Pulmonary Arterial Hypertension

Disease Overview

Summary

Pulmonary arterial hypertension (PAH) is a term that refers to a group of rare diseases where the blood pressure in the arteries of the lungs (pulmonary arteries) becomes abnormally high.

The term “pulmonary hypertension” is more general and refers to high blood pressure in the pulmonary arteries. Pulmonary arterial hypertension (PAH), the subject of this report, is a specific type of pulmonary hypertension where the pulmonary arteries become narrowed, thickened, or blocked. Not all forms of pulmonary hypertension are PAH.

The pulmonary arteries carry blood from the right side of the heart to the lungs, where it picks up oxygen. In PAH, the arteries become narrow or blocked, increasing pressure. This puts a strain on the right side of the heart, which must work harder to pump blood. If not treated, over time, this can lead to right heart failure.

PAH usually affects females between the ages of 30-60. People with PAH may go years without a diagnosis, either because their symptoms are mild, nonspecific, or only present during demanding exercise.

The cause is unknown in many cases (idiopathic). It can also be inherited or familial (heritable) or it may be caused by drugs or toxins or be associated with other medical conditions.

About 15-20% of people with PAH have heritable forms of PAH. Research has found gene changes (variants) in people with heritable PAH or with other forms of PAH, in particular a variant in the BMPR2 gene. However, in some people, even when there are several people with PAH in a family, no gene variant is identified.

PAH is a progressive and can be a very severe and potentially fatal condition if it is not treated. The progressive nature of this disease means that an individual may have only mild symptoms at first but will eventually require treatment and medical care to maintain a reasonable quality of life. Although treatable, there is no known cure for the disease. Treatment may include medications to open lung arteries (vasodilators), oxygen therapy, water pills (diuretics) for fluid buildup, blood thinners to prevent clots and lung or heart-lung transplants for advanced cases. Early diagnosis is very important for better outcomes.

Introduction

The first case of PAH was described in 1891 by German physician E. Romberg, who noted thickening of the pulmonary artery without any clear heart or lung disease. In 1951, Dr. D.T. Dresdale reported three more cases and used the term primary pulmonary hypertension, which is no longer used but refers to what we now classify under idiopathic PAH.

In the 1990s, studies linked PAH to diet pills like Fen-Phen, Pondimin, and Redux, which were removed from the market in 1997. Other drugs such as methamphetamines, have also been associated with PAH.

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Synonyms

• PAH

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Subdivisions

• heritable pulmonary arterial hypertension (HPAH)
• idiopathic pulmonary arterial hypertension (IPAH)
• associated pulmonary arterial hypertension (APAH)
• drug- or Toxin-Induced pulmonary arterial hypertension (drug-or toxic-induced PAH)
• persistent pulmonary hypertension of the newborn (PPHN)

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Signs & Symptoms

Pulmonary arterial hypertension (PAH) symptoms are usually due to not having enough oxygen in the blood or inability of the heart to pump enough blood to meet the demands of the body. In most people, the initial symptom is severe shortness of breath following exertion. Additional symptoms include:

• Fatigue or weakness
• Chest pain
• Lightheadedness or fainting (syncope)
• Swelling of the feet, ankles, abdomen, or face from fluid buildup (edema)
• Bluish skin or lips due to low oxygen (cyanosis)
• Cough, possibly with blood (hemoptysis)
• Hoarseness caused by pressure on a nerve in the chest
• Low blood pressure (hypotension)
• Enlarged liver or heart

Some people with PAH are diagnosed with more advanced disease when they are no longer able to continue with their normal activities. At this time, the disease may have progressed to a point where the affected person is completely bedridden from shortness of breath or other symptoms.

People with PAH, or a family history of it should avoid living at high altitudes, as the lower oxygen levels can worsen symptoms.

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Causes

The exact cause of PAH is unknown. Researchers think that injury to the layer of cells that line the small blood vessels of the lung, perhaps then causing or in concert with changes in the smooth muscle cells in the vessel wall, initiates blood vessel disease. This injury, which occurs for unknown reasons, results in the contraction of smooth muscle and therefore narrows the vessel. Researchers also think that some people who develop PAH have blood vessels that are particularly sensitive to certain internal or external factors or exposures and constrict, or narrow, when exposed to these factors.

