Association of dietary and gut microbiota-related metabolites with calcific aortic stenosis

Histopathological changes in calcific aortic stenosis (CAS) resemble changes in coronary atherosclerosis. Concerning recent evidence on dietary and gut microbiota-related metabolites representing players in atherosclerosis, we aimed to investigate the link between dietary and gut microbiota-derived metabolites and CAS. We consecutively recruited eligible subjects with moderate-severe CAS (<i>n</i> = 60), aortic sclerosis (ASc) (<i>n</i> = 49) and age and gender-matched control subjects (<i>n</i> = 48) in May 2016-December 2016. Plasma dietary and gut microbiota-related metabolite levels, namely choline, betaine, and trimethylamine N-oxide (TMAO), were measured using ultra-performance liquid chromatography-tandem mass spectroscopy method. Histopathological examinations were performed in patients that underwent aortic valve surgery. Prevalence of traditional cardiovascular risk factors or co-morbidities did not differ among groups (all <i>p</i> &gt; 0.05). CAS patients had higher plasma choline levels compared to both control (<i>p</i> p = 0.006). Plasma betaine and TMAO levels were similar (both <i>p</i> &gt; 0.05). Compared to the lowest quartile choline levels (&lt;11.15 μM), patients with the highest quartile choline levels (≥14.98 μM) had higher aortic valvular (<i>p</i> p = 0.013) calcification scores. Plasma choline levels were independently associated with aortic peak flow velocity (B ± SE:0.165 ± 0.060, <i>p</i> = 0.009). Choline levels were elevated in subjects who had aortic valves with denser lymphocyte infiltration (<i>p</i> p = 0.011), osseous metaplasia (<i>p</i> = 0.004), more severe tissue remodelling (<i>p</i> = 0.002) and calcification (<i>p</i> = 0.002). We found a significant association between choline levels and CAS presence and severity depicted on imaging modalities and histopathological examinations. Our study may open new horizons for prevention of CAS.

钙化性主动脉瓣狭窄（calcific aortic stenosis, CAS）的病理组织学改变与冠状动脉粥样硬化高度相似。鉴于近期研究证实膳食与肠道菌群相关代谢物是动脉粥样硬化的关键介导因子，本研究旨在探究膳食及肠道菌群来源代谢物与CAS之间的关联。本研究于2016年5月至2016年12月期间，连续招募符合入组标准的受试者：中重度CAS患者（n=60）、主动脉硬化（aortic sclerosis, ASc）患者（n=49），以及年龄与性别匹配的对照受试者（n=48）。采用超高效液相色谱-串联质谱法（ultra-performance liquid chromatography-tandem mass spectroscopy）检测受试者血浆中膳食及肠道菌群相关代谢物水平，具体包括胆碱（choline）、甜菜碱（betaine）以及氧化三甲胺（trimethylamine N-oxide, TMAO）。对接受主动脉瓣手术的患者开展组织病理学检查。各组间传统心血管危险因素与合并症的患病率均无显著差异（所有p>0.05）。与对照组相比，CAS患者血浆胆碱水平更高（p=0.006）。各组血浆甜菜碱与TMAO水平均无显著差异（均p>0.05）。与血浆胆碱水平最低四分位组（<11.15 μM）相比，胆碱水平最高四分位组（≥14.98 μM）的患者主动脉瓣钙化评分更高（p=0.013）。血浆胆碱水平与主动脉峰值流速呈独立相关（B±SE：0.165±0.060，p=0.009）。当主动脉瓣出现更显著的淋巴细胞浸润（p=0.011）、骨化生（p=0.004）、更严重的组织重塑（p=0.002）及钙化（p=0.002）时，受试者的胆碱水平显著升高。本研究证实，血浆胆碱水平与经影像学及组织病理学检查确认的CAS患病情况及严重程度呈显著相关。本研究可为CAS的预防策略开辟全新的研究方向。