循环脂肪酸与心血管疾病风险的关联：三项大型前瞻性队列的个体水平数据分析及更新的荟萃分析

饱和脂肪酸（SFAs）与不饱和脂肪酸（FAs）与心血管疾病（CVD）的关系仍存在争议。因此，本研究旨在探讨客观测量的脂肪酸（FAs）与CVD的前瞻性关联，包括新发冠心病（CHD）和中风，以及CVD死亡。循环脂肪酸浓度以占总脂肪酸百分比表达，在欧洲癌症与营养前瞻性调查-CVD（EPIC-CVD）（7343例CHD；6499例中风）、英国生物库（UK Biobank）（1825；1474）和INTERVAL（285；209）队列研究中，在基线时无既往血管疾病的17万2891名参与者中进行检测。通过Cox回归模型估算脂肪酸浓度每标准差（SD）升高的风险比（HR），并采用随机效应荟萃分析进行合并。系统性检索2023年5月6日前发表的脂肪酸与CVD关系的Meta分析，更新采用随机效应模型进行荟萃分析，并总结随机对照试验（RCTs）的证据。合并分析显示，总饱和脂肪酸（SFAs）浓度升高与心血管风险升高相关，在进一步限制于EPIC-CVD的亚组分析中，不同SFA亚型表现出不同的关联：偶链SFA与CHD（HR 1.24，95% CI：1.18-1.32）和中风（HR 1.23，95% CI：1.10-1.38）呈正相关；奇链SFA（HR 0.82，95% CI：0.76-0.87）和长链SFA（HR 0.95，95% CI：0.80-1.12）则呈负相关。在合并分析中，总n-3多不饱和脂肪酸（PUFA）（HR 0.91，95% CI：0.85-0.97），包括二十二碳六烯酸（DHA）（HR 0.91，95% CI：0.84-0.98），与新发CHD风险呈负相关。同样，总n-6 PUFA（HR 0.94，95% CI：0.91-0.98），包括亚油酸（LA）（HR 0.89，95% CI：0.83-0.95），与新发中风风险呈负相关。相反，在EPIC-CVD中的更详细分析显示，LA的几个下游n-6 PUFA与CHD风险正相关。共49项非重复研究，涉及7787至22802例CHD和6499至14221例中风的37种脂肪酸的更新荟萃分析显示，与我们的联合实证分析结果大致一致，且进一步提示个别长链n-3 PUFA和LA对CHD和中风具有显著的逆相关。长链n-3 PUFA的发现与已发表的关于CHD的RCTs结果一致，尽管单药疗法的证据不足，而其他脂肪酸的RCT证据尚不明确。本研究提供了关于客观测量脂肪酸与CVD结局关系的最新证据综述，数据揭示SFA亚型之间存在显著差异，呼吁进一步的研究，特别是随机对照试验，以探索这些关联。

Associations of saturated and unsaturated fatty acids (FAs) with cardiovascular disease (CVD) remain controversial. We therefore aimed to investigate the prospective associations of objectively measured FAs with CVD, including incident coronary heart disease (CHD) and stroke, as well as CVD mortality.Circulating FA concentrations expressed as the percentage of total FAs were assayed in 172 891 participants without prior vascular disease at baseline from the European Prospective Investigation into Cancer and Nutrition-CVD (EPIC-CVD) (7343 CHD; 6499 stroke), UK Biobank (1825; 1474), and INTERVAL (285; 209) cohort studies. Hazard ratio (HR) per 1-standard deviation (SD) higher FA concentrations was estimated using Cox regression models and pooled by random-effects meta-analysis. Systematic reviews with meta-analysis published by 6 May 2023 on associations between FAs and CVDs were systematically searched and updated meta-analyses using random-effects model were conducted. Evidence from randomized controlled trials (RCTs) was also summarized. Higher concentrations of total saturated FAs (SFAs) were associated with higher cardiovascular risks in the combined analysis, with differential findings noted for SFA sub-types in further analysis restricted to EPIC-CVD: positive associations for even-chain SFA [HR for CHD 1.24 (95% CI: 1.18-1.32); stroke 1.23 (1.10-1.38)] and negative associations for odd-chain [0.82 (0.76-0.87); 0.73 (0.67-0.78)] and longer-chain [0.95 (0.80-1.12); 0.84 (0.72-0.99)] SFA. In the combined analysis, total n-3 polyunsaturated FA (PUFA) [0.91 (0.85-0.97)], including docosahexaenoic acid (DHA) [0.91 (0.84-0.98)], was negatively associated with incident CHD risk. Similarly, total n-6 PUFA [0.94 (0.91-0.98)], including linoleic acid (LA) [0.89 (0.83-0.95)], was negatively associated with incident stroke risk. In contrast, more detailed analyses in EPIC-CVD revealed that several downstream n-6 PUFAs of LA were positively associated with CHD risk. Updated meta-analyses of 37 FAs including 49 non-overlapping studies, involving between 7787 and 22 802 CHD cases and between 6499 and 14 221 stroke cases, showed broadly similar results as our combined empirical analysis and further suggested significant inverse associations of individual long-chain n-3 PUFAs and LA on both CHD and stroke. The findings of long-chain n-3 PUFAs were consistent with those from published RCTs on CHD despite insufficient evidence in monotherapy, while RCT evidence remained unclear for the rest of the explored FAs.Our study provides an overview of the most recent evidence on the associations between objectively measured FAs and CVD outcomes. Collectively, the data reveal notable differences in associations by SFA sub-types and call for further studies, especially RCTs, to explore these links.