Plasma metabolomics exhibit response to therapy in chronic thromboembolic pulmonary hypertension

医学 代谢物 代谢组 代谢组学 慢性血栓栓塞性肺高压 内科学 肺动脉高压 疾病 曲线下面积 心脏病学 胃肠病学 生物信息学 生物
作者
Emilia M. Swietlik,Pavandeep Ghataorhe,Kasia Zalewska,John Wharton,Luke Howard,Dolores Taboada,John Cannon,Nicholas W. Morrell,Martin R. Wilkins,Mark Toshner,Joanna Pepke‐Żaba,Christopher J. Rhodes
出处
期刊:The European respiratory journal [European Respiratory Society]
卷期号:57 (4): 2003201-2003201 被引量:33
标识
DOI:10.1183/13993003.03201-2020
摘要

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.
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