://www.who.int/ncd/cvd/pph.html | archive-url=https://web.archive.org/web/20020408173726/http://www.who.int/ncd/cvd/pph.html | archive-date=April 8, 2002}} Subsequent third,{{cite journal | vauthors = Simonneau G, Galiè N, Rubin LJ, Langleben D, Seeger W, Domenighetti G, Gibbs S, Lebrec D, Speich R, Beghetti M, Rich S, Fishman A | display-authors = 6 | title = Clinical classification of pulmonary hypertension | journal = Journal of the American College of Cardiology | volume = 43 | issue = 12 Suppl S | pages = 5S–12S | date = June 2004 | pmid = 15194173 | doi = 10.1016/j.jacc.2004.02.037 | doi-access = free }} fourth,{{cite journal | vauthors = Simonneau G, Robbins IM, Beghetti M, Channick RN, Delcroix M, Denton CP, Elliott CG, Gaine SP, Gladwin MT, Jing ZC, Krowka MJ, Langleben D, Nakanishi N, Souza R | display-authors = 6 | title = Updated clinical classification of pulmonary hypertension | journal = Journal of the American College of Cardiology | volume = 54 | issue = 1 Suppl | pages = S43–S54 | date = June 2009 | pmid = 19555858 | doi = 10.1016/j.jacc.2009.04.012 | doi-access = free }} and fifth (2013){{cite journal | vauthors = Simonneau G, Gatzoulis MA, Adatia I, Celermajer D, Denton C, Ghofrani A, Gomez Sanchez MA, Krishna Kumar R, Landzberg M, Machado RF, Olschewski H, Robbins IM, Souza R | display-authors = 6 | title = Updated clinical classification of pulmonary hypertension | journal = Journal of the American College of Cardiology | volume = 62 | issue = 25 Suppl | pages = D34–D41 | date = December 2013 | pmid = 24355639 | doi = 10.1016/j.jacc.2013.10.029 | doi-access = free }} World Symposia on PAH have further defined the classification of PH. The classification continues to evolve based on improved understanding of the disease mechanisms.{{citation needed|date=December 2018}}

Most recently in 2022, the WHO guidelines were updated by the European Society of Cardiology (ESC) and European Respiratory Society (ERS). These guidelines are endorsed by the International Society for Heart and Lung Transplantation, and provide the current framework for understanding and treatment of pulmonary hypertension.

Mutations in several genes have been associated with this condition{{cite journal | vauthors = Rabinovitch M | title = Molecular pathogenesis of pulmonary arterial hypertension | journal = The Journal of Clinical Investigation | volume = 122 | issue = 12 | pages = 4306–4313 | date = December 2012 | pmid = 23202738 | pmc = 3533531 | doi = 10.1172/JCI60658 }}{{cite journal | vauthors = Hadinnapola C, Bleda M, Haimel M, Screaton N, Swift A, Dorfmüller P, Preston SD, Southwood M, Hernandez-Sanchez J, Martin J, Treacy C, Yates K, Bogaard H, Church C, Coghlan G, Condliffe R, Corris PA, Gibbs S, Girerd B, Holden S, Humbert M, Kiely DG, Lawrie A, Machado R, MacKenzie Ross R, Moledina S, Montani D, Newnham M, Peacock A, Pepke-Zaba J, Rayner-Matthews P, Shamardina O, Soubrier F, Southgate L, Suntharalingam J, Toshner M, Trembath R, Vonk Noordegraaf A, Wilkins MR, Wort SJ, Wharton J, Gräf S, Morrell NW | display-authors = 6 | title = Phenotypic Characterization of EIF2AK4 Mutation Carriers in a Large Cohort of Patients Diagnosed Clinically With Pulmonary Arterial Hypertension | journal = Circulation | volume = 136 | issue = 21 | pages = 2022–2033 | date = November 2017 | pmid = 28972005 | pmc = 5700414 | doi = 10.1161/CIRCULATIONAHA.117.028351 }} these include bone morphogenetic protein receptor type 2 (BMPR2) and eukaryotic translation initiation factor 2 alpha kinase 4 gene (EIF2AK4). 80% of familial pulmonary arterial hypertension and 20% of sporadic variants have mutations in BMPR2.{{cite journal |last1=Hassoun |first1=Paul M. |title=Pulmonary Arterial Hypertension |journal=New England Journal of Medicine |date=16 December 2021 |volume=385 |issue=25 |pages=2361–2376 |doi=10.1056/NEJMra2000348|pmid=34910865 }} BMPR2 is involved in endothelial proliferation and remodeling. Other mutations associated with PAH include ACVRL1 (which encodes activin receptor–like kinase 1) and ENG encoding endoglin, two proteins which also participate in BMPR2 signaling. The SMAD transcription factor family, including SMAD1, SMAD4, and SMAD9 are involved in signaling pathways downstream from BMPR2 and are also implicated in the development of pulmonary arterial hypertension.

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File:Pulmonary hypertensive arteriopathy (4348170715).jpg showing arteries in pulmonary hypertensive with marked thickening of the walls]]

The pathogenesis of pulmonary arterial hypertension (WHO Group I) involves the narrowing of blood vessels connected to and within the lungs. This makes it harder for the heart to pump blood through the lungs, as it is much harder to make water flow through a narrow pipe as opposed to a wide one. Over time, the affected blood vessels become stiffer and thicker, in a process known as fibrosis. The mechanisms involved in this narrowing process include vasoconstriction, thrombosis, and vascular remodeling (excessive cellular proliferation, fibrosis, and reduced apoptosis/programmed cell death in the vessel walls, caused by inflammation, disordered metabolism and dysregulation of certain growth factors).{{cite journal | vauthors = Jacob AS, Nielsen DH, Gianelly RE | title = Fatal ventricular fibrillation following verapamil in Wolff-Parkinson-White syndrome with atrial fibrillation | journal = Annals of Emergency Medicine | volume = 14 | issue = 2 | pages = 159–160 | date = February 1985 | pmid = 3970402 | pmc = 3970402 | doi = 10.1016/j.jacc.2013.10.025 }}{{cite journal | vauthors = Vonk-Noordegraaf A, Haddad F, Chin KM, Forfia PR, Kawut SM, Lumens J, Naeije R, Newman J, Oudiz RJ, Provencher S, Torbicki A, Voelkel NF, Hassoun PM | display-authors = 6 | title = Right heart adaptation to pulmonary arterial hypertension: physiology and pathobiology | journal = Journal of the American College of Cardiology | volume = 62 | issue = 25 Suppl | pages = D22–D33 | date = December 2013 | pmid = 24355638 | doi = 10.1016/j.jacc.2013.10.027 | doi-access = free }} This further increases the blood pressure within the lungs and impairs their blood flow. In common with other types of pulmonary hypertension, these changes result in an increased workload for the right side of the heart.{{cite journal | vauthors = Galiè N, Hoeper MM, Humbert M, Torbicki A, Vachiery JL, Barbera JA, Beghetti M, Corris P, Gaine S, Gibbs JS, Gomez-Sanchez MA, Jondeau G, Klepetko W, Opitz C, Peacock A, Rubin L, Zellweger M, Simonneau G | display-authors = 6 | title = Guidelines for the diagnosis and treatment of pulmonary hypertension | journal = The European Respiratory Journal | volume = 34 | issue = 6 | pages = 1219–1263 | date = December 2009 | pmid = 19749199 | doi = 10.1183/09031936.00139009 | doi-access = free }} The right ventricle is normally part of a low pressure system, with systolic ventricular pressures that are lower than those that the left ventricle normally encounters. As such, the right ventricle cannot cope as well with higher pressures, and although right ventricular adaptations (hypertrophy and increased contractility of the heart muscle) initially help to preserve stroke volume, ultimately these compensatory mechanisms are insufficient; the right ventricular muscle cannot get enough oxygen to meet its needs and right heart failure follows. As the blood flowing through the lungs decreases, the left side of the heart receives less blood. This blood may also carry less oxygen than normal. Therefore, it becomes harder and harder for the left side of the heart to supply sufficient oxygen to the rest of the body, especially during physical activity.{{cite journal | vauthors = Yuan JX, Rubin LJ | title = Pathogenesis of pulmonary arterial hypertension: the need for multiple hits | journal = Circulation | volume = 111 | issue = 5 | pages = 534–538 | date = February 2005 | pmid = 15699271 | doi = 10.1161/01.CIR.0000156326.48823.55 | doi-access = free }}{{cite journal | vauthors = Tuder RM, Marecki JC, Richter A, Fijalkowska I, Flores S | title = Pathology of pulmonary hypertension | journal = Clinics in Chest Medicine | volume = 28 | issue = 1 | pages = 23–42, vii | date = March 2007 | pmid = 17338926 | pmc = 1924722 | doi = 10.1016/j.ccm.2006.11.010 }} During the end-systolic volume phase of the cardiac cycle, the Gaussian curvature and the mean curvature of right ventricular endocardial wall of PH patients was found to be significantly different as compared to controls.{{cite journal | vauthors = Bordones-Crom A, Patnaik SS, Menon PG, Murali S, Finol E | title = Morphological Analysis of the Right Ventricular Endocardial Wall in Pulmonary Hypertension | journal = Journal of Biomechanical Engineering | volume = 143 | issue = 7 | date = July 2021 | pmid = 33704381 | doi = 10.1115/1.4050457 | s2cid = 232193407 }}

