Repurposing Medications for Treatment of Pulmonary Arterial Hypertension: What's Old Is New Again

P ulmonary arterial hypertension (PAH) is a rare but lethal disorder caused by several pathological changes in the pulmonary vasculature. There is endothelial cell dysfunction characterized by exaggerated secretion of vasoconstrictive, pro-proliferative substances, such as endothelin, and impaired release of vasodilatory, antiproliferative molecules, such as nitric oxide and prostacyclin. This imbalance contributes to increases in pulmonary artery (PA) smooth muscle cell (PASMC) tone and proliferation. Moreover, endothelial cells exhibit metabolic reprogramming with a switch to anaerobic glycolysis. In PASMCs, there is evidence of hypercontractility, proliferation and apoptosis resistance due to genetically and epigenetically controlled mechanisms, calcium mishandling, metabolic reprogramming, and abnormal mitochondrial dynamics. Mitochondrial metabolic reprogramming, creating a Warburg metabolic phenotype that promotes proliferation, is also observed in pulmonary vascular fibroblasts. Extracellular matrix (ECM) remodeling promotes PAH by increasing vessel stiffness and thereby altering signaling pathways and inducing metabolic derangements through mechanotransduction. Finally, there is evidence of a significant inflammatory response with T cell, B cell, and dendritic cell infiltration into the pulmonary vasculature and elevated levels of circulating inflammatory cytokines. These molecular, cellular, and histological changes manifest as reduced pulmonary arterial compliance and elevated pulmonary vascular resistance (PVR) and pulmonary arterial pressures that, in aggregate, augment the workload of the right ventricle. As PAH progresses, the heightened demands on the right ventricle lead to right ventricular hypertrophy (RVH), fibrosis, and metabolic derangements that often culminate in RV failure. RV dysfunction is the strongest predictor of mortality in PAH and is the major reason that the median survival with PAH is only 5 to 7 years, both in registries and in population-based studies. Although there have been significant gains in the understanding of the pathophysiology of PAH in recent years, advances in PAH therapeutics have not kept pace, and many promising basic science discoveries have not been tested in patients. Approved PAH medications are predominately pulmonary vasodilators that modulate the endothelin, nitric oxide, and prostacyclin pathways. These therapies primarily address the vasoconstrictive phenotype of PAH, which is the predominant feature in only 5% to 10% of patients or those patients deemed vasoresponders. Although current medications provide benefits to nearly all PAH patients even if they are not vasoresponders, they were approved because they significantly increase exercise capacity (6-minute walk distance [6MWD]), improve quality of life, and/or reduce morbidity; however, only epoprostenol confers a clear survival benefit. Consequently, there is an urgent need to develop novel, effective therapies that target additional molecular pathways that drive the pathogenesis of PAH in order to supplement our current treatment options with the hopes of accelerating progress toward a cure. The strategy of expanding the PAH pharmacopeia by repurposing medications that are used as therapy for other medical conditions is attractive because it may accelerate the development of new therapies and reduce the costs associated with new drug discovery for this orphan disease. In PAH, this consideration is important because, worldwide, many PAH patients do not even have access to currently approved therapies, so discovery of an inexpensive treatment option would very likely have a significant global impact. Available drugs have established safety profiles, so the considerable time and money required to exclude common toxicities and to demonstrate tolerability and safety can be reduced. Nevertheless, even for available agents, the need to confirm dosing and to establish the disease-specific adverse effect profiles cannot be circumvented. Experience suggests that PAH patients may be either more or less sensitive to many drugs. From the Cardiovascular Division, University of Minnesota Medical School, Minneapolis, MN (K.W.P., T.T., E.K.W., R.K., M.P.); Department of Medicine, Queen’s University, Kingston, ON (S.L.A.). Correspondence to: Kurt Prins, MD, PhD, Cardiovascular Division, University of Minnesota Medical School, 420 Delaware Street SE, Minneapolis, MN 55455. E-mail: prin0088@umn.edu J Am Heart Assoc. 2019;8:e011343. DOI: 10.1161/JAHA.118. 011343. a 2018 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.