Hyperlipidaemia is a major risk factor of atherosclerotic cardiovascular disease (ASCVD). Risk of cardiovascular events depends on cumulative lifetime exposure to low-density lipoprotein cholesterol (LDL-C) and, independently, on the time course of exposure to LDL-C, with early exposure being associated with a higher risk¹. Furthermore, LDL-C fluctuations are associated with ASCVD outcomes^2-4. However, the precise mechanisms behind this increased ASCVD risk are not understood. Here, we make the unexpected observation that early intermittent feeding of mice with a high-cholesterol Western-type diet (WD) accelerates atherosclerosis compared with late continuous exposure to WD, despite similar cumulative circulating LDL-C levels. We find that early intermittent hyperlipidaemia alters the number and homeostatic phenotype of resident-like arterial macrophages. Macrophage genes with altered expression are enriched for genes linked to human ASCVD in genome-wide association studies. We show that LYVE1⁺ resident macrophages are atheroprotective, and identify new biological pathways, related to actin filament organisation, whose alteration accelerates atherosclerosis. Using the Young Finns Study, we show that exposure to cholesterol early in life is significantly associated with the incidence and size of carotid atherosclerotic plaques in mid-adulthood. In summary, our results identify early intermittent exposure to cholesterol as a strong determinant of accelerated atherosclerosis, highlighting the importance of optimal control of hyperlipidaemia early in life, and providing insight into the underlying biological mechanisms. This knowledge will be essential to designing effective therapeutic strategies to combat atherosclerotic cardiovascular disease.

高脂血症是动脉粥样硬化性心血管疾病 （ASCVD） 的主要危险因素。心血管事件的风险取决于终生累积暴露于低密度脂蛋白胆固醇 （LDL-C），并且独立于暴露于 LDL-C 的时间进程，早期暴露与更高的风险相关¹。此外，LDL-C 波动与 ASCVD 结局相关^2-4。然而，这种 ASCVD 风险增加背后的确切机制尚不清楚。在这里，我们出乎意料地观察到，与晚期连续暴露于 WD 相比，早期间歇性喂养具有高胆固醇西式饮食 （WD） 的小鼠会加速动脉粥样硬化，尽管累积循环 LDL-C 水平相似。我们发现早期间歇性高脂血症改变了常驻样动脉巨噬细胞的数量和稳态表型。在全基因组关联研究中，表达改变的巨噬细胞基因在与人 ASCVD 相关的基因中富集。我们表明 LYVE1 ⁺ 驻留巨噬细胞具有动脉粥样硬化保护作用，并确定了与肌动蛋白丝组织相关的新生物途径，其改变会加速动脉粥样硬化。使用年轻芬兰人研究，我们表明，生命早期接触胆固醇与成年中期颈动脉粥样硬化斑块的发生率和大小显着相关。总之，我们的研究结果确定早期间歇性暴露于胆固醇是加速动脉粥样硬化的重要决定因素，强调了在生命早期最佳控制高脂血症的重要性，并提供了对潜在生物学机制的见解。这些知识对于设计有效的治疗策略来对抗动脉粥样硬化性心血管疾病至关重要。