Department of Epidemiology, University of Washington School of Public Health, Seattle.
Cardiovascular Health Research Unit, University of Washington, Seattle.
JAMA Netw Open. 2022 May 2;5(5):e2213242. doi: 10.1001/jamanetworkopen.2022.13242.
Little is known about the association of trimethylamine N-oxide (TMAO), a novel plasma metabolite derived from L-carnitine and phosphatidylcholine, and related metabolites (ie, choline, betaine, carnitine, and butyrobetaine) with risk of death among older adults in the general population.
To investigate the associations of serial measures of plasma TMAO and related metabolites with risk of total and cause-specific death (ie, deaths from cardiovascular diseases [CVDs] and non-CVDs) among older adults in the US.
DESIGN, SETTING, AND PARTICIPANTS: This prospective cohort study involved 5333 participants from the Cardiovascular Health Study-a community-based longitudinal cohort of adults aged 65 years or older-who were followed up from June 1, 1989, to December 31, 2015. Participants were from 4 communities in the US (Forsyth County, North Carolina; Sacramento County, California; Washington County, Maryland; and Allegheny County, Pennsylvania). Data were analyzed from March 17 to June 23, 2021.
Plasma TMAO, choline, betaine, carnitine, and butyrobetaine levels were measured using stored samples from baseline (June 1, 1989, to May 31, 1990, or November 1, 1992, to June 31, 1993) and follow-up examination (June 1, 1996, to May 31, 1997). Measurements were performed through stable-isotope dilution liquid chromatography with tandem mass spectrometry using high-performance liquid chromatography with online electrospray ionization tandem mass spectrometry.
Deaths (total and cause specific) were adjudicated by a centralized Cardiovascular Health Study events committee based on information from medical records, laboratory and diagnostic reports, death certificates, and/or interviews with next of kin. The associations of each metabolite with mortality were assessed using Cox proportional hazards regression models.
Among 5333 participants in the analytic sample, the mean (SD) age was 73 (6) years; 2149 participants (40.3%) were male, 3184 (59.7%) were female, 848 (15.9%) were African American, 4450 (83.4%) were White, and 35 (0.01%) were of other races (12 were American Indian or Alaska Native, 4 were Asian or Pacific Islander, and 19 were of other races or ethnicities). During a median follow-up of 13.2 years (range, 0-26.9 years), 4791 deaths occurred. After adjustment for potential confounders, the hazard ratios for death from any cause (ie, total mortality) comparing extreme quintiles (fifth vs first) of plasma concentrations were 1.30 (95% CI, 1.17-1.44) for TMAO, 1.19 (95% CI, 1.08-1.32) for choline, 1.26 (95% CI, 1.15-1.40) for carnitine, and 1.26 (95% CI, 1.13-1.40) for butyrobetaine. Plasma betaine was not associated with risk of death. The extent of risk estimates was similar for CVD and non-CVD mortality.
In this cohort study, plasma concentrations of TMAO and related metabolites were positively associated with risk of death. These findings suggest that circulating TMAO is an important novel risk factor associated with death among older adults.
关于三甲胺 N-氧化物（TMAO）与死亡风险之间的关联，人们知之甚少，TMAO 是一种源自左旋肉碱和磷脂酰胆碱的新型血浆代谢物，以及相关代谢物（即胆碱、甜菜碱、肉碱和丁酰甜菜碱）与普通人群中老年人的死亡风险之间的关联。
调查血浆 TMAO 和相关代谢物的连续测量值与美国老年人全因和特定原因死亡（即心血管疾病[CVD]和非 CVD 死亡）风险之间的关系。
设计、地点和参与者：这项前瞻性队列研究涉及来自心血管健康研究的 5333 名参与者-一个由年龄在 65 岁或以上的成年人组成的社区为基础的纵向队列-从 1989 年 6 月 1 日至 2015 年 12 月 31 日进行随访。参与者来自美国的 4 个社区（北卡罗来纳州福赛斯县、加利福尼亚州萨克拉门托县、马里兰州华盛顿县和宾夕法尼亚州阿勒格尼县）。数据于 2021 年 3 月 17 日至 6 月 23 日进行分析。
使用基线（1989 年 6 月 1 日至 5 月 31 日或 1992 年 11 月 1 日至 6 月 31 日）和随访检查（1996 年 6 月 1 日至 5 月 31 日）的存储样本测量血浆 TMAO、胆碱、甜菜碱、肉碱和丁酰甜菜碱水平。使用高效液相色谱与在线电喷雾串联质谱法进行稳定同位素稀释液相色谱-串联质谱法进行测量。
根据医疗记录、实验室和诊断报告、死亡证明和/或与近亲的访谈，由心血管健康研究事件委员会对死亡（总死亡和特定原因死亡）进行裁决。使用 Cox 比例风险回归模型评估每种代谢物与死亡率的关系。
在分析样本中的 5333 名参与者中，平均（SD）年龄为 73（6）岁；2149 名参与者（40.3%）为男性，3184 名（59.7%）为女性，848 名（15.9%）为非裔美国人，4450 名（83.4%）为白人，35 名（0.01%）为其他种族（12 名是美国印第安人或阿拉斯加原住民，4 名是亚洲或太平洋岛民，19 名是其他种族或族裔）。在中位随访 13.2 年（范围 0-26.9 年）期间，发生了 4791 例死亡。在调整潜在混杂因素后，血浆浓度的极端五分位数（第五分位与第一分位）比较的全因死亡率（即总死亡率）的危险比为 TMAO 为 1.30（95%CI，1.17-1.44），胆碱为 1.19（95%CI，1.08-1.32），肉碱为 1.26（95%CI，1.15-1.40），丁酰甜菜碱为 1.26（95%CI，1.13-1.40）。血浆甜菜碱与死亡风险无关。风险估计的程度对于 CVD 和非 CVD 死亡率相似。
在这项队列研究中，TMAO 和相关代谢物的血浆浓度与死亡风险呈正相关。这些发现表明，循环 TMAO 是与老年人死亡相关的一个重要的新型危险因素。