In PVOD (WHO Group I'), pulmonary blood vessel narrowing occurs preferentially (though not exclusively) in post-capillary venous blood vessels.{{cite journal | vauthors = Montani D, Price LC, Dorfmuller P, Achouh L, Jaïs X, Yaïci A, Sitbon O, Musset D, Simonneau G, Humbert M | display-authors = 6 | title = Pulmonary veno-occlusive disease | journal = The European Respiratory Journal | volume = 33 | issue = 1 | pages = 189–200 | date = January 2009 | pmid = 19118230 | doi = 10.1183/09031936.00090608 | doi-access = free }} PVOD shares several characteristics with PAH, but there are also some important differences, for example differences in prognosis and response to medical therapy.{{cite journal |last1=Montani |first1=David |last2=Lau |first2=Edmund M. |last3=Dorfmüller |first3=Peter |last4=Girerd |first4=Barbara |last5=Jaïs |first5=Xavier |last6=Savale |first6=Laurent |last7=Perros |first7=Frederic |last8=Nossent |first8=Esther |last9=Garcia |first9=Gilles |last10=Parent |first10=Florence |last11=Fadel |first11=Elie |last12=Soubrier |first12=Florent |last13=Sitbon |first13=Olivier |last14=Simonneau |first14=Gérald |last15=Humbert |first15=Marc |title=Pulmonary veno-occlusive disease |journal=European Respiratory Journal |date=May 2016 |volume=47 |issue=5 |pages=1518–1534 |doi=10.1183/13993003.00026-2016}}

Persistent pulmonary hypertension of the newborn occurs when the circulatory system of a newborn baby fails to adapt to life outside the womb; it is characterized by high resistance to blood flow through the lungs, right-to-left cardiac shunting and severe hypoxemia.

Pathogenesis in pulmonary hypertension due to left heart disease (WHO Group II) is completely different in that constriction or damage to the pulmonary blood vessels is not the issue. Instead, the left heart fails to pump blood efficiently, leading to pooling of blood in the lungs and back pressure within the pulmonary system. This causes pulmonary edema and pleural effusions.{{cite journal | vauthors = Guazzi M, Galiè N | title = Pulmonary hypertension in left heart disease | journal = European Respiratory Review | volume = 21 | issue = 126 | pages = 338–346 | date = December 2012 | pmid = 23204122 | pmc = 9487233 | doi = 10.1183/09059180.00004612 | doi-access = free }} In the absence of pulmonary blood vessel narrowing, the increased back pressure is described as 'isolated post-capillary pulmonary hypertension' (older terms include 'passive' or 'proportionate' pulmonary hypertension or 'pulmonary venous hypertension'). However, in some patients, the raised pressure in the pulmonary vessels triggers a superimposed component of vessel narrowing, which further increases the workload of the right side of the heart. This is referred to as 'post-capillary pulmonary hypertension with a pre-capillary component' or 'combined post-capillary and pre-capillary pulmonary hypertension' (older terms include 'reactive' or 'out-of-proportion' pulmonary hypertension).{{cite journal | vauthors = Vachiéry JL, Adir Y, Barberà JA, Champion H, Coghlan JG, Cottin V, De Marco T, Galiè N, Ghio S, Gibbs JS, Martinez F, Semigran M, Simonneau G, Wells A, Seeger W | display-authors = 6 | title = Pulmonary hypertension due to left heart diseases | journal = Journal of the American College of Cardiology | volume = 62 | issue = 25 Suppl | pages = D100–D108 | date = December 2013 | pmid = 24355634 | doi = 10.1016/j.jacc.2013.10.033 | hdl-access = free | doi-access = free | hdl = 11585/534481 }}

In pulmonary hypertension due to lung diseases and/or hypoxia (WHO Group III), low levels of oxygen in the alveoli (due to respiratory disease or living at high altitude) cause constriction of the pulmonary arteries. This phenomenon is called hypoxic pulmonary vasoconstriction and it is initially a protective response to stop too much blood flowing to areas of the lung that are damaged and do not contain oxygen. When the alveolar hypoxia is widespread and prolonged, this hypoxia-mediated vasoconstriction occurs across a large portion of the pulmonary vascular bed and leads to an increase in pulmonary arterial pressure, with thickening of the pulmonary vessel walls contributing to the development of sustained pulmonary hypertension.{{cite journal | vauthors = Shanks N, Macklin J, Coles S | title = Comparison of oral erythromycin ethylsuccinate and clavulanate-potentiated amoxicillin in the treatment of acute respiratory tract infections | journal = Clinical Therapeutics | volume = 11 | issue = 6 | pages = 812–819 | year = 2009 | pmid = 2692823 | pmc = 2692823 | doi = 10.1016/j.coph.2009.02.006 }}{{cite journal | vauthors = Sommer N, Dietrich A, Schermuly RT, Ghofrani HA, Gudermann T, Schulz R, Seeger W, Grimminger F, Weissmann N | display-authors = 6 | title = Regulation of hypoxic pulmonary vasoconstriction: basic mechanisms | journal = The European Respiratory Journal | volume = 32 | issue = 6 | pages = 1639–1651 | date = December 2008 | pmid = 19043010 | doi = 10.1183/09031936.00013908 | doi-access = free }}{{cite journal | vauthors = Stenmark KR, Fagan KA, Frid MG | title = Hypoxia-induced pulmonary vascular remodeling: cellular and molecular mechanisms | journal = Circulation Research | volume = 99 | issue = 7 | pages = 675–691 | date = September 2006 | pmid = 17008597 | doi = 10.1161/01.RES.0000243584.45145.3f | doi-access = free }} Prolonged hypoxia also induces the transcription factor HIF1A, which directly activates downstream growth factor signaling that causes irreversible proliferation and remodeling of pulmonary arterial endothelial cells, leading to chronic pulmonary arterial hypertension.{{citation needed|date=August 2020}}

In chronic thromboembolic pulmonary hypertension, or CTEPH (WHO Group IV), the initiating event is thought to be blockage or narrowing of the pulmonary blood vessels with unresolved blood clots; these clots can lead to increased pressure and shear stress in the rest of the pulmonary circulation, precipitating structural changes in the vessel walls (remodeling) similar to those observed in other types of severe pulmonary hypertension. This combination of vessel occlusion and vascular remodeling once again increases the resistance to blood flow and so the pressure within the system rises.{{cite journal | vauthors = McNeil K, Dunning J | title = Chronic thromboembolic pulmonary hypertension (CTEPH) | journal = Heart | volume = 93 | issue = 9 | pages = 1152–1158 | date = September 2007 | pmid = 17699182 | pmc = 1955041 | doi = 10.1136/hrt.2004.053603 }}{{cite journal | vauthors = Hoeper MM, Mayer E, Simonneau G, Rubin LJ | title = Chronic thromboembolic pulmonary hypertension | journal = Circulation | volume = 113 | issue = 16 | pages = 2011–2020 | date = April 2006 | pmid = 16636189 | doi = 10.1161/CIRCULATIONAHA.105.602565 | doi-access = free }}

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The molecular mechanism of pulmonary arterial hypertension (PAH) is not known yet, but it is believed that the endothelial dysfunction results in a decrease in the synthesis of endothelium-derived vasodilators such as nitric oxide and prostacyclin.{{cite journal | vauthors = Budhiraja R, Tuder RM, Hassoun PM | title = Endothelial dysfunction in pulmonary hypertension | journal = Circulation | volume = 109 | issue = 2 | pages = 159–165 | date = January 2004 | pmid = 14734504 | doi = 10.1161/01.CIR.0000102381.57477.50 | doi-access = free }} Moreover, there is a stimulation of the synthesis of vasoconstrictors such as thromboxane and vascular endothelial growth factor (VEGF). These result in a severe vasoconstriction and vascular smooth muscle and adventitial hypertrophy characteristic of patients with PAH.

