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Pulmonary hypertension is increased pressure in the pulmonary circulation. It has many secondary causes; some cases are idiopathic. In pulmonary hypertension, pulmonary vessels become constricted, hypertrophied, and fibrosed. Severe pulmonary hypertension leads to right ventricular overload and failure. Symptoms are fatigue, exertional dyspnea, and, occasionally, chest discomfort and syncope. Diagnosis is made by measuring pulmonary artery pressure. Treatment is with vasodilators and diuretics. In some advanced cases, lung transplantation is an option. Prognosis is poor overall if a treatable secondary cause is not found.
Pulmonary hypertension is defined as a mean pulmonary arterial pressure ≥ 25 mm Hg at rest or ≥ 35 mm Hg during exercise.
Etiology
Many conditions and drugs cause pulmonary hypertension. A small number of cases occur sporadically, unrelated to any identifiable disorder; these cases are termed idiopathic pulmonary arterial hypertension. The most common overall causes of pulmonary hypertension include
Pulmonary hypertension is currently classified into 5 groups (see Table 1: Pulmonary Hypertension: Classification of Pulmonary Hypertension ) based on a number of pathologic, physiologic, and clinical factors. In the first group (pulmonary arterial hypertension), the primary disorder affects the small pulmonary arterioles.
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Table 1
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| Classification of Pulmonary Hypertension |
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Group
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Type
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Specific Disorders
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1
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Pulmonary arterial hypertension (PAH)
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Familial PAH
Idiopathic PAH
Associated with PAH:
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Connective tissue disorders
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HIV infection
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Portal hypertension
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Drugs or toxins
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Congenital heart disorders
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Other (eg, thyroid disorders, glycogen storage disease, Gaucher's disease, hemoglobinopathies, myeloproliferative disorders)
Persistent pulmonary hypertension of the newborn
Associated with significant venous or capillary involvement:
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2
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Pulmonary hypertension with left-heart disease
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Atrial or ventricular heart disorders
Valvular heart disorders
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3
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Pulmonary hypertension associated with lung disorders, hypoxemia, or both
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Alveolar hypoventilation disorders
COPD
Chronic exposure to high altitude
Developmental abnormalities
Interstitial lung disease
Sleep-disordered breathing
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4
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Pulmonary hypertension due to chronic thrombotic or embolic disorders
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Nonthrombotic pulmonary embolism (eg, tumors, parasites, foreign materials)
Thromboembolic obstruction of distal or proximal pulmonary arteries
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5
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Miscellaneous
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Compression of pulmonary vessels by adenopathy
Fibrosing mediastinitis
Lymphangiomatosis
Pulmonary Langerhans' cell histiocytosis (granulomatosis)
Sarcoidosis
Tumors
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Adapted from the Third WHO World Symposium on PAH, Venice, 2003; Simonneau G, Galié N, Rubin LJ, et al: Clinical classification of pulmonary hypertension. Journal of the American College of Cardiology 43 (supplement 1):S5–S12, 2004.
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Pathophysiology
Pathophysiologic mechanisms that cause pulmonary hypertension include increased pulmonary vascular resistance and increased pulmonary venous pressure. Pulmonary vascular resistance can be caused by obliteration of the pulmonary vascular bed or hypoxic vasoconstriction. Pulmonary hypertension is characterized by variable vasoconstriction, smooth muscle hypertrophy, and vascular wall remodeling. Vasoconstriction is thought to be due in part to enhanced activity of thromboxane and endothelin-1 (both vasoconstrictors) and reduced activity of prostacyclin and nitric oxide (both vasodilators). The increased pulmonary vascular pressure that results from vascular obstruction further injures the endothelium. Injury activates coagulation at the intimal surface, which may worsen the hypertension. Thrombotic coagulopathy due to increased activity of plasminogen activator inhibitor type 1 and fibrinopeptide A and decreased tissue plasminogen activator activity may also contribute. Focal coagulation at the endothelial surface should not be confused with chronic thromboembolic pulmonary hypertension, in which pulmonary hypertension is caused by organized pulmonary emboli.
In most patients, pulmonary hypertension eventually leads to right ventricular hypertrophy followed by dilation and right ventricular failure.
Symptoms and Signs
Progressive exertional dyspnea and easy fatigability occur in almost all patients. Atypical chest discomfort and exertional light-headedness or presyncope may accompany dyspnea. These symptoms are due primarily to insufficient cardiac output. Raynaud's syndrome occurs in about 10% of patients with idiopathic pulmonary arterial hypertension; the majority are women. Hemoptysis is rare but may be fatal.Hoarseness due to recurrent laryngeal nerve compression by an enlarged pulmonary artery (ie, Ortner syndrome) also occurs rarely.