Pulmonary arterial hypertension (PAH) is divided into several categories:

• Idiopathic PAH (IPAH): No known cause
• Heritable PAH (HPAH): Caused by genetic changes and may run in families
• Drug- or toxin-induced PAH: Caused by substances like certain diet pills or methamphetamines
• Associated PAH (APAH): Where PAH is part of other diseases like:
  • Connective tissue diseases (e.g., scleroderma)
  • Liver disease (e.g., cirrhosis)
  • Congenital heart defects
  • HIV infection

In many people, the exact cause is unknown (idiopathic).

Heritable PAH (HPAH): About 15–20% of PAH cases are heritable, meaning they are caused by gene variants passed through families. The most common variant is in the BMPR2 gene. Females with a BMPR2 gene variant are more likely to develop the disease than males. Interestingly, 80% of people with a BMPR2 variant never develop PAH, suggesting other factors (genes or environment) also play a role.

Other genes linked to PAH include:

• CAV1
• KCNK3
• EIF2AK4 (associated with rare types like pulmonary veno-occlusive disease and pulmonary capillary hemangiomatosis)

Drug and toxin exposure: Certain drugs and substances increase the risk of PAH, especially when used over a long time including:

• Appetite-suppressant drugs: In 1996, the U.S. Food and Drug Administration (FDA) reviewed data from the International Primary Pulmonary Hypertension Study (IPPHS). This study examined the relationship between appetite suppressants such as dexfenfluramine (Redux) and fenfluramine (Pondimin)
  • The study found that people who used these drugs for three months or longer had a risk of developing what was then called primary pulmonary hypertension (now known as a form of PAH) that was about 9 times higher than non-users and up to 23 times higher according to the final IPPHS report.
  • These drugs were removed from the market in 1997. However, other diet drugs such as benfluorex (used in Europe until 2009) have also been associated with PAH.
• Additional drugs and substances linked to PAH include:

• • Methamphetamines (illegal stimulants)
  • Dasatinib (cancer drug)

Female hormones are being studied as a possible contributing factor because PAH is more common in females and some females develop PAH during or shortly after pregnancy (especially around childbirth, called the peripartum period).

Associated medical conditions where PAH develops alongside other health issues:

• Connective tissue diseases, especially scleroderma. Up to 30% of people with scleroderma may develop PAH.
  • Scleroderma causes thickening and scarring of the skin and organs.
  • Many patients also have Raynaud’s phenomenon (cold or discolored fingers/toes), though Raynaud’s can occur without scleroderma.
• Liver disease, particularly cirrhosis
• Congenital heart disease
• HIV infection (AIDS)

In addition, persistent pulmonary hypertension of the newborn (PPHN) occurs when a baby’s circulation doesn’t adjust properly after birth. It’s more common in full-term or overdue babies after a difficult birth.

Symptoms include:

• Fast breathing
• Bluish skin or lips from low oxygen levels (cyanosis)

The exact cause is not known but it is linked to low oxygen levels during or after birth.

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Affected populations

PAH occurs 3-5 times more frequently in females than males. It tends to affect females between the ages of 30 and 60. About in one to two individuals per million people are diagnosed with PAH each year in the U.S. (500-1,000 people) The incidence is estimated to be similar in Europe. There is no ethnic or racial group that is known to have a higher frequency of PAH.

According to a systematic review in 2020, prevalence ranged from 0.4 to 1.4 per 100,000 people.

A rare form of pulmonary hypertension affects individuals who are at high altitude levels (e.g., mountain climbing). It is not recommended for people with PAH or a family history of PAH to live at high altitudes.

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Disorders with Similar Symptoms

Pulmonary hypertension is a general term that means high blood pressure that occurs only in the arteries in the lungs may affect the right side of the heart. The term PAH refers to a specific cause of pulmonary hypertension, but not all pulmonary hypertension (high pressure in lung arteries) is PAH as there are other causes of pulmonary hypertension as well. There are four other main causes of pulmonary hypertension:

These other conditions look similar but are treated differently:

• Left heart disease as the heart valve problems or heart failure can raise pressure in the lungs (pulmonary venous hypertension)
• Lung disease such as COPD or interstitial pneumonia

• • Interstitial pneumonia affects lung tissue and causes cough, shortness of breath, and appetite loss.

• Chronic blood clots can block arteries and cause chronic thromboembolic pulmonary hypertension (CTEPH).

• • This type may be curable with surgery.

• Other rare diseases including kidney disease and sarcoidosis

All types of pulmonary hypertension can cause right heart failure, fluid retention and symptoms like needing to sleep sitting up, waking up short of breath and dizziness during activity.

These are signs the condition may be getting worse and need further evaluation.

