Pulmonary Arterial Hypertension: Advancing Insights into a Historically Neglected Disease

Abstract

Pulmonary arterial hypertension (PAH) is a rare spectrum of closely related diseases with myriad genetic, infectious, toxic, and immunologic triggers characterized by pathologic pulmonary vascular remodeling. While the natural history of PAH is marked by progressive dyspnea, hypoxia, right ventricular failure, and death, modern insights into disease pathogenesis, combined with breakthroughs in therapeutics, has greatly improved morbidity and time to disease worsening over the past two decades. Traditionally thought of as a disease of imbalance between vasodilators, such as nitric oxide and prostacyclin, and vasoconstrictors such as endothelin-1, more recent investigations have revealed important roles for perturbations in cellular metabolism, fibroblast activity, extracellular matrix maintenance, and apoptosis which contribute to pulmonary artery smooth muscle cell proliferation. Careful history and physical exam, along with echocardiography and right heart catheterization, remain essential for accurate workup and diagnosis. Cardiopulmonary exercise testing, cardiac magnetic resonance, and genetic testing have important ancillary roles. The number of approved pulmonary vasodilator therapies for PAH continues to expand, with evidence demonstrating the survival benefits of up-front combination therapy. Future prospects of next generation therapies that address the molecular origins of disease combined with comprehensive molecular profiling may usher in a new era of precision medicine for PAH. This review contains 7 figures, 5 tables, and 57 references. Keywords: pulmonary hypertension, vascular biology, therapeutics, hemodynamics, epidemiology, exercise physiology, genetic basis of disease, connective tissue disease, cardiac magnetic resonance imagining