Importance Low-density lipoprotein cholesterol (LDL-C) is a major risk factor for cardiovascular disease (CVD). Most observational studies on the association between LDL-C and CVD have focused on LDL-C level at a single time point (usually in middle or older age), and few studies have characterized long-term exposures to LDL-C and their role in CVD risk.

Objective To evaluate the associations of cumulative exposure to LDL-C, time-weighted average (TWA) LDL-C, and the LDL-C slope change during young adulthood and middle age with incident CVD later in life.

Design, Setting, and Participants This cohort study analyzed pooled data from 4 prospective cohort studies in the US (Atherosclerosis Risk in Communities Study, Coronary Artery Risk Development in Young Adults Study, Framingham Heart Study Offspring Cohort, and Multi-Ethnic Study of Atherosclerosis). Participants were included if they had 2 or more LDL-C measures that were at least 2 years apart between ages 18 and 60 years, with at least 1 of the LDL-C measures occurring during middle age at 40 to 60 years. Data from 1971 to 2017 were collected and analyzed from September 25, 2020, to January 10, 2021.

Exposures Cumulative exposure to LDL-C, TWA LDL-C, and LDL-C slope from age 18 to 60 years.

Main Outcomes and Measures Incident coronary heart disease (CHD), ischemic stroke, and heart failure (HF).

Results A total of 18 288 participants were included in this study. These participants had a mean (SD) age of 56.4 (3.7) years and consisted of 10 309 women (56.4%). During a median follow-up of 16 years, 1165 CHD, 599 ischemic stroke, and 1145 HF events occurred. In multivariable Cox proportional hazards regression models that adjusted for the most recent LDL-C level measured during middle age and for other CVD risk factors, the hazard ratios for CHD were as follows: 1.57 (95% CI, 1.10-2.23; P for trend = .01) for cumulative LDL-C level, 1.69 (95% CI, 1.23-2.31; P for trend <.001) for TWA LDL-C level, and 0.88 (95% CI, 0.69-1.12; P for trend = .28) for LDL-C slope. No association was found between any of the LDL-C variables and ischemic stroke or HF.

Conclusions and Relevance This cohort study showed that cumulative LDL-C and TWA LDL-C during young adulthood and middle age were associated with the risk of incident CHD, independent of midlife LDL-C level. These findings suggest that past levels of LDL-C may inform strategies for primary prevention of CHD and that maintaining optimal LDL-C levels at an earlier age may reduce the lifetime risk of developing atherosclerotic CVD.

重要性 低密度脂蛋白胆固醇 (LDL-C) 是心血管疾病 (CVD) 的主要危险因素。大多数关于 LDL-C 和 CVD 之间关联的观察性研究都集中在单个时间点（通常在中年或老年）的 LDL-C 水平，很少有研究描述长期暴露于 LDL-C 及其在心血管疾病中的作用心血管疾病风险。

目的 评估青年期和中年期 LDL-C 累积暴露、时间加权平均 (TWA) LDL-C 和 LDL-C 斜率变化与晚年 CVD 事件的关联。

设计、设置和参与者 这项队列研究分析了美国 4 项前瞻性队列研究的汇总数据（社区动脉粥样硬化风险研究、年轻人冠状动脉风险发展研究、弗雷明汉心脏研究后代队列和动脉粥样硬化多种族研究） . 如果参与者在 18 至 60 岁之间有 2 项或更多的 LDL-C 测量值至少相隔 2 年，并且至少有 1 项 LDL-C 测量值发生在 40 至 60 岁的中年期间，则他们被纳入。从 2020 年 9 月 25 日到 2021 年 1 月 10 日收集和分析了 1971 年至 2017 年的数据。

暴露 LDL-C、TWA LDL-C 和 LDL-C 斜率从 18 岁到 60 岁的累积暴露。

主要结果和措施 冠心病 (CHD)、缺血性卒中和心力衰竭 (HF) 事件。

结果 本研究共纳入 18 288 名受试者。这些参与者的平均 (SD) 年龄为 56.4 (3.7) 岁，包括 10 309 名女性 (56.4%)。在中位随访 16 年期间，发生了 1165 起冠心病、599 起缺血性卒中和 1145 起心衰事件。在针对中年期间测量的最近 LDL-C 水平和其他 CVD 风险因素进行调整的多变量 Cox 比例风险回归模型中，CHD 的风险比如下：1.57（95% CI，1.10-2.23；趋势P = .01) 累积 LDL-C 水平，1.69 (95% CI, 1.23-2.31; P for trend <.001) TWA LDL-C level, 0.88 (95% CI, 0.69-1.12; P对于趋势 = .28) 对于 LDL-C 斜率。未发现任何 LDL-C 变量与缺血性中风或 HF 之间存在关联。

结论和相关性 该队列研究表明，青年期和中年期间累积的 LDL-C 和 TWA LDL-C 与冠心病事件的风险相关，与中年 LDL-C 水平无关。这些发现表明，过去的 LDL-C 水平可能为 CHD 的一级预防策略提供信息，并且在较早的年龄保持最佳的 LDL-C 水平可能会降低患动脉粥样硬化性 CVD 的终生风险。