In normal conditions, the vascular endothelial nitric oxide synthase produces nitric oxide from L-arginine in the presence of oxygen.{{cite journal | vauthors = Förstermann U, Münzel T | title = Endothelial nitric oxide synthase in vascular disease: from marvel to menace | journal = Circulation | volume = 113 | issue = 13 | pages = 1708–1714 | date = April 2006 | pmid = 16585403 | doi = 10.1161/CIRCULATIONAHA.105.602532 | doi-access = free }}

This nitric oxide diffuses into neighboring cells (including vascular smooth muscle cells and platelets), where it increases the activity of the enzyme soluble guanylate cyclase, leading to increased formation of cyclic guanosine monophosphate (cGMP) from guanosine triphosphate (GTP).{{cite journal | vauthors = Murad F | title = Shattuck Lecture. Nitric oxide and cyclic GMP in cell signaling and drug development | journal = The New England Journal of Medicine | volume = 355 | issue = 19 | pages = 2003–2011 | date = November 2006 | pmid = 17093251 | doi = 10.1056/NEJMsa063904 | doi-access = free }} The cGMP then activates cGMP-dependent kinase or PKG (protein kinase G). Activated PKG promotes vasorelaxation (via a reduction of intracellular calcium levels), alters the expression of genes involved in smooth muscle cell contraction, migration and differentiation, and inhibits platelet activation.{{cite journal | vauthors = Francis SH, Busch JL, Corbin JD, Sibley D | title = cGMP-dependent protein kinases and cGMP phosphodiesterases in nitric oxide and cGMP action | journal = Pharmacological Reviews | volume = 62 | issue = 3 | pages = 525–563 | date = September 2010 | pmid = 20716671 | pmc = 2964902 | doi = 10.1124/pr.110.002907 }} Nitric oxide–soluble guanylate cyclase signaling also leads to anti-inflammatory effects.{{cite journal | vauthors = Zelia OP, Kovalenko FP | title = Comparative efficiency of infecting laboratory animals via intravenous and subcutaneous administration of Schistosoma mansoni cercaria | journal = Parazitologiia | volume = 20 | issue = 6 | pages = 461–465 | year = 2011 | pmid = 3103045 }}

Phosphodiesterase type 5 (PDE5), which is abundant in the pulmonary tissue, hydrolyzes the cyclic bond of cGMP. Consequently, the concentration of cGMP (and thus PKG activity) decreases.{{cite journal | vauthors = Ghofrani HA, Pepke-Zaba J, Barbera JA, Channick R, Keogh AM, Gomez-Sanchez MA, Kneussl M, Grimminger F | display-authors = 6 | title = Nitric oxide pathway and phosphodiesterase inhibitors in pulmonary arterial hypertension | journal = Journal of the American College of Cardiology | volume = 43 | issue = 12 Suppl S | pages = 68S–72S | date = June 2004 | pmid = 15194181 | doi = 10.1016/j.jacc.2004.02.031 | doi-access = free }}

Endothelin-1 is a peptide (comprising 21 amino acids) that is produced in endothelial cells. It acts on the endothelin receptors ETA and ETB in various cell types including vascular smooth muscle cells and fibroblasts, leading to vasoconstriction, hypertrophy, proliferation, inflammation, and fibrosis. It also acts on ETB receptors in endothelial cells; this leads to the release of both vasoconstrictors and vasodilators from those cells, and clears endothelin-1 from the system.{{cite journal | vauthors = McLaughlin VV, McGoon MD | title = Pulmonary arterial hypertension | journal = Circulation | volume = 114 | issue = 13 | pages = 1417–1431 | date = September 2006 | pmid = 17000921 | doi = 10.1161/CIRCULATIONAHA.104.503540 | doi-access = free }}{{cite journal | vauthors = Fonseca C, Abraham D, Renzoni EA | title = Endothelin in pulmonary fibrosis | journal = American Journal of Respiratory Cell and Molecular Biology | volume = 44 | issue = 1 | pages = 1–10 | date = January 2011 | pmid = 20448055 | doi = 10.1165/rcmb.2009-0388TR }}

Prostacyclin is synthesized from arachidonic acid in endothelial cells. In vascular smooth muscle cells, prostacyclin binds mainly to the prostaglandin I receptor. This sends a signal to increase adenylate cyclase activity, which leads to increased synthesis of cyclic adenosine monophosphate (cAMP). This in turn leads to increased cAMP-dependent protein kinase or PKA (protein kinase A) activity, ultimately promoting vasodilation and inhibiting cell proliferation. Prostacyclin signaling also leads to anti-thrombotic, anti-fibrotic, and anti-inflammatory effects. Levels of cAMP (which mediates most of the biological effects of prostacyclin) are reduced by phosphodiesterases 3 and 4.{{cite journal | pmid=2869481 | date=1986 | last1=Wood | first1=S. F. | title=Astemizole and terfenadine compared in hay fever | journal=The Practitioner | volume=230 | issue=1411 | pages=41–44 }}{{cite journal | vauthors = Gomberg-Maitland M, Olschewski H | title = Prostacyclin therapies for the treatment of pulmonary arterial hypertension | journal = The European Respiratory Journal | volume = 31 | issue = 4 | pages = 891–901 | date = April 2008 | pmid = 18378784 | doi = 10.1183/09031936.00097107 | doi-access = free }}

The vasoconstrictor thromboxane is also synthesized from arachidonic acid. In PAH, the balance is shifted away from synthesis of prostacyclin toward synthesis of thromboxane.

The three pathways described above are all targeted by currently available medical therapies for PAH. However, several other pathways have been identified that are also altered in PAH and are being investigated as potential targets for future therapies. For example, the mitochondrial enzyme pyruvate dehydrogenase kinase (PDK) is pathologically activated in PAH, causing a metabolic shift from oxidative phosphorylation to glycolysis and leading to increased cell proliferation and impaired apoptosis.{{cite journal | vauthors = Lenfant M | title = [Dihydrostreptomycin fixation on the ribosomes of E. coli] | journal = Biochimie | volume = 54 | issue = 2 | pages = 283–285 | year = 2013 | pmid = 4117578 | pmc = 4117578 | doi = 10.1016/j.jacc.2013.10.026 | doi-access = free }} Expression of vasoactive intestinal peptide, a potent vasodilator with anti-inflammatory and immune-modulatory roles, is reduced in PAH, while expression of its receptor is increased.

Plasma levels of serotonin, which promotes vasoconstriction, hypertrophy and proliferation, are increased in patients with PAH, although the role played by serotonin in the pathogenesis of PAH remains uncertain. The expression or activity of several growth factors (including platelet-derived growth factor, basic fibroblast growth factor, epidermal growth factor, and vascular endothelial growth factor) is increased and contributes to vascular remodeling in PAH. Other factors underlying the proliferative state of pulmonary vascular smooth muscle cells include OPG{{cite journal | vauthors = Lawrie A | title = The role of the osteoprotegerin/tumor necrosis factor related apoptosis-inducing ligand axis in the pathogenesis of pulmonary arterial hypertension | journal = Vascular Pharmacology | volume = 63 | issue = 3 | pages = 114–117 | date = December 2014 | pmid = 25446166 | doi = 10.1016/j.vph.2014.10.002 }} and TRAIL.{{cite journal | vauthors = Braithwaite AT, Marriott HM, Lawrie A | title = Divergent Roles for TRAIL in Lung Diseases | journal = Frontiers in Medicine | volume = 5 | page = 212 | date = 2018 | pmid = 30101145 | pmc = 6072839 | doi = 10.3389/fmed.2018.00212 | doi-access = free }} Focusing only on the pulmonary vasculature provides an incomplete picture of PAH; the ability of the right ventricle to adapt to the increased workload varies between patients and is an important determinant of survival. The molecular pathology of PAH in the right ventricle is therefore also being investigated, and recent research has shifted to consider the cardiopulmonary unit as a single system rather than two separate systems. Importantly, right ventricular remodeling is associated with increased apoptosis; this is in contrast to pulmonary vascular remodeling which involves inhibition of apoptosis.

Even though the primary cause of PAH is unknown, inflammation and oxidative stress have been shown to have a key role in vascular remodeling.{{cite journal |vauthors=Ranchoux B, Meloche J, Paulin R, Boucherat O, Provencher S, Bonnet S |title=DNA Damage and Pulmonary Hypertension |journal=Int J Mol Sci |volume=17 |issue=6 |pages=990 |date=June 2016 |pmid=27338373 |pmc=4926518 |doi=10.3390/ijms17060990 |doi-access=free}} These factors are known to cause DNA damage, and may also promote the proliferative and apoptosis-resistant phenotype that is observed in PAH vascular cells. Elevated levels of DNA damage have been reported to occur in PAH lungs and remodeled arteries, and also in animal models of PH, indicating that DNA damage likely contributes to PAH pathogenesis.

File:Phonocardiogram.jpg pulse tracing demonstrates a prominent a wave without a c or v wave being observed. The phonocardiograms (fourth left interspace and cardiac apex) show a murmur of tricuspid insufficiency and ventricular and atrial gallops.]]

File:Pulmonary artery catheter english.JPG File:Severe tricuspid regurgitation E00572 (CardioNetworks ECHOpedia).jpg

In terms of the diagnosis of pulmonary hypertension, it has five major types, and a series of tests must be performed to distinguish pulmonary arterial hypertension from venous, hypoxic, thromboembolic, or unclear multifactorial varieties. PAH is diagnosed after exclusion of other possible causes of pulmonary hypertension.

