Pulmonary Arterial Hypertension
NORD is very grateful to Eric D. Austin, MD, MSCI, Vanderbilt University Medical Center, Department of Pediatrics, and James E. Loyd, MD, Vanderbilt University Medical Center, Department of Medicine, for their assistance in the preparation of this report.
Synonyms of Pulmonary Arterial Hypertension
- idiopathic pulmonary arterial hypertension
- precapillary pulmonary hypertension
- primary obliterative pulmonary vascular disease
- primary pulmonary hypertension
- heritable pulmonary arterial hypertension (HPAH)
- idiopathic pulmonary arterial hypertension (IPAH)
Pulmonary arterial hypertension (PAH) is a rare, progressive disorder characterized by high blood pressure (hypertension) of the main artery of the lungs (pulmonary artery) for no apparent reason. The pulmonary artery is the blood vessel that carries blood from the heart through the lungs. Symptoms of PAH include shortness of breath (dyspnea) especially during exercise, chest pain, and fainting episodes. The exact cause of PAH is unknown and although treatable, there is no known cure for the disease.
PAH usually affects women between the ages of 20-50. Individuals with PAH may go years without a diagnosis, either because their symptoms are mild, nonspecific, or only present during demanding exercise. However, it is important to treat PAH because without treatment high blood pressure causes the heart to work much harder, and over time, these muscles may weaken or fail. The progressive nature of this disease means that an individual may experience only mild symptoms at first, but will eventually require treatment and medical care to maintain a normal lifestyle.
Approximately 15-20% of patients with PAH have heritable PAH. People with heritable PAH have eitehr: (1) an autosomal dominant genetic condition associated with mutations in the BMPR2 gene or another gene in the TGFbeta pathway now associated with HPAH, or (2) are members of a family in which PAH is known to occur as primary disease.
The first reported case of PAH occurred in 1891, when the German doctor E. Romberg published a description of a patient who, at autopsy, showed thickening of the pulmonary artery but no heart or lung disease that might have caused the condition. In 1951, 3 cases were reported by Dr. D.T. Dresdale in the U.S. and the illness was originally called primary pulmonary hypertension.
PAH has been directly linked to diet drugs such as Fen Phen, Pondimin and Redux. These drugs were taken off the market in 1997, although cases related to diet drugs and toxins, such as methamphetamines do still appear.
PAH symptoms are those that are normally associated with not having enough oxygen in the blood. In most cases, the initial symptom is shortness of breath following slight exertion. Additional symptoms include excessive fatigue, weakness, chest pain, dizzy spells, and fainting episodes.
Affected individuals may also have a cough, sometimes with blood (hemoptysis), an enlarged heart and liver, low blood pressure (hypotension), and hoarseness due to compression of a nerve in the chest by an enlarged pulmonary artery.
In some cases, affected individuals may experience puffiness or swelling of the face, ankles, and feet due to abnormal accumulation of fluid (edema) within fascial tissues.
In approximately 10 percent of cases, individuals experience Raynaud's phenomenon, a condition characterized by painfully cold fingers and toes caused by widening (dilation) or narrowing (constriction) of small blood vessels in the hands and feet in response to cold.
Individuals with advanced stages of PAH may have abnormal bluish discoloration of the skin due to low levels of circulating oxygen in the blood (cyanosis). In addition, in severe cases of PAH, the right chamber (ventricle) of the heart is abnormally enlarged (hypertrophy), resulting in diminished functioning of the right portion of the heart and, potentially, right heart failure. Other muscles in the heart can weaken or fail from strenuous use if not treated. Some patients with PAH do not seek medical advice until they are no longer able to continue with their normal activities. At this time, the disease may have progressed to a point where the patient is completely bedridden.
The exact cause of PAH is unknown. Researchers believe 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 most people who develop PAH have blood vessels that are particularly sensitive to certain internal or external factors and constrict, or narrow, when exposed to these factors.
Approximately 15-20% of patients with PAH have heritable PAH. Heritable PAH is an autosomal dominant genetic condition caused by mutations in the BMPR2 gene or PAH that occurs in families due to other as yet unknown gene mutations. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation in the affected individual. Approximately 80% of individuals who have a mutated (abnormal) BMPR2 gene will not develop PAH, so other genes or environmental triggers must be necessary for PAH to develop. The risk of passing the abnormal gene from parent to offspring is 50% for each pregnancy and the risk is the same for males and females. Of note, there now exist several publications associating PAH with mutations in other genes in a small number of subjects, although all of those genes are closely linked to BMPR2 in terms of biologic signaling (SMAD9, ALK1, endoglin).
