Information on the following diseases can be found in the Related Disorders section of this report:

• Cor pulmonale
• Interstitial pneumonia
• Pulmonary hypertension, secondary
• Persistent pulmonary hypertension of the newborn

In most cases, the initial symptom associated with primary pulmonary hypertension is shortness of breath following slight exertion. Additional symptoms include excessive fatigue, weakness, chest pain, dizzy spells, and fainting episodes.

In some cases, affected individuals may experience puffiness or swelling of the face due to abnormal accumulation of fluid (edema) within facial tissues. In addition, affected individuals may have abnormal bluish discoloration of the skin due to low levels of circulating oxygen in the blood (cyanosis).

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 approximately 10 percent of cases, individuals may have 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.

In severe cases of primary pulmonary hypertension, 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.
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The exact cause of primary pulmonary hypertension is unknown. In approximately 6-10 percent of cases (familial cases), a genetic predisposition to this disorder has been observed. A genetic predisposition means that a person may carry a gene for a disease, but the gene may not be expressed unless something in the environment triggers the disease process.

In familial cases, primary pulmonary hypertension is transmitted as an autosomal dominant trait if it occurs in several generations of the same family. Genetic diseases are determined by two genes, one received from the father and one from the mother. 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 (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy regardless of the sex of the resulting child.

Investigators have determined that some cases of primary pulmonary hypertension are caused by disruption or changes (mutations) of the bone morphogenic protein receptor II (BMPR2) gene located on the long arm (q) of chromosome 2 (2q33). Chromosomes are found in the nucleus of all body cells. They carry the genetic characteristics of each individual. Pairs of human chromosomes are numbered from 1 through 22, with an unequal 23rd pair of X and Y chromosomes for males and two X chromosomes for females. Each chromosome has a short arm designated as "p" and a long arm identified by the letter "q." Chromosomes are further subdivided into bands that are numbered. For example, "chromosome 2q33" refers to band 33 on the long arm of chromosome 2.

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 Primary Pulmonary Hypertension. Preliminary findings indicate that the risk of Primary Pulmonary Hypertension 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.

ADDITIONAL NEWS ABOUT FEN/PHEN
Based upon new evidence about significant side effects associated with the use of the diet drugs fenfluramine (Pondimin) or dexfenfluramine (Redux) in combination with phentermine (fen-phen or dexfen-phen), the Food and Drug Administration (FDA) requested that the manufacturers voluntarily withdraw fenfluramine and dexfenfluramine from the market. The Mayo Clinic reported a rare clustering of unusual cases of heart valve disease (e.g., leaky valves, backward flow of blood through the valve, etc.) in individuals who had taken these anti-obesity drug combinations. These patients were evaluated through an echocardiogram, a specialized imaging procedure that can test the functions of heart valves. A group of five physicians reported that about 30 percent of former fen/phen users who were evaluated had an abnormal echocardiogram. Though fen-phen and dexfen-phen were a popular diet drug combination, no studies were submitted to the FDA to demonstrate long-term safety or effectiveness of these drugs when taken together. Therefore, the manufacturers have withdrawn these drugs from the market and the FDA has recommended that people who took these drugs should contact their physicians for heart examinations

Primary pulmonary hypertension 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 United States. The incidence is estimated to be similar in Europe as well. Approximately 500-800 new cases of primary pulmonary hypertension are diagnosed each year in the United States. Approximately 6% of cases run in families.

A rare form of pulmonary hypertension affects individuals who are at high altitude levels (e.g., mountain climbing).

Symptoms of the following disorders can be similar to those of primary pulmonary hypertension. Comparisons may be useful for a differential diagnosis:

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 chronic bronchitis, emphysema, and 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.)

Interstitial pneumonia is a type of primary pneumonia. 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).

Persistent pulmonary hypertension of the newborn occurs most often in full-term or overdeveloped newborns. Infants with this disorder have no obvious symptoms of heart or lung disease, but will have a high level of acid, or a lack of bicarbonate content in the blood and body tissues (acidosis). They will also 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).
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Primary pulmonary hypertension is treated with drugs that cause widening of blood vessels (vasodilators) and lessen blood pressure. In most cases, calcium channel blockers (e,g, nifedipine and diltiazem) are used to treat primary pulmonary hypertension as vasodilators. Other vasodilator drugs have been used including phentolamine, phenoxybenzamine and prazosin. The effectiveness of vasodilator therapy varies from case to case.

In December 2004 the US Food and Drug Administration (FDA) approved iloprost (Ventavis), for the treatment of pulmonary arterial hypertension. 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 CoTherix. For information, call (877) 483-6828 or go to www.4ventavis.com.

The FDA has approved the use of the orphan drug treprostinil (Remodulin) for use in the treatment of primary pulmonary hypertension. The drug is made by:

United Therapeutics Corp.
68 T. W. Alexander Drive
P.O. Box 14186
Research Triangle Park, NC 27709

The orphan drug bosentan (Tracleer) has been approved by the U.S. Food and Drug Administration (FDA) for treatment of pulmonary hypertension. The drug improves the exercise ability of individuals with primary pulmonary hypertension allowing them to exert themselves physically without shortness of breath. It should be carefully monitored while in use. Tracleer is manufactured by Actelion Pharmaceuticals US, Inc., of San Francisco, California. For information, contact the Tracleer Access Program Monday through Friday from 8 a.m. to 8 p.m. at 1-866-228-3546.

The orphan drug Flolan (epoprostenol sodium for injection or prostacycline) has been approved as a standard long-term treatment of individuals with severe primary pulmonary hypertension. This drug is used in individuals who do not respond to other types of therapy. 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..

Other treatments such as anticoagulants, diuretics, and oxygen are used to treat primary pulmonary hypertension as second-line 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 primary pulmonary hypertension.

Diuretics are used to treat fluid retention and swelling (edema) often associated with primary pulmonary hypertension.

Genetic counseling may be of benefit for affected individuals and their families with a family history of this disorder.
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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

Researchers are studying oral treatments for primary pulmonary hypertension. Encysive Pharmaceuticals is recruiting patients for a phase III study comparing sitaxsentan sodium (Thelin) with placebo. For information, call PharmaTech Solutions at (866) 332-3275.

The drug Beraprost received an orphan drug designation in 1999 for its use in the treatment of pulmonary arterial hypertension. Beraprost is an oral form of prostacyclin and is currently (2004) in stage III trials. More studies are needed to determine the long-term safety and effectiveness of this drug for the treatment of pulmonary arterial hypertension. For more information, contact:

United Therapeutics Corporation
68 T.W. Alexander Drive
PO Box 14186
Research Triangle Park, NC 27709

McKusick VA, ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No:178600; Last Update:9/18/2000.

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:

REVIEW ARTICLES
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.

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.

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