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.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.
PAH symptoms are those that are normally associated with 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.
In some cases, affected individuals may experience puffiness or swelling of the face, ankles, abdomen 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. 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 subjects (e.g. CAV1, KCNK3, etc), although many of those genes are closely linked to BMPR2 in terms of biologic signaling (SMAD9, ALK1, endoglin).
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, 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. 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).
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.
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.
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.
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.
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).
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.
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.
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 idiopathic and heritable forms of 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 may be used.
Refer to Research Publications.