A physical examination is performed to look for typical signs of pulmonary hypertension (described above),{{Cite web|title = How Is Pulmonary Hypertension Diagnosed? – NHLBI, NIH|url = http://www.nhlbi.nih.gov/health/health-topics/topics/pah/diagnosis|website = www.nhlbi.nih.gov|access-date = 2015-12-30|url-status = live|archive-url = https://web.archive.org/web/20160105180446/http://www.nhlbi.nih.gov/health/health-topics/topics/pah/diagnosis|archive-date = 2016-01-05}} and a detailed family history is established to determine whether the disease might be heritable.{{Cite book | vauthors = Austin ED, Phillips III JA, Loyd JE | chapter = Pulmonary arterial hypertension| chapter-url = http://ghr.nlm.nih.gov/condition/pulmonary-arterial-hypertension | veditors = Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LH, Gripp KW, Amemiya A | title = Genetics Home Reference|date = 2015-12-28|access-date = 2015-12-30|url-status = live|archive-url = https://web.archive.org/web/20151224100323/http://ghr.nlm.nih.gov/condition/pulmonary-arterial-hypertension|archive-date = 2015-12-24}}{{Cite book | chapter-url = https://www.ncbi.nlm.nih.gov/books/NBK1485/ |id=NBK1485 |publisher = University of Washington, Seattle|date = January 1993|location = Seattle (WA)|pmid = 20301658| vauthors = Austin ED, Loyd JE, Phillips JA | chapter = Heritable Pulmonary Arterial Hypertension Overview | title = GeneReviews | veditors = Pagon RA, Adam MP, Ardinger HH, Wallace SE, Amemiya A, Bean LJ, Bird TD, Fong C, Mefford HC }}{{cite journal | vauthors = Hoeper MM, Bogaard HJ, Condliffe R, Frantz R, Khanna D, Kurzyna M, Langleben D, Manes A, Satoh T, Torres F, Wilkins MR, Badesch DB | display-authors = 6 | title = Definitions and diagnosis of pulmonary hypertension | journal = Journal of the American College of Cardiology | volume = 62 | issue = 25 Suppl | pages = D42–D50 | date = December 2013 | pmid = 24355641 | doi = 10.1016/j.jacc.2013.10.032 | doi-access = free }} A history of exposure to drugs such as benfluorex (a fenfluramine derivative), dasatinib, cocaine, methamphetamine, ethanol leading to cirrhosis, and tobacco leading to emphysema is considered significant.{{Cite book|title = Drug Safety Data: How to Analyze, Summarize and Interpret to Determine Risk|url = https://books.google.com/books?id=Rj7KAcOspvcC|publisher = Jones & Bartlett Learning|date = 2010-10-25|page = 86|isbn = 978-0-7637-6912-3| vauthors = Klepper MJ, Cobert B |url-status = live|archive-url = https://web.archive.org/web/20160504000601/https://books.google.com/books?id=Rj7KAcOspvcC|archive-date = 2016-05-04}} Use of selective serotonin reuptake inhibitors during pregnancy (particularly late pregnancy) is associated with an increased risk of the baby developing persistent pulmonary hypertension of the newborn.

If pulmonary hypertension is suspected based on the above assessments, echocardiography is performed as the next step. A meta-analysis of Doppler echocardiography for predicting the results of right heart catheterization reported a sensitivity and specificity of 88% and 56%, respectively.{{cite journal | vauthors = Taleb M, Khuder S, Tinkel J, Khouri SJ | title = The diagnostic accuracy of Doppler echocardiography in assessment of pulmonary artery systolic pressure: a meta-analysis | journal = Echocardiography | volume = 30 | issue = 3 | pages = 258–265 | date = March 2013 | pmid = 23227919 | doi = 10.1111/echo.12061 | s2cid = 7460778 }} Thus, Doppler echocardiography can suggest the presence of pulmonary hypertension, but right heart catheterization (described below) remains the gold standard for diagnosis of PAH.

Echocardiography can also help to detect congenital heart disease as a cause of pulmonary hypertension.

If the echocardiogram is compatible with a diagnosis of pulmonary hypertension, common causes of pulmonary hypertension (left heart disease and lung disease) are considered and further tests are performed accordingly. These tests generally include electrocardiography (ECG), pulmonary function tests including lung diffusion capacity for carbon monoxide and arterial blood gas measurements, X-rays of the chest and high-resolution computed tomography (CT) scanning.{{cite web |title=How Is Pulmonary Hypertension Diagnosed? |url=https://www.nhlbi.nih.gov/node/4225 |publisher=National Heart, Lung, and Blood Institute }}

If heart disease and lung disease have been excluded, a ventilation/perfusion scan is performed to rule out CTEPH. If unmatched perfusion defects are found, further evaluation by CT pulmonary angiography, right heart catheterization, and selective pulmonary angiography is performed.

File:PulArtHyperandEmphysemaMark.png

Signs of pulmonary hypertension on CT scan of the chest are:

• Enlargement of the pulmonary trunk (measured at its bifurcation). It is, however, a poor predictor of pulmonary hypertension in patients with interstitial lung disease.{{cite web |url= https://radiopaedia.org/articles/pulmonary-hypertension-1 |title= Pulmonary hypertension |website= Radiopaedia | vauthors = Gaillard F |access-date= 2018-03-12}}

:*A diameter of more than 27 mm for women and 29 mm for men is suggested as a cutoff.

:*A cutoff of 31.6 mm may be a more statistically robust in individuals without interstitial lung disease.

• Increased ratio of the diameter of the main pulmonary artery (pulmonary trunk) to the ascending aorta (measured at its bifurcation).

:*A ratio of 1.0 is suggested as a cutoff in adults.

:*Cutoff ~1.09 in children.

• Increased diameter ratio of segmental arteries to bronchi. This finding in three or four lobes, in the presence of a dilated pulmonary trunk (≥29 mm), and absence of significant structural lung disease confers a specificity of 100% for pulmonary hypertension.
• Mural calcification in central pulmonary arteries is most frequently seen in patients with Eisenmenger's syndrome.

Although pulmonary arterial pressure (PAP) can be estimated on the basis of echocardiography,{{cite journal | vauthors = Bossone E, D'Andrea A, D'Alto M, Citro R, Argiento P, Ferrara F, Cittadini A, Rubenfire M, Naeije R | display-authors = 6 | title = Echocardiography in pulmonary arterial hypertension: from diagnosis to prognosis | journal = Journal of the American Society of Echocardiography | volume = 26 | issue = 1 | pages = 1–14 | date = January 2013 | pmid = 23140849 | doi = 10.1016/j.echo.2012.10.009 }} pressure measurements with a Swan-Ganz catheter inserted through the right side of the heart provide the most definite assessment.[42] Pulmonary hypertension is defined as a mean PAP of at least 20 mm Hg (3300 Pa) at rest, and PAH is defined as precapillary pulmonary hypertension (i.e. mean PAP ≥ 20 mm Hg with pulmonary arterial occlusion pressure [PAOP] ≤ 15 mm Hg and pulmonary vascular resistance [PVR] > 3 Wood Units). PAOP and PVR cannot be measured directly with echocardiography. Therefore, diagnosis of PAH requires right-sided cardiac catheterization. A Swan-Ganz catheter can also measure the cardiac output; this can be used to calculate the cardiac index, which is far more important in measuring disease severity than the pulmonary arterial pressure.{{cite encyclopedia |title=Swan-Ganz – right heart catheterization |date=2022 |encyclopedia=Medical Encyclopedia |publisher=MedlinePlus, National Library of Medicine |url=https://medlineplus.gov/ency/article/003870.htm}}

Mean PAP (mPAP) should not be confused with systolic PAP (sPAP), which is often reported on echocardiogram reports. A systolic pressure of 40 mm Hg typically implies a mean pressure of more than 25 mm Hg. Roughly, mPAP = 0.61•sPAP + 2.{{cite book | vauthors = Khouri SJ, Pandya U | date = 2012 | chapter = Pulmonary hypertension. | veditors = Garcia MJ | title = NonInvasive cardiovascular imaging: a multimodality approach | publisher = Lippincott Williams & Wilkins | pages = 655–668 }} Due to the invasive nature of this procedure, the use of computational fluid dynamics based hemodynamic indices have been postulated.{{cite journal | vauthors = Piskin S, Patnaik SS, Han D, Bordones AD, Murali S, Finol EA | title = A canonical correlation analysis of the relationship between clinical attributes and patient-specific hemodynamic indices in adult pulmonary hypertension | journal = Medical Engineering & Physics | volume = 77 | pages = 1–9 | date = March 2020 | pmid = 32007361 | pmc = 7069525 | doi = 10.1016/j.medengphy.2020.01.006 }}{{cite journal | vauthors = Pillalamarri NR, Piskin S, Patnaik SS, Murali S, Finol EA | title = Patient-Specific Computational Analysis of Hemodynamics in Adult Pulmonary Hypertension | journal = Annals of Biomedical Engineering | volume = 49 | issue = 12 | pages = 3465–3480 | date = December 2021 | pmid = 34799807 | pmc = 8684831 | doi = 10.1007/s10439-021-02884-y }}

For people considered likely to have PAH based on the above tests, the specific associated condition is then determined based on the physical examination, medical/family history and further specific diagnostic tests (for example, serological tests to detect underlying connective tissue disease, HIV infection or hepatitis, ultrasonography to confirm the presence of portal hypertension, echocardiography/cardiac magnetic resonance imaging for congenital heart disease, laboratory tests for schistosomiasis, and high-resolution CT for PVOD and pulmonary capillary hemangiomatosis). Routine lung biopsy is discouraged in patients with PAH, because of the risk to the patient and because the findings are unlikely to alter the diagnosis and treatment.

