Basic Science of Pulmonary Arterial Hypertension for Clinicians

Abstract

P ulmonary arterial hypertension (PAH) is a syndrome in which pulmonary arterial obstruction increases pulmonary vascular resistance, which leads to right ventricular (RV) failure and a 15% annual mortality rate. The present review highlights recent advances in the basic science of PAH. New concepts clarify the nature of PAH and provide molecular blueprints that explain how PAH is initiated and maintained. Five basic science concepts provide a framework to understand and treat PAH: (1) Endothelial dysfunction creates an imbalance that favors vasoconstriction, thrombosis, and mitogenesis. Restoration of this balance by inhibition of endothelin and thromboxane or augmentation of nitric oxide (NO) and prostacyclin is the paradigm on which most current therapy is based. (2) PAH has a genetic component. Mutations (bone morphogenetic protein receptor-2 [BMPR2]) and single-nucleotide polymorphisms (SNPs; ion channels and transporter genes) predispose to PAH. (3) Excess proliferation, impaired apoptosis, and glycolytic metabolism in pulmonary artery smooth muscle, fibroblasts, and endothelial cells suggest analogies to cancer. Many experimental therapies reduce PAH by decreasing the proliferation/apoptosis ratio; these include inhibitors of pyruvate dehydrogenase kinase (PDK), serotonin transporters (SERT), survivin, 3-hydroxy-3-methylglutaryl coenzyme A reductase, transcription factors (hypoxia-inducible factor [HIF]-1␣ and nuclear factor of activated T lymphocytes [NFAT]), and tyrosine kinases. Augmentation of voltage-gated K ϩ channels (Kv1.5) and BMPR2 signaling also addresses this imbalance. Tyrosine kinase inhibitors used to treat cancer are currently in phase 1 PAH trials. (4) Refractory vasoconstriction may occur due to rho kinase activation. Fewer than 20% of PAH patients respond to conventional vasodilators; however, refractory vasoconstriction may respond to rho kinase inhibitors. (5) The RV can be targeted therapeutically. Although increased afterload initiates RV failure, which is the major cause of death/dysfunction in PAH, the RV may be amenable to cardiac-targeted therapies. The RV in PAH has features of ischemic, hibernating myocardium.Guided by these new concepts and armed with a better understanding of disease mechanisms, we are poised to identify new therapeutic targets. To achieve balance in a rapidly evolving field, we invited colleagues to contribute Figures and legends illustrating pathways in their area of expertise that are important to the pathogenesis and treatment of PAH. These contributors are acknowledged in the Acknowledgments section.

Translational Advances in the Field of Pulmonary Hypertension.Translating MicroRNA Biology in Pulmonary Hypertension. It Will Take More Than “miR” Words

“…It involves both multiple vascular and nonvascular cell types and depends on several pathogenic events (i.e., genetic susceptibility, hypoxia, inflammation, viral infection, DNA damage, and shear stress, among others) for disease manifestation and progression (1,2). An inability to fully unravel these molecular complexities has led to multiple clinical challenges in developing both new diagnostics and therapeutics for this disease.…”

The Effects of a Novel Endothelin Receptor Antagonist, Macitentan, on Right Ventricular Substrate Utilization and Function in a Sugen5416/Hypoxia Rat Model of Severe Pulmonary Artery Hypertension

“…Production of vasodilators, nitric oxide (NO) and prostacyclin are decreased while vasoconstrictors thromboxane, serotonin and endothelin-1 (ET-1) are increased with the outcome favouring vasoconstriction Crosswhite et al, 2014). Apart from affecting vascular tone, the endothelin releases a number of paracrine factors (Budhiraja et al, 2004;Humbert et al, 2008;Archer et al, 2010) that are important for the proliferative activity of pulmonary artery smooth muscle cells (PASMC) (Stewart et al, 1991;Farber et al, 2005). Disturbances in signaling due to dysfunctional endothelium may play a role in medial thickening observed in PAH (Stewart et al, 1991;Budhiraja et al, 2004;Humbert et al, 2008).…”

“…Recently, studies have revealed that metabolic perturbations may be an important mechanism of RV failure (Fang et al, 2012) and may be implicated in pathogenic pulmonary vascular remodeling Marsboom et al, 2012). Additionally, metabolic modulation has been shown to have beneficial effects on RV function by therapeutically improving metabolic efficiency and enhancing glucose oxidation (GO) Archer et al, 2010;Fang et al, 2012;Marsboom et al, 2012). This may provide a new treatment avenue to directly and selectively target the failing RV and improve prognosis in patients with PAH however, there have been limited studies evaluating in-vivo metabolism of the RV Fang et al, 2012).…”

“…PAH is hemodynamically defined as elevated mean pulmonary artery pressures (PAP) > 25mmHg at rest, increased pulmonary vascular resistance (PVR) >3 Wood units and a decrease in pulmonary capillary wedge pressure <15 mmHg and presents without underlying lung of left-heart disease (Peacock et al, 2007;Archer et al, 2010;Rabinovitch et al, 2012).…”

The Robyn Barst Memorial Lecture: Differences between the Fetal, Newborn, and Adult Pulmonary Circulations: Relevance for Age‐Specific Therapies (2013 Grover Conference Series)

“…1 Mechanisms contributing to PAH and its progression are complex and remain incompletely understood. Insights into vascular biology over the past few decades have led to remarkable improvements in the clinical course, outcomes, and survival in adults with PAH, yet relatively few studies have been performed in children.…”