The trapping of LDL and other apolipoprotein B-containing lipoproteins within the artery wall causes atherosclerosis. As more LDL becomes trapped within the artery wall over time, the atherosclerotic plaque burden gradually increases, raising the risk of an acute cardiovascular event. Therefore, the biological effect of LDL on the risk of atherosclerotic cardiovascular disease (ASCVD) depends on both the magnitude and duration of exposure. Maintaining low levels of LDL-cholesterol (LDL-C) over time decreases the number of LDL particles trapped within the artery wall, slows the progression of atherosclerosis and, by delaying the age at which mature atherosclerotic plaques develop, substantially reduces the lifetime risk of ASCVD events. Summing LDL-C measurements over time to calculate cumulative exposure to LDL generates a unique biomarker that captures both the magnitude and duration of exposure, which facilitates the estimation of the absolute risk of having an acute cardiovascular event at any point in time. Titrating LDL-C lowering to keep cumulative exposure to LDL below the threshold at which acute cardiovascular events occur can effectively prevent ASCVD. In this Review, we provide the first comprehensive overview of how the LDL cumulative exposure hypothesis can guide the prevention of ASCVD. We also discuss the benefits of maintaining lower LDL-C levels over time and how this knowledge can be used to inform clinical practice guidelines as well as to design novel primary prevention trials and ASCVD prevention programmes.

低密度脂蛋白和其他含载脂蛋白 B 的脂蛋白滞留在动脉壁内会导致动脉粥样硬化。随着时间的推移，越来越多的低密度脂蛋白被困在动脉壁内，动脉粥样硬化斑块的负担逐渐增加，从而增加了急性心血管事件的风险。因此，低密度脂蛋白对动脉粥样硬化性心血管疾病 (ASCVD) 风险的生物学影响取决于暴露的程度和持续时间。随着时间的推移，保持低密度脂蛋白胆固醇 (LDL-C) 水平较低，可减少滞留在动脉壁内的低密度脂蛋白颗粒数量，减缓动脉粥样硬化的进展，并通过延迟成熟动脉粥样硬化斑块形成的年龄，大大降低终生风险ASCVD 事件。将一段时间内的 LDL-C 测量值相加，计算出 LDL 的累积暴露量，生成一种独特的生物标志物，可以捕获暴露的程度和持续时间，从而有助于估计在任何时间点发生急性心血管事件的绝对风险。滴定降低 LDL-C，将 LDL 累积暴露量保持在发生急性心血管事件的阈值以下，可有效预防 ASCVD。在这篇综述中，我们首次全面概述了 LDL 累积暴露假说如何指导 ASCVD 的预防。我们还讨论了随着时间的推移维持较低 LDL-C 水平的好处，以及如何利用这些知识为临床实践指南提供信息以及设计新的一级预防试验和 ASCVD 预防计划。