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Diagnosis

Diagnosing PAH can be challenging because the symptoms are similar to those of many other conditions. Even when the disease has progressed, it can be difficult to detect during a routine medical exam.

PAH symptoms such as shortness of breath, fatigue and dizziness are not unique and may be mistaken for other illnesses that reduce oxygen in the blood. To make matters more complicated, PAH is often a “diagnosis of exclusion”. That means doctors will first rule out other possible conditions that can increase the pressure inside the lungs before confirming that a person has PAH.

To determine whether someone has PAH, and to exclude other diseases, doctors typically use several of the following tests:

• Echocardiography (heart ultrasound) that checks how well the heart is pumping and whether pressures in the heart are elevated
• Blood tests to look for signs of inflammation, autoimmune disease, liver problems and other underlying conditions
• Pulmonary function tests that assess lung capacity and function
• Chest X-rays that help visualize the heart and lungs
• Lung blood flow scans which show how well blood flows through the lungs
• Electrocardiography (ECG) to measure the heart’s electrical activity to detect strain on the right side of the heart
• Walking test which measures how far someone can walk in six minutes, helping doctors assess endurance and oxygen levels during activity

The most accurate test to confirm PAH is a procedure called cardiac catheterization which involves inserting a thin tube into a blood vessel and guiding it into the heart and lungs. This test directly measures the pressure in the pulmonary arteries and is often done with and without vasodilator testing (testing how the arteries respond to medication that relaxes blood vessels).

If two or more family members have PAH, or if a variant in the BMPR2 gene or another PAH-related gene is found in a patient, a diagnosis of heritable PAH is confirmed.

Genetic testing for PAH-related genes is available but should only be done after speaking with a genetic counselor, who can help interpret the results and explain what they mean for the individual and their family.

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Standard Therapies

Treatment

There are several FDA-approved treatments available for managing PAH. These medications help reduce symptoms, improve quality of life and in some people slow down the progression of the disease.

Medications are grouped into different categories based on how they work in the body:

Prostaglandins: These medications mimic a natural chemical in the body called prostacyclin, which relaxes narrowed blood vessels in the lungs and improves blood flow.

• Epoprostenol (Flolan): The first drug approved for PAH. It is given by continuous IV infusion through a permanent catheter. This treatment must be continuous and should never be stopped suddenly, as this can be dangerous.
• Veletri: This is a room-temperature stable form of epoprostenol, making storage and delivery easier.
• Treprostinil (Remodulin): This drug is given under the skin (subcutaneous) or by IV.
• Tyvaso: This is an inhaled form of treprostinil.
• Orenitram: This is a pill version of treprostinil.
• Iloprost (Ventavis): This is an inhaled prostaglandin that opens lung blood vessels and helps prevent blood clots. It is taken using a nebulizer several times a day.

Endothelin receptor antagonists: These drugs block endothelin, a substance in the body that causes blood vessels to narrow. All medications in this class can cause serious birth defects. They are available only through a restricted distribution program, and females who can become pregnant must undergo monthly pregnancy tests while using them.

• Bosentan (Tracleer): This helps improve exercise ability and reduce breathlessness. Regular monitoring is needed because it may affect the liver.
• Ambrisentan (Letairis): This helps make breathing and exercise easier.
• Macitentan (Opsumit): This has been shown in studies to slow down disease progression.
• Opsynvi: This is a combination of macitentan and tadalafil, approved by the FDA in 2024 to treat adults with PAH.

Phosphodiesterase type 5 (PDE5) inhibitors: These drugs help relax the lung arteries and lower pressure.

• Sildenafil (Revatio): This increases the distance patients can walk and lowers pressure in the lungs. It contains the same active ingredient as Viagra.
• Tadalafil (Adcirca): This is taken once daily and helps improve exercise capacity. It is the same ingredient as in Cialis.

Other medications may include:

• Riociguat (Adempas): This drug works on a pathway similar to PDE5 inhibitors and also helps improve exercise ability.
• Selexipag (Uptravi): This oral medication helps relax blood vessels in the lungs.
• Sotatercept (Winrevair): This drug was FDA-approved in 2024 and is the first medication that targets the BMPR2 signaling pathway, the pathway affected in many patients with heritable PAH. It is FDA-approved for all forms of PAH, not just genetic cases. It increases exercise capacity and reduces the risk of disease worsening.

In addition to the main PAH medications, other treatments may help with symptoms and improve overall well-being.