Treatment of pulmonary hypertension is determined by whether the PH is arterial, venous, hypoxic, thromboembolic, or miscellaneous. If it is caused by left heart disease, the treatment is to optimize left ventricular function by the use of medication or to repair/replace the mitral valve or aortic valve.{{Cite web|title = How Is Pulmonary Hypertension Treated? – NHLBI, NIH|url = https://www.nhlbi.nih.gov/health/health-topics/topics/pah/treatment|website = www.nhlbi.nih.gov|access-date = 2015-12-30|url-status = live|archive-url = https://web.archive.org/web/20160105180457/http://www.nhlbi.nih.gov/health/health-topics/topics/pah/treatment|archive-date = 2016-01-05}} Patients with left heart failure or hypoxemic lung diseases (groups II or III pulmonary hypertension) should not routinely be treated with vasoactive agents including prostanoids, phosphodiesterase inhibitors, or endothelin antagonists, as these are approved for the different condition called primary pulmonary arterial hypertension.{{Citation |author1 = American College of Chest Physicians |author1-link = American College of Chest Physicians |author2 = American Thoracic Society |author2-link = American Thoracic Society |date = September 2013 |title = Five Things Physicians and Patients Should Question |publisher = American College of Chest Physicians and American Thoracic Society |work = Choosing Wisely: an initiative of the ABIM Foundation |url = http://www.choosingwisely.org/doctor-patient-lists/american-college-of-chest-physicians-and-american-thoracic-society/ |access-date = 6 January 2013 |url-status = live |archive-url = https://web.archive.org/web/20131103063427/http://www.choosingwisely.org/doctor-patient-lists/american-college-of-chest-physicians-and-american-thoracic-society/ |archive-date = 3 November 2013 }}, which cites

• {{cite journal | vauthors = McLaughlin VV, Archer SL, Badesch DB, Barst RJ, Farber HW, Lindner JR, Mathier MA, McGoon MD, Park MH, Rosenson RS, Rubin LJ, Tapson VF, Varga J, Harrington RA, Anderson JL, Bates ER, Bridges CR, Eisenberg MJ, Ferrari VA, Grines CL, Hlatky MA, Jacobs AK, Kaul S, Lichtenberg RC, Lindner JR, Moliterno DJ, Mukherjee D, Pohost GM, Rosenson RS, Schofield RS, Shubrooks SJ, Stein JH, Tracy CM, Weitz HH, Wesley DJ | display-authors = 6 | title = ACCF/AHA 2009 expert consensus document on pulmonary hypertension: a report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents and the American Heart Association: developed in collaboration with the American College of Chest Physicians, American Thoracic Society, Inc., and the Pulmonary Hypertension Association | journal = Circulation | volume = 119 | issue = 16 | pages = 2250–2294 | date = April 2009 | pmid = 19332472 | doi = 10.1161/CIRCULATIONAHA.109.192230 | doi-access = free }}
• {{cite journal | vauthors = Galiè N, Hoeper MM, Humbert M, Torbicki A, Vachiery JL, Barbera JA, Beghetti M, Corris P, Gaine S, Gibbs JS, Gomez-Sanchez MA, Jondeau G, Klepetko W, Opitz C, Peacock A, Rubin L, Zellweger M, Simonneau G | display-authors = 6 | title = Guidelines for the diagnosis and treatment of pulmonary hypertension: the Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS), endorsed by the International Society of Heart and Lung Transplantation (ISHLT) | journal = European Heart Journal | volume = 30 | issue = 20 | pages = 2493–2537 | date = October 2009 | pmid = 19713419 | doi = 10.1093/eurheartj/ehp297 | doi-access = free }}
• {{cite journal | vauthors = Hoeper MM, Barberà JA, Channick RN, Hassoun PM, Lang IM, Manes A, Martinez FJ, Naeije R, Olschewski H, Pepke-Zaba J, Redfield MM, Robbins IM, Souza R, Torbicki A, McGoon M | display-authors = 6 | title = Diagnosis, assessment, and treatment of non-pulmonary arterial hypertension pulmonary hypertension | journal = Journal of the American College of Cardiology | volume = 54 | issue = 1 Suppl | pages = S85–S96 | date = June 2009 | pmid = 19555862 | doi = 10.1016/j.jacc.2009.04.008 | doi-access = free }} To make the distinction, doctors at a minimum will conduct cardiac catheterization of the right heart, echocardiography, chest CT, a seven-minute walk test, and pulmonary function testing. Using treatments for other kinds of pulmonary hypertension in patients with these conditions can harm the patient and wastes substantial medical resources.

High-dose calcium channel blockers are useful in only 5% of IPAH patients who are vasoreactive by Swan-Ganz catheter. Calcium channel blockers have been largely misused, being prescribed to many patients with non-vasoreactive PAH, leading to excess morbidity and mortality. The criteria for vasoreactivity have changed. Only those patients whose mean pulmonary artery pressure falls by more than 10 mm Hg to less than 40 mm Hg with an unchanged or increased cardiac output when challenged with adenosine, epoprostenol, or nitric oxide are considered vasoreactive.{{cite journal | vauthors = Barst RJ, McGoon M, Torbicki A, Sitbon O, Krowka MJ, Olschewski H, Gaine S | title = Diagnosis and differential assessment of pulmonary arterial hypertension | journal = Journal of the American College of Cardiology | volume = 43 | issue = 12 Suppl S | pages = 40S–47S | date = June 2004 | pmid = 15194177 | doi = 10.1016/j.jacc.2004.02.032 | doi-access = free }} Of these, only half of the patients are responsive to calcium channel blockers in the long term.{{cite journal | vauthors = Sitbon O, Humbert M, Jaïs X, Ioos V, Hamid AM, Provencher S, Garcia G, Parent F, Hervé P, Simonneau G | display-authors = 6 | title = Long-term response to calcium channel blockers in idiopathic pulmonary arterial hypertension | journal = Circulation | volume = 111 | issue = 23 | pages = 3105–3111 | date = June 2005 | pmid = 15939821 | doi = 10.1161/CIRCULATIONAHA.104.488486 | doi-access = free }}

A number of agents have recently been introduced for primary and secondary PAH. The trials supporting the use of these agents have been relatively small, and the only measure consistently used to compare their effectivity is the "six-minute walk test". Many have no data on mortality benefit or time to progression.{{cite journal | vauthors = Torres F | title = Systematic review of randomised, double-blind clinical trials of oral agents conducted in patients with pulmonary arterial hypertension | journal = International Journal of Clinical Practice | volume = 61 | issue = 10 | pages = 1756–1765 | date = October 2007 | pmid = 17877662 | doi = 10.1111/j.1742-1241.2007.01545.x | s2cid = 1191543 | doi-access = free }}

Sotatercept (Winrevair) was approved for medical use in the United States in March 2024.{{cite press release | title=FDA Approves Merck's Winrevair (sotatercept-csrk), a First-in-Class Treatment for Adults with Pulmonary Arterial Hypertension (PAH, WHO* Group 1) | publisher=Merck | date=27 March 2024 | url=https://www.merck.com/news/fda-approves-mercks-winrevair-sotatercept-csrk-a-first-in-class-treatment-for-adults-with-pulmonary-arterial-hypertension-pah-who-group-1/ | access-date=27 March 2024}} Keros Therapeutics has decided to end a mid-stage trial of its experimental treatment, cibotercept, after identifying safety concerns, including fluid buildup around the heart in patients with PAH.{{Cite news |last=Santhosh |first=Kristy |date=15 Jan 2025 |title=Keros halts blood pressure treatment trial on safety issues |url=https://www.reuters.com/business/healthcare-pharmaceuticals/keros-halts-hypertension-treatment-trial-safety-issues-2025-01-15/?utm_campaign=pharmalittle&utm_medium=email&_hsenc=p2ANqtz-_UXWHm5bs39um7sjNerRV4q88ZolVJBj7Bu96B6Dq1QEdsL-hxt7VloT6CI-risEOLZcQdRY9iuFkHmcOXPs1T14tp7g&_hsmi=342793277&utm_content=342793277 |work=Reuters}} Keros had aimed to compete with Merck's FDA-approved PAH drug, Sotatercept.

