Targeting Dimethylarginine Dimethylaminohydrolases in Pulmonary Arterial Hypertension

Abstract

Pulmonary arterial hypertension (PAH) is a devastating and life-threatening clinical syndrome characterized by elevated pulmonary artery pressures leading to progressive symptoms, including shortness of breath, fatigue, and a decline in functional ability. The hemodynamic definition of PAH is a mean pulmonary artery pressure of >25 mm Hg at rest or >30 mm Hg during exercise, with a normal pulmonary arterial wedge pressure ≤15 mm Hg.1 Recent data from a French registry suggests that the prevalence of PAH is about 15 cases per 1 million,1 and the Registry to Evaluate Early and Long-Term Pulmonary Arterial Hypertension Disease Management (REVEAL) demonstrates that the mean age at diagnosis is 48 years and that mostly women (80%) are affected.2 The pathophysiology of PAH includes endothelial dysfunction, vascular remodeling with progressive obstruction and obliteration of pulmonary arteries, and ultimately, high right atrial pressure, right ventricular hypertrophy, right ventricular failure, and death.1 Endothelial dysfunction is believed to be an early event in PAH, and is characterized by overproduction of vasoconstrictor/mitogenic compounds, such as endothelin and thromboxane A2, and by insufficient production of vasodilators, such as prostacyclin and nitric oxide (NO). These observations led to the development of 3 different classes of therapies that are currently in clinics, either alone or in combination: prostacyclin analogs, endothelin receptor antagonists, and phosphodiesterase (PDE) inhibitors. Although current therapies can improve symptoms and reduce severity of the hemodynamic disorders, gradual deterioration of pulmonary and cardiac functions often necessitates lung transplantation. The prognosis of PAH is reportedly poor, with ≈15% mortality within 1 year of modern therapy.1 Therefore, a renewed interest has been focused on the mechanisms of PAH pathogenesis to identify a novel therapeutic target. Article see p 1194 It is now well established that disruption or dysfunction of the endothelium promotes vascular lesion formation. This …