The availability of newer drugs for pulmonary arterial hypertension (PAH) has radically changed its management and significantly improved both quality of life and mortality for patients, according to a review published in the April issue of the Southern Medical Journal. This review highlights the presentation of PAH, the diagnostic approach, and treatment options.
"Pulmonary arterial hypertension (PAH), a rare disease involving the pulmonary vascular circuit, is defined as an elevation in pulmonary arterial pressures and is characterized by symptoms of dyspnea, chest pain, and syncope," write Anne V. LaRaia, MD, and Aaron B. Waxman, MD, PhD, from Massachusetts General Hospital, Harvard Medical School, in Boston, Massachusetts. "If left untreated, the disease carries a high mortality rate, with the most common cause of death being decompensated right-sided heart failure. Over the past 5 years, there have been significant advances in this field in regards to understanding the pathogenesis, diagnosis, and classification of PAH."
PAH is a progressive disease causing narrowing and occlusion of pulmonary blood vessels, and has an estimated median survival of approximately 2.8 years. Despite the development of newer medical therapies, therapeutic options remain limited, and treatment is aimed at improving quality of life and survival.
According to the National Institutes of Health Registry on Primary Pulmonary Hypertension, the definition of PAH is a mean pulmonary arterial pressure of 25 mm Hg or greater at rest, with pulmonary capillary wedge pressure of 15 mm Hg or less, and mean pulmonary arterial pressure greater than 30 mm Hg with exercise.
In 2003, the World Health Organization revised the classification of PAH into 5 categories based in part on etiology: pulmonary arterial hypertension, pulmonary venous hypertension, pulmonary hypertension associated with hypoxemia, pulmonary hypertension resulting from chronic thrombotic or embolic disease, and miscellaneous.
Pulmonary arterial hypertension includes idiopathic PAH; familial PAH; disease associated with collagen vascular disease, congenital systemic to pulmonary shunts, portal hypertension, HIV infection, drugs and toxins, or other diseases (glycogen storage disease, Gaucher's disease, hereditary hemorrhagic telangiectasia, hemoglobinopathies, myeloproliferative disorders, splenectomy); and PAH associated with significant venous or capillary involvement (pulmonary veno-occlusive disease, pulmonary capillary hemangiomatosis, and persistent pulmonary hypertension).
Pulmonary venous hypertension associated with left-sided heart disease includes left-sided atrial or ventricular heart disease and left-sided valvular heart disease.
Pulmonary hypertension associated with hypoxemia includes chronic obstructive pulmonary disease, interstitial lung disease, sleep-disordered breathing, alveolar hypoventilation disorders, long-term exposure to high altitude, and developmental abnormalities.
Pulmonary hypertension resulting from chronic thrombotic and/or embolic disease includes thromboembolic obstruction of proximal or distal pulmonary arteries, thromboembolic obstruction of distal pulmonary arteries, and pulmonary embolism caused by tumor, parasites, or foreign material.
The miscellaneous group of PAH includes sarcoidosis, histiocytosis X, lymphangiomatosis, and compression of pulmonary vessels by adenopathy, tumor, or fibrosing mediastinitis.
Whatever the cause, the common end result of processes leading to PAH is elevation of pulmonary artery pressures and vascular resistance, with resultant right-sided heart failure. Progressive dyspnea is almost a cardinal feature of PAH, sometimes accompanied by fatigue, syncope, or chest pain.
Diagnostic workup for PAH includes history focusing on the above features and physical examination findings of paradoxical splitting of the second heart sound, the murmur of pulmonic regurgitation and tricuspid regurgitation, right ventricle heave, increased jugular venous pressure with prominent V waves, hepatomegaly with pulsations of the liver, and lower extremity edema associated with right-sided heart failure.
Electrocardiographic changes may include right ventricular hypertrophy, right atrial enlargement, and right axis deviation. Pulmonary function testing, chest radiography including contrast computed tomography and ventilation perfusion scanning, and transthoracic echocardiography also may be helpful. The gold standard is right-sided heart catheterization.
Current wisdom concerning the endothelial dysfunction underlying PAH includes a decrease in nitric oxide and prostacyclin synthesis, and an increase in thromboxane and enthothelin-1 synthesis, resulting in the typical pathology of small vessel smooth muscle hypertrophy, adventitial and intimal proliferation, and plexiform vascular lesions resulting in vascular thrombosis. This physiological basis provides the rationale for many of the new treatment options.
"The availability of newer drugs has resulted in a radical change in the management of this disease with significant improvement in both quality of life and mortality," the authors write. "Ongoing research promises to lead to a more comprehensive understanding of the genetics, etiology, and pathogenesis of pulmonary arterial hypertension, which may ultimately translate into more effective therapeutic options."
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