Pulmonary Arterial Hypertension

Pulmonary Arterial Hypertension

National Organization for Rare Disorders, Inc.

Important

It is possible that the main title of the report Pulmonary Arterial Hypertension is not the name you expected. Please check the synonyms listing to find the alternate name(s) and disorder subdivision(s) covered by this report.

Synonyms

  • PAH
  • primary obliterative pulmonary vascular disease
  • primary pulmonary hypertension
  • precapillary pulmonary hypertension
  • idiopathic pulmonary arterial hypertension
  • IPAH
  • FPAH
  • HPAH

Disorder Subdivisions

  • idiopathic pulmonary arterial hypertension (IPAH)
  • heritable pulmonary arterial hypertension (HPAH)

General Discussion

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.

Symptoms

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.

Causes

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.

Affected Populations

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.

Standard Therapies

Diagnosis

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.



Treatment

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:



Pfizer Pharmaceuticals

235 East 42nd Street

NY, NY 10017

Phone: 1-212-733-2323



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:



Gilead Headquarters

333 Lakeside Drive

Foster City, CA 94404

Phone: (650) 574-3000

1-800-GILEAD-5 (1-800-445-3235)



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:



United Therapeutics

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.

Investigational Therapies

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

Email: prpl@cc.nih.gov



For information about clinical trials sponsored by private sources, contact:

www.centerwatch.com



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

lisa.wheeler@vanderbilt.edu



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

Phone: 615.343.7617

Fax: 615.343.9951

eric.austin@vanderbilt.edu



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

Phone: 615.322.3412

Fax: 615.343.7448

jim.loyd@vanderbilt.edu

References

TEXTBOOKS

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



Beers MH, Berkow R, eds. The Merck Manual, 17th ed. Whitehouse Station, NJ: Merck Research Laboratories; 1999:



Fishman AP, ed. Pulmonary Diseases and Disorders, 2nd ed. New York, NY: McGraw-Hill Book Company; 1988:



JOURNAL ARTICLES

Michelakis ED, et al. Long-term treatment with oral sildenafil is safe and improves functional capacity and himodynamics in patients with pulmonary arterial hypertension. Circulation. 2003;108:2066-9.



Ghofrani, HA, et al. Combination therapy with oral sildenafil and inhaled iloprost for severe pulmonary hypertension. Ann Intern Med. 2002;136:515-22.



Simonneau G, et al. Continuous subcutaneous infusion of treprostinil, a prostacyclin analogue, in patients with pulmonary arterial hypertension. Am J Respir Crit Care Med. 2002;165:800-04.



Rubin L, et al. Bosentan therapy for pulmonary arterial hypertension. N Engl J Med. 2002;346:896-903.



Channick RN, et al., Effectsn of dual endothelin-receptor antagonist bosentan in patients with primary pulmonary hypertension: a randomized, placebo-controlled study. Lancet. 2001;358:1119-23.



Trembath RC, et al. Clinical and molecular genetic features of pulmonary hypertension in patients with hereditary hemorrhagic telangiectasia. New Engl. J Med. 2001;345:325-34.



Klings ES, et al. Current management of primary pulmonary hypertension. Drugs. 2001;61:1945-56.



Abrams D, et al. Sildenafil as a selective pulmonary vasodilator in childhood primary pulmonary hypertension. Heart. 2000;84:E4.



Rich S. Primary pulmonary hypertension. Curr Treat Options Cardiovasc Med. 2000;2:135-40.



Archer S, et al. Primary pulmonary hypertension: a vascular, biology and translational research "Work in Progress". Circulation. 2000;102:2781-91.



Puigarnau Vallhonrat R, et al. Nebulized prostacyclin treatment for pulmonary hypertension in a 2-year-old girl. An Esp Pediatr. 2000;53:372-76.



Franke U, et al. Ten years experience with lung and heart-lung transplantation in primary and secondary pulmonary hypertension. Eur J Cardiothorac Surg. 2000;18:447-52.



O'Brien A, et al. Pulmonary hypertension update. Compr Ther. 2000;26:190-96.



Krishnan U. Diagnosis and management of primary pulmonary hypertension. Indian J Pediatr. 2000;67:523-27.



Machado RD, et al. A physical and transcript map based upon refinement of the critical interval for PPH1, a gene for familial primary pulmonary hypertension. Genomics. 2000;68:220-28.



Benvenuto DB. Prostacyclin (Flolan). Intravenous nursing responsibilities in the care of the patient with primary pulmonary hypertension. J Intraven Nurs. 1999;22:267-72.



Svendsen UG, et al. Primary pulmonary hypertension. Ugeskr Laeger. 1999;161:935-40.



Rich S, et al. The short-term effects of digoxin in patients with right ventricular dysfunction from pulmonary hypertension. Chest. 1998;114:787-92.



Rubin LJ. Primary pulmonary hypertension. New Eng. J. Med. 1997;336:111-17.



Nichols WC et al. Localization of the gene for familial primary pulmonary hypertension to chromosome 2q31-32. Nature Genet. 1997;15:277-80.



Mark EJ, et al. Fatal pulmonary hypertension associated with short-term use of fenfluramine and phentermine. New Eng. J. Med. 1997;337:602-06.



Shapiro SM, et al. Primary pulmonary hypertension: improved long-term effects and survival with continuous intravenous epoprostenol infusion. J Am Coll Cardiol. 1997;30:343-49.



Connolly HM. Valcular heart disease associated with fenfluramine-phentermine. New Eng. J. Med. 1997;337:1772-76.



Barst RJ, et al. A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension. New Eng. J. Med. 1996;334:296-301.



Schilze-Neicke I, et al. Intravenous epoprostenol for primary pulmonary hypertension. New Eng J Med. 1996;334:1477-78.



Pharmacotherapy for obesity -- "Do the benefits outweigh the risks?" triggered a second layer of controversy. New Eng J Med. (1996; 335). P. 659.



Langleben D, et al. Familial pulmonary capillary hemangiomatosis resulting in primary pulmonary hypertension. Ann Intern Med. 1988;109:106-09.



Groves BM, et al. Current approach to treatment of primary pulmonary hypertension. Chest. 1988;93:175s



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



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.



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.



McKusick VA, ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No:178600; Last Update: 7/1/10. http://omim.org/entry/178600



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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