Exercise-based rehabilitation

A 2023 Cochrane review found that exercise-based rehabilitation may lead to a large increase in exercise capacity and an improvement in health related quality of life, without significantly increasing adverse events.{{cite journal | vauthors = Morris NR, Kermeen FD, Jones AW, Lee JY, Holland AE | title = Exercise-based rehabilitation programmes for pulmonary hypertension | journal = The Cochrane Database of Systematic Reviews | volume = 2023 | issue = 3 | pages = CD011285 | date = March 2023 | pmid = 36947725 | pmc = 10032353 | doi = 10.1002/14651858.CD011285.pub3 | collaboration = Cochrane Airways Group }}

Many pathways are involved in the abnormal proliferation and contraction of the smooth muscle cells of the pulmonary arteries in patients with pulmonary arterial hypertension. Three of these pathways are important since they have been targeted with drugs – endothelin receptor antagonists, phosphodiesterase type 5 (PDE-5) inhibitors, and prostacyclin derivatives.{{cite journal | vauthors = Raja SG, Raja SM | title = Treating pulmonary arterial hypertension: current treatments and future prospects | journal = Therapeutic Advances in Chronic Disease | volume = 2 | issue = 6 | pages = 359–370 | date = November 2011 | pmid = 23251761 | pmc = 3513893 | doi = 10.1177/2040622311420773 }}

Prostacyclin (prostaglandin I₂) is commonly considered the most effective treatment for PAH. Epoprostenol (synthetic prostacyclin) is given via continuous infusion that requires a semi-permanent central venous catheter. This delivery system can cause sepsis and thrombosis. Prostacyclin is unstable, and therefore has to be kept on ice during administration. Since it has a half-life of 3 to 5 minutes, the infusion has to be continuous, and interruption can be fatal.{{cite journal | vauthors = Safdar Z | title = Treatment of pulmonary arterial hypertension: the role of prostacyclin and prostaglandin analogs | journal = Respiratory Medicine | volume = 105 | issue = 6 | pages = 818–827 | date = June 2011 | pmid = 21273054 | doi = 10.1016/j.rmed.2010.12.018 | doi-access = free }} Other prostanoids have therefore been developed. Treprostinil can be given intravenously or subcutaneously, but the subcutaneous form can be very painful. An increased risk of sepsis with intravenous Remodulin has been reported by the CDC. Iloprost is also used in Europe intravenously and has a longer half life. Iloprost was the only inhaled form of prostacyclin approved for use in the US and Europe, until the inhaled form of treprostinil was approved by the FDA in July 2009.{{cite web | url=https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=022387 | title=Drugs@FDA: FDA-Approved Drugs }}

Moderate quality evidence suggests that endothelin receptor antagonists improve exercise capacity and decrease symptoms severity.{{cite journal | vauthors = Liu C, Chen J, Gao Y, Deng B, Liu K | title = Endothelin receptor antagonists for pulmonary arterial hypertension | journal = The Cochrane Database of Systematic Reviews | volume = 2021 | issue = 3 | pages = CD004434 | date = March 2021 | pmid = 33765691 | pmc = 8094512 | doi = 10.1002/14651858.CD004434.pub6 | collaboration = Cochrane Airways Group }} The dual (ET_A and ET_B) endothelin receptor antagonist bosentan was approved in 2001. Macitentan is another ET_A and ET_B dual endothelin receptor blocker that is used. Sitaxentan (Thelin) was approved for use in Canada, Australia, and the European Union,{{cite news |date=2008-05-30 |url=https://www.reuters.com/article/governmentFilingsNews/idUSBNG28335020070530 |title=UPDATE 1-Encysive gets Canadian approval for hypertension drug |newspaper=Reuters |access-date=2007-07-08 |url-status=live |archive-url=https://web.archive.org/web/20070704163058/http://www.reuters.com/article/governmentFilingsNews/idUSBNG28335020070530 |archive-date=2007-07-04 }} but not in the United States. In 2010, Pfizer withdrew sitaxentan worldwide because of fatal liver complications.{{cite web |title=Citing Liver Damage, Pfizer Withdraws Thelin – CBS Detroit |url=https://www.cbsnews.com/detroit/news/citing-liver-damage-pfizer-withdraws-thelin/ |website=www.cbsnews.com |date=10 December 2010}} A similar drug, ambrisentan (which is a ET_A endothelin receptor blocker) is sold under the brand name Letairis in the US by Gilead Sciences.{{cite press release | title = U.S. Food and Drug Administration Approves Gilead's Letairis Treatment of Pulmonary Arterial Hypertension | publisher = Gilead Sciences | date = 2007-06-15 | url = http://www.gilead.com/wt/sec/pr_1016053 | access-date = 2007-06-16 | archive-url = https://web.archive.org/web/20070927064048/http://www.gilead.com/wt/sec/pr_1016053 | archive-date = 2007-09-27 }}

The US FDA approved sildenafil, a selective inhibitor of cGMP specific phosphodiesterase type 5 (PDE5), for the treatment of PAH in 2005. It is marketed for PAH as Revatio. In 2009, they also approved tadalafil, another PDE5 inhibitor, marketed under the name Adcirca.{{cite press release|date=2009-05-26|url=http://www.news-medical.net/news/2009/05/26/FDA-approves-Adcirca-(tadalafil)-tablets-for-pulmonary-arterial-hypertension.aspx|title=FDA approves Adcirca (tadalafil) tablets for pulmonary arterial hypertension|access-date=2010-12-06|url-status=live|archive-url=https://web.archive.org/web/20101203185840/http://www.news-medical.net/news/2009/05/26/FDA-approves-Adcirca-(tadalafil)-tablets-for-pulmonary-arterial-hypertension.aspx|archive-date=2010-12-03}} PDE5 inhibitors are believed to increase pulmonary artery vasodilation, and inhibit vascular remodeling, thus lowering pulmonary arterial pressure and pulmonary vascular resistance.{{cite journal | vauthors = Duarte JD, Hanson RL, Machado RF | title = Pharmacologic treatments for pulmonary hypertension: exploring pharmacogenomics | journal = Future Cardiology | volume = 9 | issue = 3 | pages = 335–349 | date = May 2013 | pmid = 23668740 | pmc = 3864092 | doi = 10.2217/fca.13.6 }}

Tadalafil is taken orally, as well as sildenafil, and it is rapidly absorbed (serum levels are detectable at 20 minutes). The T_1/2 (biological half-life) hovers around 17.5 hours in healthy subjects.{{cite journal | vauthors = Forgue ST, Patterson BE, Bedding AW, Payne CD, Phillips DL, Wrishko RE, Mitchell MI | title = Tadalafil pharmacokinetics in healthy subjects | journal = British Journal of Clinical Pharmacology | volume = 61 | issue = 3 | pages = 280–288 | date = March 2006 | pmid = 16487221 | pmc = 1885023 | doi = 10.1111/j.1365-2125.2005.02553.x }} Moreover, if we consider pharmacoeconomic implications, patients that take tadalafil would pay two-thirds of the cost of sildenafil therapy.{{cite journal |vauthors=Arif SA, Poon H |title=Tadalafil: a long-acting phosphodiesterase-5 inhibitor for the treatment of pulmonary arterial hypertension |journal=Clin Ther |volume=33 |issue=8 |pages=993–1004 |date=August 2011 |pmid=21762988 |doi=10.1016/j.clinthera.2011.06.008 }} However, there are some adverse effects of this drug such as headache, diarrhea, nausea, back pain, dyspepsia, flushing and myalgia.{{cite journal | vauthors = Galiè N, Brundage BH, Ghofrani HA, Oudiz RJ, Simonneau G, Safdar Z, Shapiro S, White RJ, Chan M, Beardsworth A, Frumkin L, Barst RJ | display-authors = 6 | title = Tadalafil therapy for pulmonary arterial hypertension | journal = Circulation | volume = 119 | issue = 22 | pages = 2894–2903 | date = June 2009 | pmid = 19470885 | doi = 10.1161/circulationaha.108.839274 | doi-access = free }}

The combination medication macitentan/tadalafil (Opsynvi) was approved for medical use in Canada in October 2021,{{cite press release | title=Opsynvi (macitentan and tadalafil) Becomes the First and Only Health Canada-Approved Once Daily Fixed Dose Combination Treatment for Patients with Pulmonary Arterial Hypertension (PAH) | website=Johnson & Johnson | date=15 October 2021 | url=https://www.jnj.com/media-center/press-releases/opsynvi-macitentan-and-tadalafil-becomes-the-first-and-only-health-canada-approved-once-daily-fixed-dose-combination-treatment-for-patients-with-pulmonary-arterial-hypertension-pah | access-date=25 March 2024}} and in the United States in March 2024.{{cite web | title = Approval Letter: Opsynvi (macitentan and tadalafil)| url = https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2024/218490Orig1s000ltr.pdf | publisher = U.S. Food and Drug Administration }}{{cite press release | title=U.S. FDA Approves Opsynvi (macitentan and tadalafil) as the First and Only Once-Daily Single-Tablet Combination Therapy for Patients with Pulmonary Arterial Hypertension (PAH) | website=Johnson & Johnson | date=22 March 2024 | url=https://www.jnj.com/media-center/press-releases/u-s-fda-approves-opsynvi-macitentan-and-tadalafil-as-the-first-and-only-once-daily-single-tablet-combination-therapy-for-patients-with-pulmonary-arterial-hypertension-pah | access-date=25 March 2024}}

