Treatment-related biomarkers in pulmonary hypertension patients on oral therapies

Abstract

Background Multiple classes of oral therapy are available for the treatment of pulmonary arterial hypertension (PAH), but there is little to guide clinicians in choosing a specific regimen or therapeutic class. We aimed to investigate whether treatment-relevant blood biomarkers can predict therapy response in prevalent PAH patients. Methods This prospective cohort study longitudinally assessed biomarkers along the endothelin-1 (ET-1) and nitric oxide (cGMP, ADMA, SDMA, nitrite, and S-nitrosohemoglobin) pathways along with the cGMP/NT-proBNP ratio over 12 months in patients with WHO Group 1 PAH on oral PAH-specific therapies. The relationship between biomarkers and 6MWD at the same and future visits was examined using mixed linear regression models adjusted for age. As cGMP can be elevated when NT-proBNP is elevated, we also tested the relationship between 6MWD and the cGMP/NT-pro BNP ratio. Patients with PAH with concomitant heart or lung disease or chronic thromboembolic pulmonary hypertension (CTEPH) were included in a sensitivity analysis. Results The study cohort included 58 patients with PAH treated with either an endothelin receptor antagonist (27.6%), phosphodiesterase-5 inhibitor (25.9%) or a combination of the two (43.1%). Among biomarkers along the current therapeutic pathways, ET-1 and the cGMP/NT-proBNP ratio associated with same visit 6MWD (p = 0.02 and p = 0.03 respectively), and ET-1 predicted future 6MWD (p = 0.02). ET-1 (p = 0.01) and cGMP/NT-proBNP ratio (p = 0.04) also predicted future 6MWD in the larger cohort (n = 108) of PAH patients with concomitant left heart disease (n = 17), lung disease (n = 20), or CTEPH (n = 13). Finally, in the larger cohort, SDMA associated with 6MWD at the same visit (p = 0.01) in all subgroups and ADMA associated with 6MWD in PAH patients with concomitant lung disease (p = 0.03) and PAH patients on ERA therapy (p = 0.01). Conclusions ET-1, cGMP/NTproBNP ratio, and dimethylarginines ADMA and SDMA are mediators along pathways targeted by oral PAH therapies that associate with or predict 6MWD.

Shufeiya Recipe Improves Monocrotaline-Induced Pulmonary Hypertension in Rats by Regulating SIRT3/FOXO3a and Its Downstream Signaling Pathways

“…However, the activated upstream PI3K could trigger AKT, activating the phosphorylation sites of eNOS Ser1177 and Thr495 to promote NO synthesis [17][18][19]. Subsequently, the soluble guanylate cyclase (sGC) in the vascular smooth muscle cells could be activated, converting guanosine triphosphate (GTP) into cyclic guanosine monophosphate (cGMP), thereby activating cGMP-dependent protein kinases G (PKG), leading to vasodilation and limiting pulmonary hypertension [20][21][22].…”

Diagnostic and prognostic significance of serum angiopoietin-1 and -2 concentrations in patients with pulmonary hypertension

“…Therefore, a novel and reliable biomarker that is easy to measure is desired for PH. Previous studies have reported that plasma endothelin-1 and cyclic guanosine monophosphate (cGMP)/NT-proBNP ratio were related to 6MWD 14 , and increased serum interleukin (IL)-6/ IL-8/IL-10/IL-12 predicted worse survival 15 in patients with PAH. In the current study, although cGMP and cytokines were not evaluated, serum ANGP-2 was identified as a useful biomarker for the diagnosis of PH.…”