In August 1996, the Food and Drug Administration (FDA) evaluated data from a report of the International Primary Pulmonary Hypertension Study (IPPHS). The study examined the relationship between appetite-suppressant drugs (dexfenfluramine [Redux] and fenfluramine [Pondimin] and what was then called PPH. Findings indicated that the risk of PPH (now called a type of PAH) in individuals using appetite-suppressant drugs for three months or longer is about nine times higher than the risk for non-users. The final IPPHS report estimated that the risk of this disorder is about 23 times higher in individuals who use appetite-suppressants for three months or longer. These drugs were taken off the market in 1997.
Along with the increased risk of diet pills, other exposures have been associated with the development of PAH. These include methamphetamines and cocaine. In addition, a very small percentage of HIV patients with AIDS develop PAH that is identical in presentation to primary PAH. In terms of other exposures which may contribute to the development of PAH, few are validated in rigorous studies. However, female sex hormones are an area of great interest for several reasons, including: (1) the higher risk of PAH among females, and (2) the association of pregnancy with the development of PAH (may be more common in the peripartum period), and (3) some association with exogenous estrogen intake the development of PAH.
PAH occurs twice as frequently in females as in males. It tends to affect females between the ages of 20 and 50. New cases are estimated to occur in one to two individuals per million each year in the U.S. The incidence is estimated to be similar in Europe. Approximately 500-1000 new cases of PAH are diagnosed each year in the U.S. There is no ethnic or racial group that is known to have a higher frequency of patients with PAH. An exception to this is an apparent paucity of cases of HPAH among subjects of African ancestry, although this may relate to reporting bias and has not been rigorously studied.
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.
Pulmonary hypertension is a general term that means high blood pressure that occurs only in the arteries in the lungs and right side of the heart. Pulmonary hypertension can be caused by a wide variety of other diseases. When the cause of pulmonary hypertension in known, it is often called secondary pulmonary hypertension, although this terminology is no longer an official term to describe a form of pulmonary hypertension. PAH is only diagnosed when all causes of secondary pulmonary hypertension have been ruled out and therefore, the cause is not known. However, many types of secondary pulmonary hypertension can be confused for PAH. Symptoms of the following disorders can be similar to those of PAH. Comparisons may be useful for a differential diagnosis:
Lung disease is a leading cause of secondary pulmonary hypertension. Most lung diseases that lead to secondary pulmonary hypertension are detected by abnormal lung sounds on physical examination, pulmonary function testing, and/or high resolution computed tomographic lung imaging.
Cor pulmonale is a term that denotes enlargement of the right ventricle of the heart that occurs as a result of severe lung disease. It is used as a term for pulmonary heart disease that affects both the heart and lungs. A common cause of cor pulmonale is massive clotting in the lungs that results in increased pressure in the right ventricle of the heart, usually resulting in heart failure. Additional causes include severe forms of chronic bronchitis and emphysema, as well as extensive loss of lung tissue from surgery or injury. Symptoms usually include enlargement of the right side of the heart, difficulty breathing, fainting spells upon exertion, and substernal angina pain in the chest. (For more information on this disorder, choose "cor pulmonale" as your search term in the Rare Disease Database.)
Most advanced stages of cardiac conditions can cause secondary pulmonary hypertension as well. These diseases include heart disease, valvular disease, and cardiomyopathy. They can be ruled out as the cause of pulmonary hypertension by careful history, and using electrocardiography, echocardiography, and cardiac catheterization.
Scleroderma is a chronic systemic autoimmune disease (primarily of the skin) characterized by fibrosis (or hardening), vascular alterations, and auto-antibodies. One of the serious complications of this rare disease is secondary pulmonary hypertension, which can occur in up to a third of scleroderma patients. Almost everyone with scleroderma experiences Raynaud's phenomenon as well. (For more information on this disorder, choose "scleroderma" as your search term in the Rare Disease Database.)
Human Immunodeficiency Virus (HIV) infection can also put a strain on the heart and cause pulmonary hypertension, typically in the setting of overt AIDS due to HIV. HIV is a rare virus which causes AIDS, a chronic and life-threatening illness. HIV lowers the immune system and makes the body much more susceptible towards disease. Symptoms of HIV are at first, similar to those of the flu, and may include fever, swollen glands, headache, sore throat, and a rash. (For more information on this disorder, choose "human immunodeficiency virus" as your search term in the Rare Disease Database.)
