Toward More Individualized Treatment of Pulmonary Arterial Hypertension: Investigation of Biomarkers for Nitric Oxide Deficiency

Abstract

SESSION TITLE: Pulmonary Arterial Hypertension Posters II SESSION TYPE: Original Investigation Poster PRESENTED ON: Wednesday, October 28, 2015 at 01:30 PM - 02:30 PM PURPOSE: Reduction in nitric oxide (NO) bioavailability has been implicated in the pathogenesis of pulmonary arterial hypertension (PAH), and it has been shown to continue declining over time in patients who have PAH as disease symptoms worsen. Exhaled NO (eNO) has been studied as a potential biomarker for PAH, but its measurement is potentially confounded by many factors, thus compromising its clinical utility for identifying patients with PAH who are NO deficient. METHODS: A roundtable of NO and PAH experts from around the United States was convened in February 2015. The objective of that roundtable was to discuss potential biomarkers of NO deficiency, with the eventual goal of developing a biomarker panel and framework for a clinical study. RESULTS: The bioavailability of NO is determined by a balance between its production, conservation, and consumption. Pulmonary arterial hypertension is associated with NO deficiency, which can be a product of imbalances in any number of factors, including l-arginine, asymmetric dimethylarginine, NO synthases. In states of deficiency of NO or its more stable derivatives, insufficient cyclic guanosine monophosphate (cGMP) is produced, resulting in dysregulation of processes that influence vascular tone, proliferation, fibrosis, and inflammation. Riociguat is a member of a new class of drugs that target the NO-sGC-cGMP pathway, because it stimulates soluble guanylate cyclase (sGC), independent of endogenous NO, to increase synthesis of cGMP. Riociguat has been shown to improve multiple outcomes, including pulmonary hemodynamics. In patients with PAH, identification of NO-deficient PAH patients has the potential to allow for better tailoring of PAH regimens to the characteristics of individual patients. CONCLUSIONS: Potential biomarkers for endogenous NO bioavailability may assist in identifying patients with PAH who are NO deficient. CLINICAL IMPLICATIONS: Patients with signs of NO deficiency may respond better to treatments targeting the NO-sGC-cGMP pathway that do not require the presence of endogenous NO. However, further study is required to confirm this hypothesis. DISCLOSURE: James Klinger: Consultant fee, speaker bureau, advisory committee, etc.: Bayer Healthcare Timothy McMahon: Consultant fee, speaker bureau, advisory committee, etc.: Bayer Healthcare Raed Dweik: Consultant fee, speaker bureau, advisory committee, etc.: Bayer Healthcare David Platt: Employee: Bayer Healthcare Gerald O'Brien: Employee: Bayer Healthcare Carol Satler: Employee: Bayer Healthcare No Product/Research Disclosure Information