In advanced disease, signs may include right ventricular heave, widely split 2nd heart sound (S2), an accentuated pulmonic component (P2) of S2, a pulmonary ejection click, a right ventricular 3rd heart sound (S3), tricuspid murmur, and jugular vein distention. Liver congestion and peripheral edema are common late manifestations.
Diagnosis
Pulmonary hypertension is suspected in patients with significant exertional dyspnea who are otherwise relatively healthy and have no history or signs of other diseases known to cause pulmonary symptoms.
Patients initially undergo chest x-ray, spirometry, and ECG to identify more common causes of dyspnea, followed by Doppler echocardiography to assess right ventricular and pulmonary artery pressures as well as to detect structural heart disease that might be causing pulmonary hypertension. CBC is obtained to document the presence or absence of polycythemia, anemia, and thrombocytopenia.
The most common x-ray finding in pulmonary hypertension is enlarged hilar vessels that rapidly prune into the periphery and a right ventricle that fills the anterior airspace on lateral view.Spirometry and lung volumes may be normal or detect mild restriction, and diffusing capacity for carbon monoxide (DLco) is usually reduced. Common ECG findings include right axis deviation, R > S in V1, S1Q3T3, and peaked P waves.
Additional tests are obtained as indicated to diagnose secondary causes that are not apparent clinically. These tests include
Chronic thromboembolic pulmonary hypertension is suggested by CT or lung scan findings and is confirmed by arteriography. CT angiography is useful to evaluate proximal clot and fibrotic encroachment of the vascular lumen. Other tests, such as HIV testing, liver function tests, and polysomnography, are done in the appropriate clinical context.
When the initial evaluation detects no conditions known to be associated with pulmonary hypertension, pulmonary artery catheterization is necessary to measure right atrial and ventricular, pulmonary artery, and pulmonary artery occlusion pressures; cardiac output; and left ventricular diastolic pressure. Right-sided O2 saturation should be measured to exclude atrial septal defect. Although finding a mean pulmonary arterial pressure of > 25 mm Hg in the absence of an underlying disorder identifies pulmonary hypertension, most patients with pulmonary arterial hypertension present with substantially higher pressure (eg, mean of 60 mm Hg). Vasodilating drugs, such as inhaled nitric oxide, IV epoprostenol, or adenosine, are often administered during catheterization. Decreasing right-sided pressures in response to these drugs may help in the choice of drugs for treatment. Lung biopsy, once widely done, is neither needed nor recommended because of its associated high morbidity and mortality.
Once pulmonary hypertension is diagnosed, the patient's family history should be reviewed to detect possible genetic transmission (eg, premature deaths in otherwise healthy members of the extended family). In familial pulmonary arterial hypertension, genetic counseling is needed to advise mutation carriers of the risk of disease (about 20%) and to advocate serial screening with echocardiography. Testing for mutations in the BMPR2 gene in idiopathic pulmonary arterial hypertension may have a future role.
Prognosis
Untreated patients have a median survival of 2.5 yr. Cause of death is usually sudden death in the context of right ventricular failure. Five-year survival for epoprostenol-treated patients is 54%, whereas that for the small minority of patients who respond to Ca channel blockers is > 90%. Signs predictive of poor survival include low cardiac output, higher pulmonary artery and right atrial pressures, lack of response to vasodilators, heart failure, hypoxemia, and reduced overall physical functioning. Patients with the connective tissue disorder systemic sclerosis are at high risk of pulmonary arterial hypertension and have a poor prognosis.
Treatment
Patients are encouraged to avoid activities or circumstances that may exacerbate their condition. Examples include cigarette smoking, exposure to high altitudes, and drugs that lead to vasoconstriction, such as sympathomimetics.
Pulmonary arterial hypertension, group 1:
Treatment is rapidly evolving. Oral Ca channel blockers reduce pulmonary arterial pressure or pulmonary vascular resistance in about 5% of patients. No differences in efficacy exist among Ca channel blocker types, though most specialists avoid verapamil because of its negative inotropic effects. Response to Ca channel blockers is a favorable prognostic sign, and patients who respond should continue this treatment. Patients who do not respond at the time of diagnosis are given other drugs.
IV epoprostenol, a prostacyclin analog, improves function and lengthens survival even in patients who are unresponsive to a vasodilator during catheterization. Epoprostenol is currently the most effective therapy for pulmonary arterial hypertension. Disadvantages are the need for continuous central catheter infusion and frequent, troubling adverse effects, including flushing, diarrhea, and bacteremia associated with the indwelling central catheter. Prostacyclin analogs that are inhaled (iloprost) or given sc or IV (treprostinil) are available.
Two oral endothelin-receptor antagonists, bosentan and ambrisentan, are available in the US; these drugs are useful in some patients, generally those with milder disease at diagnosis. Oral sildenafil is also effective.
