The Search for Disease-Modifying Therapies in Pulmonary Hypertension

Pulmonary hypertension (PH) and its severe subtype pulmonary arterial hypertension (PAH) encompass a set of multifactorial diseases defined by sustained elevation of pulmonary arterial pressure and pulmonary vascular resistance leading to right ventricular failure and subsequent death. Pulmonary hypertension is characterized by vascular remodeling in association with smooth muscle cell proliferation of the arterioles, medial thickening, and plexiform lesion formation. Despite our recent advances in understanding its pathogenesis and related therapeutic discoveries, PH still remains a progressive disease without a cure. Nevertheless, development of drugs that specifically target molecular pathways involved in disease pathogenesis has led to improvement in life quality and clinical outcomes in patients with PAH. There are presently more than 12 Food and Drug Administration-approved vasodilator drugs in the United States for the treatment of PAH; however, mortality with contemporary therapies remains high. More recently, there have been exuberant efforts to develop new pharmacologic therapies that target the fundamental origins of PH and thus could represent disease-modifying opportunities. This review aims to summarize recent developments on key signaling pathways and molecular targets that drive PH disease progression, with emphasis on new therapeutic options under development.