Vasodilators: Some people may benefit from medications that relax blood vessels and lower pressure:

• Calcium channel blockers (like nifedipine or diltiazem) are used in some patients, but only a small number of people respond well to these drugs.
• Other vasodilators like phentolamine, phenoxybenzamine and prazosin have also been used, but their effectiveness varies from person to person.
• Diuretics: These medications help remove extra fluid from the body, reducing swelling in the legs, abdomen, or lungs. Diuretics are important for managing right heart failure symptoms.
• Oxygen therapy: Some people with PAH need supplemental oxygen, especially during activity or at high altitudes. Portable oxygen tanks allow patients to maintain their independence while managing low oxygen levels.
• Blood thinners (anticoagulants): Drugs like warfarin are used to prevent blood clots. However, the evidence for their benefit in PAH is mixed, and they carry a risk of bleeding. Many specialized PAH centers use them less often now that better treatments are available.
• Light physical activity like walking is often safe and recommended to maintain strength and improve overall health. People with PAH may feel tired more easily but can still benefit from gentle, regular movement as tolerated.

In severely affected people, when medications no longer work, doctors may recommend lung transplant (single or double) or a heart-lung transplant.

Transplantation can significantly improve heart function, especially the right side of the heart. However, it is a major surgery with potential risks like organ rejection and infection. After transplant, people need lifelong medications to suppress the immune system.

Some doctors may advise people with PAH to avoid getting pregnant because it puts extra strain on the heart, and it is considered high risk. Estrogen-containing birth control pills are generally not advised. Other forms of non-estrogen contraception should be discussed with a healthcare provider.

People diagnosed with PAH, especially those with a family history or known gene variant should consider genetic counseling. A genetic counselor can help explain the risks to family members, discuss options for genetic testing and provide resources for support.

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Clinical Trials and Studies

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. funding, and some supported by private industry, are posted on this government website.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Recruitment Office:

Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]

Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/

For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com

For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/

Familial Pulmonary Arterial Hypertension (FPAH) Study

The major goals of the study are to understand the gene(s) that causes the disease, attempt to develop new treatments, and provide information to patients and physicians. Current studies are varied and include: 1) Estrogen study to determine if estrogen effects explain why women get this disease more frequently than men. For this study, urine samples are needed, and a health history questionnaire must be completed by study participants– patients and family members, males and females. 2) Why do some family members with a variant in the BMPR2 gene never develop disease? Are other genes involved in controlling who gets FPAH and who is protected? This study requires blood samples and possibly a small skin biopsy (no stitches required) from patients and family members to provide the materials needed to evaluate other possible genetic influences on disease development.

For more information contact:

Kelly Fox, Coordinator
Vanderbilt University Medical Center
1161 21st Ave. S., T-1218 MCN
Nashville, TN 37232-2650
1-800-288-0378
FAX 1-615-343-7587
[email protected]

For further information regarding Pulmonary Arterial Hypertension:

Anna R. Hemnes, MD
Vanderbilt University Medical Center,
Division of Allergy, Pulmonary and Critical Care Medicine
T1218 Medical Center North
1161 21st Avenue South
Vanderbilt University School of Medicine
Nashville, TN 37232
Phone: 615-322-3412
Fax: 615-343-7448
[email protected]

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References

TEXTBOOK

McGoon MD. Primary Pulmonary Hypertension. In: The NORD Guide to Rare Disorders, Philadelphia: Lippincott, Williams and Wilkins, 2003:678.

JOURNAL ARTICLES

Emmons-Bell S, Johnson C, Boon-Dooley A, et al. Prevalence, incidence, and survival of pulmonary arterial hypertension: A systematic review for the global burden of disease 2020 study. Pulm Circ. 2022;12(1):e12020. Published 2022 Jan 18. doi:10.1002/pul2.12020

Taichman D OJ, Chung L, Klinger J, Lewis S, Mandel J, Palevsky H, Rich S, Sood N, Trow T, Yung R, Elliott C, Badesch D. Pharmacological therapy for pulmonary arterial hypertension in adults: Chest guideline. Chest. 2014;146(2):449-475. 2014;146(2):449-475.

Ghofrani HA, D’Armini AM, Grimminger F, Hoeper MM, Jansa P, Kim NH, Mayer E, Simonneau G, Wilkins MR, Fritsch A, Neuser D, Weimann G, Wang C, Group C-S. Riociguat for the treatment of chronic thromboembolic pulmonary hypertension. N Engl J Med. 2013;369:319-329.

McLaughlin VV, Gaine SP, Howard LS, Leuchte HH, Mathier MA, Mehta S, Palazzini M, Park MH, Tapson VF, Sitbon O. Treatment goals of pulmonary hypertension. J Am Coll Cardiol. 2013;62:D73-81.