Soluble guanylate cyclase (sGC) is the intracellular receptor for NO. {{As of|April 2009}}, the sGC activators cinaciguat and riociguat were undergoing clinical trials for the treatment of PAH.{{cite journal | vauthors = Lasker GF, Maley JH, Pankey EA, Kadowitz PJ | title = Targeting soluble guanylate cyclase for the treatment of pulmonary hypertension | journal = Expert Review of Respiratory Medicine | volume = 5 | issue = 2 | pages = 153–161 | date = April 2011 | pmid = 21510726 | pmc = 3108035 | doi = 10.1586/ers.11.9 }}

Atrial septostomy is a surgical procedure that creates a communication between the right and left atria. It relieves pressure on the right side of the heart, but at the cost of lower oxygen levels in blood (hypoxemia). Lung transplantation replaces a chronic condition with the ongoing need for treatment.{{cite journal | vauthors = George MP, Champion HC, Pilewski JM | title = Lung transplantation for pulmonary hypertension | journal = Pulmonary Circulation | volume = 1 | issue = 2 | pages = 182–191 | date = 2011 | pmid = 22034605 | pmc = 3198646 | doi = 10.4103/2045-8932.83455 | doi-access = free }} There is a post-surgical median survival of just over five years.{{cite web |date=2006-05-01 |url=http://www.ustransplant.org/annual_reports/current/113_surv-new_dh.htm |title=2006 OPTN/SRTR Annual Report |publisher=US Scientific Registry of Transplant Recipients |access-date=2007-03-28 |archive-url=https://web.archive.org/web/20100605083802/http://www.ustransplant.org/annual_reports/current/113_surv-new_dh.htm |archive-date=2010-06-05 }}

Pulmonary thromboendarterectomy (PTE) is a surgical procedure that is used for chronic thromboembolic pulmonary hypertension. It is the surgical removal of an organized thrombus (clot) along with the lining of the pulmonary artery; it is a very difficult, major procedure that is currently performed in a few select centers.{{cite journal | vauthors = Cerveri I, D'Armini AM, Viganò M | title = Pulmonary thromboendarterectomy almost 50 years after the first surgical attempts | journal = Heart | volume = 89 | issue = 4 | pages = 369–370 | date = April 2003 | pmid = 12639858 | pmc = 1769265 | doi = 10.1136/heart.89.4.369 }}

Established clinical practice guidelines dictate the frequency of pulmonary nodule evaluation and surveillance,{{Citation |author1 = American College of Chest Physicians |author1-link = American College of Chest Physicians |author2 = American Thoracic Society |author2-link = American Thoracic Society |date = September 2013 |title = Five Things Physicians and Patients Should Question |publisher = American College of Chest Physicians and American Thoracic Society |work = Choosing Wisely: an initiative of the ABIM Foundation |url = http://www.choosingwisely.org/doctor-patient-lists/american-college-of-chest-physicians-and-american-thoracic-society/ |access-date = 6 January 2013 |url-status = live |archive-url = https://web.archive.org/web/20131103063427/http://www.choosingwisely.org/doctor-patient-lists/american-college-of-chest-physicians-and-american-thoracic-society/ |archive-date = 3 November 2013 }}

patients are normally monitored through commonly available tests such as:{{citation needed|date=October 2016}}

{{columns-list|colwidth=30em|

• Pulse oximetry
• Arterial blood gas tests
• Chest X-rays
• Serial ECG tests
• Serial echocardiography
• Spirometry or more advanced lung function studies
• Six-minute walk testGuidelines: Six-minute Walk Test. Accessed: 2015

}}

File:Heart - cor pulmonale- right ventricular hypertrophy (4351912426).jpg

PAH is considered a universally fatal illness, although survival time may vary between individuals. The prognosis of pulmonary arterial hypertension (WHO Group I) has an untreated median survival of 2–3 years from time of diagnosis, with the cause of death usually being right ventricular failure (cor pulmonale).{{Cite web|title = Pulmonary Hypertension. About Pulmonary Hypertension {{!}} Patient|url = http://patient.info/doctor/pulmonary-hypertension-pro|website = Patient|access-date = 2015-12-30|language = en-GB|url-status = live|archive-url = https://web.archive.org/web/20160102193628/http://patient.info/doctor/pulmonary-hypertension-pro|archive-date = 2016-01-02}} The survival time is variable and depends on many factors.{{cite journal | vauthors = Mouratoglou SA, Bayoumy AA, Noordegraaf AV | title = Prediction Models and Scores in Pulmonary Hypertension: A Review | journal = Current Pharmaceutical Design | volume = 27 | issue = 10 | pages = 1266–1276 | date = 2021 | pmid = 33155897 | doi = 10.2174/1381612824999201105163437 | s2cid = 226272078 }} A recent outcome study of those patients who had started treatment with bosentan (Tracleer) showed that 89% of patients were alive at 2 years.{{cite journal | vauthors = McLaughlin VV, Sitbon O, Badesch DB, Barst RJ, Black C, Galiè N, Rainisio M, Simonneau G, Rubin LJ | display-authors = 6 | title = Survival with first-line bosentan in patients with primary pulmonary hypertension | journal = The European Respiratory Journal | volume = 25 | issue = 2 | pages = 244–249 | date = February 2005 | pmid = 15684287 | doi = 10.1183/09031936.05.00054804 | doi-access = free }} With new therapies, survival rates are increasing. For 2,635 patients enrolled in The Registry to Evaluate Early and Long-term Pulmonary Arterial Hypertension Disease Management (REVEAL Registry) from March 2006 to December 2009, 1-, 3-, 5-, and 7-year survival rates were 85%, 68%, 57%, and 49%, respectively. For patients with idiopathic/familial PAH, survival rates were 91%, 74%, 65%, and 59%.{{cite journal | vauthors = Benza RL, Miller DP, Barst RJ, Badesch DB, Frost AE, McGoon MD | title = An evaluation of long-term survival from time of diagnosis in pulmonary arterial hypertension from the REVEAL Registry | journal = Chest | volume = 142 | issue = 2 | pages = 448–456 | date = August 2012 | pmid = 22281797 | doi = 10.1378/chest.11-1460 }} Levels of mortality are very high in pregnant women with severe pulmonary arterial hypertension (WHO Group I). Pregnancy is sometimes described as contraindicated in these women.{{cite book | vauthors = Kaufman MH, Stead L, Feig R |title=First aid for the obstetrics & gynecology clerkship |url=https://archive.org/details/maxwellquickmedi00stea |url-access=limited |publisher=McGraw-Hill, Medical Pub. Division |location=New York |year=2007 |page=[https://archive.org/details/maxwellquickmedi00stea/page/n98 100] |isbn=978-0-07-144874-1 }}{{cite book | vauthors = Ghosh AK |title=Mayo Clinic Internal Medicine Review |edition=8th |url=https://archive.org/details/mayoclinicintern00ghos_466 |url-access=limited |publisher=Informa Healthcare |year=2008 |page=[https://archive.org/details/mayoclinicintern00ghos_466/page/n79 55] |isbn=978-1-4200-8478-8 }}[http://bja.oxfordjournals.org/content/87/2/295.full British Journal of Anaesthesia: "Primary pulmonary hypertension in pregnancy; a role for novel vasodilators"] {{webarchive|url=https://web.archive.org/web/20110121035550/http://bja.oxfordjournals.org/content/87/2/295.full |date=2011-01-21 }} March 19, 2011

The epidemiology of IPAH is about 125–150 deaths per year in the U.S., and worldwide the incidence is similar at 4 cases per million. However, in parts of Europe (France), indications are 6 cases per million of IPAH. Females have a higher incidence rate than males (2–9:1).{{cite journal | vauthors = Oudiz RJ | title=Idiopathic Pulmonary Arterial Hypertension: Practice Essentials, Background, Pathophysiology | website=Medscape Reference | date=6 February 2023 | url=https://emedicine.medscape.com/article/301450-overview#a6?form=fpf}}

