New Drugs and Therapies in Pulmonary Arterial Hypertension

Abstract

Pulmonary arterial hypertension is a chronic, progressive disorder of the pulmonary vasculature with associated pulmonary and cardiac remodeling. PAH was a uniformly fatal disease until the late 1970s, but with the advent of targeted therapies, the life expectancy of patients with PAH has now considerably improved. Despite these advances, PAH inevitably remains a progressive disease with significant morbidity and mortality. Thus, there is still an unmet need for the development of new drugs and other interventional therapies for the treatment of PAH. One shortcoming of currently approved vasodilator therapies is that they do not target or reverse the underlying pathogenesis of the disease process itself. A large body of evidence has evolved in the past two decades clarifying the role of genetics, dysregulation of growth factors, inflammatory pathways, mitochondrial dysfunction, DNA damage, sex hormones, neurohormonal pathways, and iron deficiency in the pathogenesis of PAH. This review focuses on newer targets and drugs that modify these pathways as well as novel interventional therapies in PAH.

Keywords: new drug targets; novel therapies; novel treatments; pathogenesis; pulmonary arterial hypertension.

Figure 1

Pulmonary arterial hypertension (PAH) is the result of complex interplay between multiple pathways and environmental and genetic stressors. This figure is a pictorial representation of the multiple pathogenetic pathways observed in PAH, with the novel therapeutic options available to target the disease process. Green arrow = activator of the pathway, red arrow = inhibitor of the pathway, blue box = pathway, red box = inhibitor of the pathway, green box = activator/modulator of the pathway. 16$\alpha$OHE = 16 Alpha Hydroxyestrone, 2-ME2 = 2 Methoxy estradiol, 2OH-E2 = 2-hydroxyestrone, 5-HT = 5-Hydroxy Tryptamine, ANS = Autonomic Nervous System, BMP = Bone Morphogenetic Protein, BMPR2 = Bone Morphogenetic Protein Receptor Type 2, CoQ = Coenzyme Q, DCA = Dichloroacetate, DHA = Dihyrodroatremisinin, DNA = Deoxyribonucleic Acid, GF = Growth Factor, IL = Interleukin, NF-$\kappa$B = Nuclear Factor Kappa B, Nrf-2 = Nuclear Factor E2-related factor 2, PDGF = Platelet-Derived Growth Factor, PDGFR = Platelet-Derived Growth Factor Receptor, RAAS = Renin-Angiotensin-Aldosterone System, ROS = Reactive Oxygen Species, TGF $\beta$ = Transforming Growth Factor beta, TK = Tyrosine Kinase, TNF = Tumor Necrosis Factor, VIP = Vasoactive Intestinal Peptide, VPAC = Vasoactive Intestinal Peptide Receptor.

Figure 2

University of Louisville School of Medicine approach to pulmonary arterial hypertension treatment. PAH = Pulmonary Arterial Hypertension, 6MWD = 6Minute Walk Distance, BNP = Brain Natriuretic Peptide, DLCO = Lung Diffusion Capacity for Carbon Monoxide, ERA = Endothelin Receptor Antagonist, i.v. = Intravenous, NT–pro BNP = N–Terminal Pro–Brain Natriuretic Peptide, PCA = Prostacyclin Analogue, PDE5i = Phosphodiesterase 5 Inhibitor, PRA = Prostacyclin Receptor Agonist, s.c. = Subcutaneous, sGCs = Soluble Guanylate Cyclase stimulator, WHO–FC = World Health Organization Functional Class, ng = Nanogram, L = Liter. * Risk is calculated by dividing the sum of all grades by the number of variables and rounding to the next integer. ^a Cardiopulmonary comorbidities are conditions associated with an increased risk of left ventricular diastolic dysfunction, and include obesity, hypertension, diabetes mellitus, and coronary heart disease; pulmonary comorbidities may include signs of mild parenchymal lung disease and are often associated with a low DLCO (<45% of the predicted value). ^b Intravenous epoprostenol or i.v./s.c. Treprostinil.