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 outcomes2-4. 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.
Minoru Takaoka, Xiaohui Zhao, Hwee Ying Lim, Costan G. Magnussen, Owen Ang, Nadine Suffee, Patricia R. Schrank, Wei Siong Ong, Dimitrios Tsiantoulas, Felix Sommer, Sarajo K. Mohanta, James Harrison, Yaxing Meng, Ludivine Laurans, Feitong Wu, Yuning Lu, Leanne Masters, Stephen A. Newland, Laura Denti, Mingyang Hong, Mouna Chajadine, Markus Juonala, Juhani S. Koskinen, Mika Kähönen, Katja Pahkala, Suvi P. Rovio, Juha Mykkänen, Russell Thomson, Tsuneyasu Kaisho, Andreas J. R. Habenicht, Marc Clement, Alain Tedgui, Hafid Ait-Oufella, Tian X. Zhao, Meritxell Nus, Christiana Ruhrberg, Soraya Taleb, Jesse W. Williams, Olli T. Raitakari, Véronique Angeli & Ziad Mallat