NORD gratefully acknowledges Anna R. Hemnes, MD, Vanderbilt University Medical Center, Department of Medicine, for assistance in the preparation of this report.
Pulmonary arterial hypertension (PAH) is a rare, progressive disorder characterized by high blood pressure (hypertension) in the arteries of the lungs (pulmonary artery) for no apparent reason. The pulmonary arteries are the blood vessels that carry blood from the right side of 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 30-60. 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 in the lungs causes the right heart to work much harder, and over time, this heart muscle 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 reasonable quality of life.
Approximately 15-20% of patients with PAH have heritable forms of PAH. People with heritable PAH have either: (1) an autosomal dominant genetic condition associated with mutations in the BMPR2 gene or other recently identified genes now associated with HPAH or other forms of PAH or associated conditions such as pulmonary capillary hemangiomatosis or pulmonary veno-occlusive disease, 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 linked to diet drugs such as Fen-Phen, Pondimin and Redux. These drugs were taken off the market in 1997, although cases related to drugs and toxins, such as methamphetamines do still appear. PAH is also associated with a number of other medical diseases such as cirrhosis and connective tissue diseases like scleroderma. About 30% of patients with PAH have an associated connective tissue disease.
PAH symptoms are those that are usually due to not having enough oxygen in the blood. In most cases, the initial symptom is severe shortness of breath following 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.
Some affected individuals may experience puffiness or swelling of the face, ankles, abdomen and feet due to abnormal accumulation of fluid (edema) within fascial tissues.
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. 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 from shortness or breath or other symptoms.
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 most commonly, though recently other genes and pathways have been identified. In approximately 20% of families with PAH, we do not yet know the underlying 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 patients (e.g. CAV1, KCNK3, etc), although many of those genes are closely linked to BMPR2 in terms of biologic signaling (SMAD9, ALK1, endoglin). Recently, pulmonary veno-occlusive disease and pulmonary capillary hemangiomatosis have been linked to mutations in the gene EIF2AK4. The function of this gene is still being studied.
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, though other diet drugs have been associated with PAH such as benfluorex that was used in Europe until 2009.
Along with the increased risk of diet pills, other exposures have been associated with the development of PAH. These include methamphetamines and dasatanib. 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.
Several conditions have been associated with PAH such as liver disease (cirrhosis), congenital heart disease and connective tissue diseases such as scleroderma. The mechanisms through which these conditions might cause PAH are presently being studied and are unknown.
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 PAH, 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 affect the pulmonary blood vessels and put a strain on the heart, 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.
Persistent pulmonary hypertension of the newborn (PPHN) is a kind of PAH that 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.
PAH occurs 3-5 times more frequently in females as in males. It tends to affect females between the ages of 30 and 60. 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.
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 echocardiography, blood tests, pulmonary function tests, 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 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 or mutation in another gene known to cause PAH 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. These medications can be broadly broken down into four categories described below.
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.
Recently, a room temperature stable form of epoprostenol had been developed. This is known and Veletri and is made by Actelion Pharmaceuticals US, Inc.
The FDA has approved the orphan drug treprostinil (Remodulin) in subcutaneous and intravenous forms and Tyvaso, an inhaled form of treprostinil, and oral form (Orenitram) for the treatment of PAH. The drug is made by United Therapeutics Corp.
In 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.
Endothelin Receptor Antagonists
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.
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).
The FDA has approved the orphan drug Macitentan (Opsumit) for treatment of PAH in October 2013. In clinical trials this drug was shown to delay disease progression. It works through similar mechanisms as bosentan and ambrisentan. Macitentan is manufactured by Actelion Pharmaceuticals US, Inc.
Phosphodiesterase Type 5 Inhibitors
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). This medication is manufactured by Pfizer Pharmaceuticals.
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.This medication is from United Therapeutics.
The FDA has approved the drug riociguat (Adempas) for the treatment of PAH. Riociguat works on the same pathway as the phosphodiesterase type 5 inhibitors. This medication is made by Bayer.
In 2016, selexipag(Uptravi) was approved for adults and acts by relaxing muscles in the walls of blood vessels. Uptravi is manufactured by Actelion Pharmaceuticals US, Inc.
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 may be used to treat PAH as supportive therapies. Anticoagulants, such as warfarin, are drugs that prevent blood clots from forming. There are equivocal data on whether these drugs are useful in PAH patients and there are significant bleeding risks associated with them. 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 and can be useful to maintain muscle strength and conditioning.
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. Estrogen-containing oral contraceptives are generally not recommended, but other types of birth control may be used.
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
Some current clinical trials also are posted on the following page on the NORD website:
For information about clinical trials sponsored by private sources, contact:
For information about clinical trials conducted in Europe, 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:
Kelly Fox, Coordinator
Vanderbilt University Medical Center
1161 21st Ave. S., T-1218 MCN
Nashville, TN 37232-2650
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
RareConnect offers a safe patient-hosted online community for patients and caregivers affected by this rare disease. For more information, visit www.rareconnect.org.
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