HIGHER CIRCULATING GUT MICROBIOTA-DEPENDENT METABOLITE TRIMETHYLAMINE N-OXIDE PLAYS AN ADVERSE EFFECT ON PULMONARY HYPERTENSION

Abstract

TOPIC: Pulmonary Vascular Disease TYPE: Original Investigations PURPOSE: The potential role of the gut microbiota-dependent metabolite trimethylamine N-oxide (TMAO) in pulmonary hypertension (PH) has never been elucidated. We aim to explore the association between TMAO and PH. METHODS: PH patients at Fuwai Hospital between October 2018 and February 2020 were enrolled. Patients received follow-up every three to six months through clinic visits. Plasma levels of TMAO were measured and associations with clinical markers including WHO-FC, NT-proBNP, hemodynamic parameters, and exercise capacity were explored. In monocrotaline (MCT)-induced PAH rat models, a normal diet and water supplemented with or without 1% 3,3-dimethyl-1-butanol (DMB), a kind of inhibitor of TMAO, were fed with for 4 weeks. Finally, rats received hemodynamic examinations, and after that blood serum as well as heart and lung tissues were collected. The ratio of right ventricle (RV) over left ventricle (LV) plus the septum was used as an index of RV hypertrophy (RVH). Elastic Van Gieson (EVG) stain was used to explore the changes of pulmonary vascular remodeling. RESULTS: One hundred and three consecutive PH patients were enrolled including patients with idiopathic/heritable pulmonary arterial hypertension (IPAH/HPAH, n=30), chronic thromboembolic PH (CTEPH, n=34), and congenital heart disease-associated PAH (CHD-PAH, n=39). After adjusting for confunders, TMAO levels were positively correlated with clinical disease severity assessed by WHO-FC, and also with NT-proBNP, hemodynamic parameters, and exercise capacity. TMAO responded to guideline-recommended treatment in patients with PH. It was noted that TMAO decreased significantly after treatment in patients with IPAH/HPAH. In linear correlation analysis, change in TMAO was positively associated with change in NT-proBNP (P=0.04) in IPAH/HPAH patients. Animal study showed that the level of TMAO in MCT-induced PH rats (22.2±8.7ng/mL) was higher than the MCT+DMB group (6.6±1.1ng/mL) and the control group (4.3±0.2ng/mL). Compared with MCT group, MCT+DMB group obtained a decreased RVH (30% vs 60%, p<0.001), right arterial pressure (4.4mmHg vs 6.2 mmHg, P=0.035), right ventricular systolic pressure (35.3mmHg vs 63.3mmHg, p<0.001), and mean pulmonary arterial pressure (22.5mmHg vs 39.5mmHg, p<0.001) as well as reduced vascular remodeling of lungs under pathological findings. CONCLUSIONS: TMAO was elevated in accordance with WHO-FC and decreased after guideline-recommended treatment in PH patients indicating higher TMAO might play an adverse effect on PH. The animal findings demonstrated that lower TMAO played a protective effect in MCT-induced PAH, which supported the clinical results. CLINICAL IMPLICATIONS: ①Demonstrated elevated TMAO was a risk factor for PH patients;②TMAO might be regarded as a novel indicator of PH patients. DISCLOSURES: No relevant relationships by Jianing Gao, source=Web Response no disclosure on file for Matthew C Konerman; no disclosure on file for Changming Xiong; No relevant relationships by Yicheng Yang, source=Web Response no disclosure on file for Qixian Zeng; no disclosure on file for Lemin Zheng