Abstract
Pulmonary hypertension is a condition with limited effective treatment options. Chronic thromboembolic pulmonary hypertension (CTEPH) is a notable exception, with pulmonary endarterectomy (PEA) often proving curative. This study investigated the plasma metabolome of CTEPH patients, estimated reversibility to an effective treatment and explored the source of metabolic perturbations.We performed untargeted analysis of plasma metabolites in CTEPH patients compared to healthy controls and disease comparators. Changes in metabolic profile were evaluated in response to PEA. A subset of patients were sampled at three anatomical locations and plasma metabolite gradients calculated.We defined and validated altered plasma metabolite profiles in patients with CTEPH. 12 metabolites were confirmed by receiver operating characteristic analysis to distinguish CTEPH and both healthy (area under the curve (AUC) 0.64–0.94, all p<2×10−5) and disease controls (AUC 0.58–0.77, all p<0.05). Many of the metabolic changes were notably similar to those observed in idiopathic pulmonary arterial hypertension (IPAH). Only five metabolites (5-methylthioadenosine, N1-methyladenosine, N1-methylinosine, 7-methylguanine, N-formylmethionine) distinguished CTEPH from chronic thromboembolic disease or IPAH. Significant corrections (15–100% of perturbation) in response to PEA were observed in some, but not all metabolites. Anatomical sampling identified 188 plasma metabolites, with significant gradients in tryptophan, sphingomyelin, methionine and Krebs cycle metabolites. In addition, metabolites associated with CTEPH and gradients showed significant associations with clinical measures of disease severity.We identified a specific metabolic profile that distinguishes CTEPH from controls and disease comparators, despite the observation that most metabolic changes were common to both CTEPH and IPAH patients. Plasma metabolite gradients implicate cardiopulmonary tissue metabolism of metabolites associated with pulmonary hypertension and metabolites that respond to PEA surgery could be a suitable noninvasive marker for evaluating future targeted therapeutic interventions.
Highlights
Pulmonary hypertension (PH) is defined by persistent elevation of resting mean pulmonary artery pressure and is associated with an increased risk of right heart failure and premature death [1]
We identified a specific metabolic profile that distinguishes chronic thromboembolic pulmonary hypertension (CTEPH) from controls and disease comparators, despite the observation that most metabolic changes were common to both CTEPH and idiopathic pulmonary arterial hypertension (IPAH) patients
We compare the plasma metabolomic profiles of patients with CTEPH with those of other disease and healthy controls and patients with IPAH/HPAH and seek to establish whether metabolic alterations are corrected by pulmonary endarterectomy (PEA)
Summary
Pulmonary hypertension (PH) is defined by persistent elevation of resting mean pulmonary artery pressure and is associated with an increased risk of right heart failure and premature death [1]. Progress in medical therapies for PH has been limited to pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) This has not been related to discovery of new disease mechanisms, but to improvements in targeting known pathways responsible for vasodilation and strategies related to early combination and escalation of treatments. CTEPH remains the only class of PH for which a potential cure exists, by means of a pulmonary endarterectomy (PEA) which commonly normalises haemodynamics [2, 3]. This provides an invaluable opportunity to study pathobiology and response to treatment [4]. We use plasma metabolome gradients between superior vena cava (SVC), pulmonary artery (PA) and radial artery (ART) to investigate the tissue of origin of any perturbation
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.