Interstitial pneumonia is a type of chronic lung disease. It involves the spaces and tissues in the lining of the lungs with abnormal increases in these tissues. Major symptoms may include shortness of breath on exertion, coughing and loss of appetite. The symptoms may vary from mild to severe according to the extent of involvement. An affected individual usually has no fever, and there is usually no overproduction of mucous. (For more information on this disorder, choose "interstitial pneumonia", as your search term in the Rare Disease Database.)
Pulmonary venous hypertension is a common disorder associated with pulmonary hypertension. Pulmonary venous hypertension is usually caused by dysfunction of the left side of the heart (e.g. mitral valve or left ventricle). This can lead to an unusual accumulation of blood flow in the lung which puts the affected individual at a higher risk for developing pleural effusions and pulmonary edema. Like PAH, pulmonary venous hypertension can cause high blood pressure, difficulty breathing, fatigue, and cough.
Persistent pulmonary hypertension of the newborn (PPHN) occurs when a newborn's circulatory system does not adapt to breathing outside the womb. It occurs most often in full-term or post-term babies who had a difficult birth. Newborns that have PPHN have rapid respiration (tachypnea) and abnormal bluish discoloration of the skin due to low levels of circulating oxygen in the blood (cyanosis). The disorder is believed to be caused by insufficient oxygen in the blood flowing to the lungs just before, during or after birth (perinatal hypoxemia), although its precise cause is unknown.
It can often be hard to detect PAH in a routine clinical examination, even if the disease has progressed. Symptoms of PAH are not unique and may be confused with many other diseases that cause a lack of oxygen in the blood. The diagnosis of PAH is also one of exclusion, meaning that PAH is only diagnosed when other causes of pulmonary hypertension have been ruled out and there seems to be no known cause of the hypertension. The tests that are commonly performed to diagnose PAH and rule out other diseases are blood tests, pulmonary function tests, arterial blood gas measurements, X-rays of the chest, electrocardiography (ECG), and the "6-minute walk test", which essentially measures how far an individual can walk in that time period. Ultimately, the majority of subjects undergo echocardiographic testing, followed by confirmation by cardiac catheterization with and without vasodilator testing.
Heritable PAH is confirmed if two or more family members have PAH or if a BMPR2 gene mutation is identified in the affected person. Molecular genetic testing is available for mutations in the BMPR2 gene, but should only be performed in concert with genetic counseling.
Clinical Testing and Work-Up
Patients suspected to have PAH should be referred to a referral center specializing in PAH diagnosis and treatment. The Pulmonary Hypertension Association website can provide contact information for these centers.
Genetic counseling is recommended for affected individuals and their families.
Several medications have been approved by the US Food and Drug Administration (FDA) for the treatment of PAH.
In December 2004, the FDA approved iloprost (Ventavis) for the treatment of PAH. The treatment is inhaled through the mouth with the assistance of a special nebulizer, dilating the arteries and preventing the formation of blood clots. Ventavis is marketed in the U.S. by Actelion Pharmaceuticals US, Inc.
The orphan drug bosentan (Tracleer) has been approved by the FDA for treatment of PAH. The drug allows affected individuals to exert themselves physically without shortness of breath. It should be carefully monitored while in use. Tracleer is manufactured by Actelion Pharmaceuticals US, Inc. For information, contact:
Actelion Pharmaceuticals US
5000 Shoreline Court, Suite 200
South San Francisco, CA 94080
Phone 1-866-ACTELION (866-228-3546)
The FDA has approved the orphan drug treprostinil (Remodulin) in subcutaneous and intravenous forms and Tyvaso, an inhaled form of treprostinil, for the treatment of PAH. The drugs is made by:
United Therapeutics Corp.