Other forms of PH are far more common. In systemic scleroderma, the incidence has been estimated to be 8 to 12% of all patients;{{cite journal | vauthors = York M, Farber HW | title = Pulmonary hypertension: screening and evaluation in scleroderma | journal = Current Opinion in Rheumatology | volume = 23 | issue = 6 | pages = 536–544 | date = November 2011 | pmid = 21934501 | doi = 10.1097/BOR.0b013e32834ba6a7 | s2cid = 19528958 }} in rheumatoid arthritis it is rare.{{cite web| vauthors = Nannini C |title=Lung Disease in Rheumatoid Arthritis|website=MedScape.com|url=http://www.medscape.com/viewarticle/573647_6|publisher=MedScape|access-date=31 December 2015|url-status=live|archive-url=https://web.archive.org/web/20160208104626/http://www.medscape.com/viewarticle/573647_6|archive-date=8 February 2016}} However, in systemic lupus erythematosus it is 4 to 14%,{{cite journal | vauthors = Mittoo S, Fell CD | title = Pulmonary manifestations of systemic lupus erythematosus | journal = Seminars in Respiratory and Critical Care Medicine | volume = 35 | issue = 2 | pages = 249–254 | date = April 2014 | pmid = 24668539 | doi = 10.1055/s-0034-1371537 | url = http://www.medscape.com/viewarticle/825749 | access-date = 31 December 2015 | publisher = MedScape | url-status = live | s2cid = 24654448 | archive-url = https://web.archive.org/web/20151026125732/http://www.medscape.com/viewarticle/825749 | archive-date = 26 October 2015 }} and in sickle cell disease, it ranges from 20 to 40%.{{cite journal | vauthors = Lee MT, Rosenzweig EB, Cairo MS | title = Pulmonary hypertension in sickle cell disease | journal = Clinical Advances in Hematology & Oncology | volume = 5 | issue = 8 | pages = 585, 645–653| date = August 2007 | pmid = 17982405 }} Up to 4% of people who develop a pulmonary embolism go on to develop chronic thromboembolic disease including pulmonary hypertension. A small percentage of patients with COPD develop pulmonary hypertension with no other disease to explain the high pressure.{{cite journal | vauthors = Minai OA, Chaouat A, Adnot S | title = Pulmonary hypertension in COPD: epidemiology, significance, and management: pulmonary vascular disease: the global perspective | journal = Chest | volume = 137 | issue = 6 Suppl | pages = 39S–51S | date = June 2010 | pmid = 20522579 | doi = 10.1378/chest.10-0087 }} On the other hand, obesity-hypoventilation syndrome is very commonly associated with right heart failure due to pulmonary hypertension.{{cite journal | vauthors = Balachandran JS, Masa JF, Mokhlesi B | title = Obesity Hypoventilation Syndrome Epidemiology and Diagnosis | journal = Sleep Medicine Clinics | volume = 9 | issue = 3 | pages = 341–347 | date = September 2014 | pmid = 25360072 | pmc = 4210766 | doi = 10.1016/j.jsmc.2014.05.007 }}

For people that inherited the disease, gene therapy is being studied.{{cite journal | vauthors = Reynolds PN | title = Gene therapy for pulmonary hypertension: prospects and challenges | journal = Expert Opinion on Biological Therapy | volume = 11 | issue = 2 | pages = 133–143 | date = February 2011 | pmid = 21219232 | doi = 10.1517/14712598.2011.542139 | s2cid = 23641857 }}

• Elaine Kaufman, American restaurateur{{cite web|title=Elaine Kaufman, famed Elaine's restaurateur, dies at age 81|url=http://www.nydailynews.com/new-york/famed-elaine-restaurateur-elaine-kaufman-dead-81-eatery-favorite-nyc-writers-actors-article-1.469449|website=Daily News|date=3 December 2010 |access-date=27 September 2016|url-status=live|archive-url=https://web.archive.org/web/20160828141155/http://www.nydailynews.com/new-york/famed-elaine-restaurateur-elaine-kaufman-dead-81-eatery-favorite-nyc-writers-actors-article-1.469449|archive-date=28 August 2016}}
• Ina Balin, American Broadway and TV actress{{cite news| vauthors = Folkart BA |title=Ina Balin, 52; Movie and TV Actress Sought Lung Implant|url=https://www.latimes.com/archives/la-xpm-1990-06-21-mn-160-story.html|newspaper=Los Angeles Times|access-date=27 September 2016|date=21 June 1990|url-status=live|archive-url=https://web.archive.org/web/20160911105214/http://articles.latimes.com/1990-06-21/news/mn-160_1_ina-balin|archive-date=11 September 2016}}
• Chloe Temtchine, American singer-songwriter{{cite news|url=https://nypost.com/2016/07/26/shes-tethered-to-an-oxygen-tank-but-her-singing-career-is-soaring/|title=She's tethered to an oxygen tank, but her singing career is soaring| vauthors = Phull H |date=July 26, 2016|newspaper=New York Post|url-status=live|archive-url=https://web.archive.org/web/20160814062758/http://nypost.com/2016/07/26/shes-tethered-to-an-oxygen-tank-but-her-singing-career-is-soaring/|archive-date=August 14, 2016}}{{cite news|url=http://www.huffingtonpost.com/annette-insdorf/chloe-temtchine_b_4246594.html|title=The Challenges of Chloe Temtchine|vauthors=Insdorf A |date=November 10, 2013|work=The Huffington Post|url-status=live|archive-url=https://web.archive.org/web/20160918180418/http://www.huffingtonpost.com/annette-insdorf/chloe-temtchine_b_4246594.html|archive-date=September 18, 2016}}
• Natalie Cole, American singer"Autopsy: The Last Hours of Natalie Cole." Autopsy. Nar. Eric Meyers. Exec. Prod. Ed Taylor and Michael Kelpie. Reelz, 27 May 2017. Television.

• Pulmonary Hypertension Association
• Cambridge Pulmonary Hypertension Outcome Review (CAMPHOR)

{{Reflist}}

{{refbegin}}

• {{cite web |title=Pulmonary arterial hypertension |date=2016 |work=Genetics: Genetic Conditions |publisher=MedlinePlus, National Library of Medicine |url=https://medlineplus.gov/genetics/condition/pulmonary-arterial-hypertension/ |ref={{harvid|MedlinePlus|Pulmonary arterial hypertension|2016}} }}
• {{cite web |title=What Is Pulmonary Hypertension? |date=May 2023 |work=Health Topics: Pulmonary Hypertension |publisher=National Heart, Lung and Blood Institute. National Library of Medicine |url=https://www.nhlbi.nih.gov/health/pulmonary-hypertension |ref={{harvid|NHLBI|What Is Pulmonary Hypertension?|2023}} }}
• {{cite journal | vauthors = Rubin LJ, Badesch DB | title = Evaluation and management of the patient with pulmonary arterial hypertension | journal = Annals of Internal Medicine | volume = 143 | issue = 4 | pages = 282–292 | date = August 2005 | pmid = 16103472 | doi = 10.7326/0003-4819-143-4-200508160-00009 | s2cid = 28841269 | citeseerx = 10.1.1.463.8466 }}
• {{cite journal | vauthors = Abman SH, Hansmann G, Archer SL, Ivy DD, Adatia I, Chung WK, Hanna BD, Rosenzweig EB, Raj JU, Cornfield D, Stenmark KR, Steinhorn R, Thébaud B, Fineman JR, Kuehne T, Feinstein JA, Friedberg MK, Earing M, Barst RJ, Keller RL, Kinsella JP, Mullen M, Deterding R, Kulik T, Mallory G, Humpl T, Wessel DL | display-authors = 6 | title = Pediatric Pulmonary Hypertension: Guidelines From the American Heart Association and American Thoracic Society | journal = Circulation | volume = 132 | issue = 21 | pages = 2037–2099 | date = November 2015 | pmid = 26534956 | doi = 10.1161/CIR.0000000000000329 | s2cid = 7412370 | doi-access = free }}

{{refend}}

• [http://www.merckmanuals.com/home/lung_and_airway_disorders/pulmonary_hypertension/pulmonary_hypertension.html#v727742 The Merck Manual Home Edition: Pulmonary Hypertension]

{{Medical resources

| DiseasesDB = 10998

| ICD10 = {{ICD10|I|27|0|i|26}}, {{ICD10|I|27|2|i|26}}

| ICD9 = {{ICD9|416.0}}, {{ICD9|416.8}}

| ICDO =

| OMIM = 178600

| MedlinePlus = 000112

| eMedicineSubj = radio

| eMedicineTopic = 583

| eMedicine_mult = {{eMedicine2|med|1962}} [http://emedicine.medscape.com/article/303098-overview Secondary pulmonary hypertension] [http://emedicine.medscape.com/article/1004828-overview Pediatric primary pulmonary hypertension] [http://emedicine.medscape.com/article/898437-overview Persistent newborn pulmonary hypertension]

| MeshID = D006976

|Orphanet=182090}}

{{commons category|Pulmonary hypertension}}

{{Scholia|topic}}

{{Vascular diseases}}

{{Respiratory pathology}}

{{Authority control}}

Category:Pulmonary heart disease and diseases of pulmonary circulation

Category:Hypertension

Category:Wikipedia medicine articles ready to translate

Category:Wikipedia emergency medicine articles ready to translate

Category:Rare diseases