Lung transplantation offers the only hope of cure but has high morbidity because of rejection, infection, and bronchiolitis obliterans. The 5-yr survival rate is 60%. Lung transplantation is reserved for patients with New York Heart Association class IV disease (defined as dyspnea associated with minimal activity, leading to bed to chair limitations) in whom all therapies have failed and who meet other health criteria to be a transplant candidate.
Many patients require adjunctive therapies to treat heart failure, including diuretics, and most should receive warfarin unless there is a contraindication.
Pulmonary hypertension, groups 2 to 5:
Primary treatment involves management of the underlying disorder. Patients with left-sided heart disease may need surgery for valvular disease. Patients with lung disorders and hypoxia benefit from supplemental O2 as well as treatment of the primary disorder.Patients with severe pulmonary hypertension secondary to chronic thromboembolic disease should be considered for pulmonary thromboendarterectomy. During cardiopulmonary bypass, an organized endothelialized thrombus is dissected along the pulmonary trunk in a procedure more complex than acute surgical embolectomy. This procedure cures pulmonary hypertension in a substantial percentage of patients and restores cardiopulmonary function; operative mortality is < 10% in patients treated in centers that have extensive experience.
Portopulmonary Hypertension
Portopulmonary hypertension is pulmonary arterial hypertension associated with portal hypertension without other secondary causes.
Pulmonary hypertension occurs in patients with various conditions that involve portal hypertension with or without cirrhosis. Portopulmonary hypertension occurs less commonly than the hepatopulmonary syndrome in patients with chronic liver disease (3.5 vs 12%).
Presenting symptoms are dyspnea and fatigue. Chest pain and hemoptysis can also occur. Patients have physical findings and ECG abnormalities consistent with pulmonary hypertension and may develop evidence of cor pulmonale (elevated jugular venous pulse, edema). Tricuspid regurgitation is common.
The diagnosis is suspected based on echocardiography findings and confirmed by right heart catheterization.
Treatment is the same as that of pulmonary arterial hypertension except that hepatotoxic drugs should be avoided. Some patients benefit from vasodilator therapy. The underlying liver disease is a major determinant of outcome. Portopulmonary hypertension is a relative contraindication to liver transplantation because of increased morbidity and mortality from the procedure. However, in some patients who receive a transplant, particularly those with mild pulmonary hypertension, pulmonary hypertension regresses. Some centers consider transplantation in patients who have mean pulmonary arterial pressures < 35 mm Hg after a trial of vasodilator therapy.
Hepatopulmonary Syndrome
Hepatopulmonary syndrome is hypoxemia caused by pulmonary microvascular vasodilation in patients with portal hypertension; dyspnea and hypoxemia are worse in the upright position.
The hepatopulmonary syndrome results from the formation of microscopic intrapulmonary arteriovenous dilations in patients with chronic liver disease. The mechanism is unknown but is thought to be due to increased hepatic production or decreased hepatic clearance of vasodilators, possibly nitric oxide. The vascular dilations cause overperfusion relative to ventilation, leading to hypoxemia. Because the lesions frequently are more numerous at the lung bases, the hepatopulmonary syndrome causes platypnea (dyspnea) and orthodeoxia (hypoxemia), which occur in the seated or upright position and are relieved by recumbency. Most patients also have characteristic findings of chronic liver disease, such as spider angiomas. About 20% of patients present with pulmonary symptoms alone.
Diagnosis
Hepatopulmonary syndrome should be suspected in a patient with known liver disease who reports dyspnea (particularly platypnea). Patients with clinically significant symptoms should have pulse oximetry. If the syndrome is advanced, ABGs should be measured with the patient breathing room air and 100% O2 to determine shunt fraction.
A useful diagnostic test is contrast echocardiography. Intravenous microbubbles from agitated saline that are normally trapped in the pulmonary capillaries rapidly (ie, within 7 heartbeats) traverse the lung and appear in the left atrium. Similarly, IV technetium-99m–labeled albumin may traverse the lungs and appear in the kidneys and brain. Pulmonary angiography may reveal a diffusely fine or blotchy vascular configuration. Angiography is generally not needed unless thromboembolism is suspected.
Treatment
The main treatment is supplemental O2 for symptoms. Other therapies, such as somatostatin to inhibit vasodilation, are of modest benefit in only some patients. Coil embolization is virtually impossible because of the number and size of the lesions. Inhaled nitric oxide synthesis inhibitors may be a future treatment option. Hepatopulmonary syndrome may regress after liver transplantation or if the underlying liver disease subsides. Prognosis is poor without treatment (survival < 2 yr).
Last full review/revision April 2008 by John H. Newman, MD
Content last modified February 2012
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