68 T. W. Alexander Drive
P.O. Box 14186
Research Triangle Park, NC 27709
The orphan drug Flolan (epoprostenol sodium for injection or prostacycline) has been approved as a standard long-term treatment of individuals with severe PAH. It was the first drug approved specifically for patients with pulmonary hypertension. This drug is used in individuals who do not respond to other types of therapy and in patients with very severe disease. This drug is administered by intravenous infusion through a permanent ambulatory in-dwelling central venous catheter. Since this drug requires continuous infusion, it must not be withdrawn suddenly (including sudden reduction of dosage). Flolan, which is a version of a natural hormone called prostacyclin that dilates constricted blood vessels, is manufactured by GlaxoSmithKline. For more information, please call GlaxoSmithKline:
US Phone: +1 888 825 5249
UK Phone: +44 (0)800 221 441
Revatio (sildenafil), a phosphodiesterase type 5 (PDE5) inhibitor is also used to treat PAH. In clinical studies it increased the distance people walked and decreased pressure in the pulmonary artery. It contains the same ingredient as Viagra (sildenafil citrate). For more information please contact:
235 East 42nd Street
NY, NY 10017
The FDA has approved the orphan drug Ambrisentan (Letairis) for treatment of PAH in June 2007. It is used primarily to make exercise and breathing easier. Because of the risk of birth defects, ambrisentan is available only through a special restricted distribution program called the Letairis Education and Access Program (LEAP). For more information please contact:
333 Lakeside Drive
Foster City, CA 94404
Phone: (650) 574-3000
Tadalafil (Adcirca) is a once-daily phosphodiesterase type 5 (PDE-5) inhibitor, shown to improve the patient's ability to exercise. Adcirca contains the same ingredient (tadalafil) as Cialis. For more information please contact:
1040 Spring Street
Silver Spring, Maryland 20910
Tel. (301) 608-9292
Drugs that cause widening of blood vessels (vasodilators) and lessen blood pressure may also be used to treat PAH. In some PAH cases, calcium channel blockers (e,g, nifedipine and diltiazem) are used as vasodilators. Unfortunately, only a small minority of patients appear to respond with improvement to the use of calcium channel blockers. Other vasodilator drugs have been used including phentolamine, phenoxybenzamine and prazosin. The effectiveness of vasodilator therapy varies from case to case.
Other treatments such as anticoagulants, diuretics, and oxygen are used to treat PAH as supportive therapies. Anticoagulants, such as warfarin, are drugs that prevent blood clots from forming. Studies have shown that treatment with anticoagulants improves the long-term prognosis in individuals with PAH. Diuretics are used to treat fluid retention and swelling (edema) often associated with the condition.
To continue with daily activities some individuals may need to carry portable oxygen when they go out. Often light exercise such as walking is still possible for PAH patients if they are able to carry portable oxygen.
In severe cases of PAH, a heart-lung, single lung or double lung transplant may be recommended. In patients with lung transplants, both the structure and function of the right ventricle markedly improve. Lung transplant is itself a difficult process and results in new challenges for patients who undergo this procedure. Complications of transplantation include rejection of the transplanted organ and infection. Patients take medications for life to reduce their immune system's ability to reject their transplanted organ.
Pregnancy is not advised for patients with PAH because it puts an extra load on the heart. Oral contraceptives are not recommended, but other types of birth control should be used.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.com. 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
For information about clinical trials sponsored by private sources, contact:
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 we need urine samples and a health history questionnaire to be completed by study participants-- patients and family members, males and females. 2) Why do some family members with a mutation in BMPR2 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:
James Loyd, M. D., Director
Lisa Wheeler, 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
For further information regarding Pulmonary Arterial Hypertension:
Eric D. Austin, MD, MSCI
Vanderbilt University Medical Center, Department of Pediatrics
Division of Allergy, Pulmonary, and Immunology Medicine
Suite DD-2205, Vanderbilt Medical Center North
Vanderbilt University School of Medicine
Nashville, TN 37232-2578
James E. Loyd, MD
Vanderbilt University Medical Center, Department of Medicine
Division of Allergy, Pulmonary & Critical Care Medicine
Suite T-1218 Vanderbilt Medical Center North
Nashville, TN 37232-2650
Pulmonary Arterial Hypertension Resources
NORD offers an online community for this rare disease. RareConnect was created by EURORDIS (European Rare Disease Organisation) and NORD (National Organization for Rare Disorders) to provide a safe space where individuals and families affected by rare diseases can connect with each other, share vital experiences, and find helpful information and resources. You can view these international, rare disease communities at www.rareconnect.org.
NORD Member Organizations:
(To become a member of NORD, an organization must meet established criteria and be approved by the NORD Board of Directors. If you're interested in becoming a member, please contact Susan Olivo, Membership Manager, at firstname.lastname@example.org.)
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FROM THE INTERNET
Loyd JE and Phillips JA. Updated March 28, 2011. Heritable Pulmonary Arterial Hypertension. In: GeneReviews at GeneTests: Medical Genetics Information Resource. Copyright, University of Washington, Seattle. 1997-2011. Available at: http://www.ncbi.nlm.nih.gov/books/NBK1485/ Accessed 9/15/11.
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Oudiz, RJ. Primary Pulmonary Hypertension. eMedicine from Medscape Reference. Updated August 11, 2011. http://emedicine.medscape.com/article/301450-overview Accessed 9/15/11.
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