Pulido et al. Macitentan and morbidity and mortality in pulmonary arterial hypertension. NEJM 2013;369:809-818.

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. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol. 2013;62:D34-41.

Galie N, Brundage BH, Ghofrani HA, Oudiz RJ, Simonneau G, Safdar Z, Shapiro S, White RJ, Chan M, Beardsworth A, Frumkin L, Barst RJ. Tadalafil therapy for pulmonary arterial hypertension. Circulation. 2009;119:2894-2903.

McLaughlin VV, Archer SL, Badesch DB, et al. 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. J Am Coll Cardiol 2009;53:1573-619.

Simonneau G, Robbins IM, Beghetti M, et al. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol 2009;54:S43-54.

INTERNET

Austin ED, Phillips JA III, Loyd JE. Heritable Pulmonary Arterial Hypertension Overview. 2002 Jul 18 [Updated 2020 Dec 23]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2025. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1485/ Accessed May 20, 2025.

McKusick VA, ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Pulmonary Hypertension, Primary. Entry No: 178600; Last Update: 04/02/2024. https://omim.org/entry/178600 Accessed May 20, 2025.

Oudiz, RJ. Idiopathic Pulmonary Arterial Hypertension. Medscape. Updated: Oct 11, 2024. https://emedicine.medscape.com/article/301450-overview Accessed May 20, 2025.

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Programs & Resources

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NORD and MedicAlert Foundation have teamed up on a new program to provide protection to rare disease patients in emergency situations.

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Ensuring that patients and caregivers are armed with the tools they need to live their best lives while managing their rare condition is a vital part of NORD’s mission.

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Patient Organizations

Pulmonary Hypertension Association

NORD Member

Email: [email protected]

Related Rare Diseases: Pulmonary Arterial Hypertension

https://rarediseases.org/organizations/pulmonary-hypertension-association/

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American Heart Association

Phone: 214-784-7212 Email: [email protected] Fax: 214-784-1307

Related Rare Diseases: Recurrent Pericarditis, Tangier Disease, Shprintzen Goldberg Syndrome, ...

https://rarediseases.org/organizations/american-heart-association/

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American Lung Association

Email: [email protected]

Related Rare Diseases: Pediatric Non-Small Cell Lung Cancer, Small Cell Lung Cancer, Antisynthetase Syndrome, ...

https://rarediseases.org/organizations/american-lung-association/

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NIH/National Heart, Lung and Blood Institute

Phone: 301-592-8573 Email: [email protected] Fax: 301-251-1223

Related Rare Diseases: Short QT Syndrome, Recurrent Pericarditis, Pediatric Non-Small Cell Lung Cancer, ...

https://rarediseases.org/organizations/nih-national-heart-lung-and-blood-institute/

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PHA EUROPE, European Pulmonary Hypertension Association

Email: [email protected]

Related Rare Diseases: Pulmonary Arterial Hypertension

https://rarediseases.org/organizations/pha-europe-european-pulmonary-hypertension-association/

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iSEEK Pulmonary Hypertension Hope Center

Email: [email protected]

Related Rare Diseases: Pulmonary Arterial Hypertension

https://rarediseases.org/organizations/iseek-pulmonary-hypertension-hope-center/

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PHAWARE GLOBAL ASSOCIATION

Email: [email protected]

Related Rare Diseases: Pulmonary Arterial Hypertension

https://rarediseases.org/organizations/phaware-global-association/

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Team PHenomenal Hope

Email: [email protected]

Related Rare Diseases: Pulmonary Arterial Hypertension

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More Information

The information provided on this page is for informational purposes only. The National Organization for Rare Disorders (NORD) does not endorse the information presented. The content has been gathered in partnership with the MONDO Disease Ontology. Please consult with a healthcare professional for medical advice and treatment.

GARD Disease Summary

The Genetic and Rare Diseases Information Center (GARD) has information and resources for patients, caregivers, and families that may be helpful before and after diagnosis of this condition. GARD is a program of the National Center for Advancing Translational Sciences (NCATS), part of the National Institutes of Health (NIH).

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Orphanet

Orphanet has a summary about this condition that may include information on the diagnosis, care, and treatment as well as other resources. Some of the information and resources are available in languages other than English. The summary may include medical terms, so we encourage you to share and discuss this information with your doctor. Orphanet is the French National Institute for Health and Medical Research and the Health Programme of the European Union.

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