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However, causality and underlying mechanisms have not yet been established. In this study, we exposed hyperlipidemic APOE*3\u2010Leiden.CETP mice to either regular light\u2010dark cycles, weekly 6\u00a0hours phase advances or delays, or weekly alternating light\u2010dark cycles (12\u00a0hours shifts), as a well\u2010established model for shift work. We found that mice exposed to 15\u00a0weeks of alternating light\u2010dark cycles displayed a striking increase in atherosclerosis, with an approximately twofold increase in lesion size and severity, while mice exposed to phase advances and delays showed a milder circadian disruption and no significant effect on atherosclerosis development. We observed a higher lesion macrophage content in mice exposed to alternating light\u2010dark cycles without obvious changes in plasma lipids, suggesting involvement of the immune system. Moreover, while no changes in the number or activation status of circulating monocytes and other immune cells were observed, we identified increased markers for inflammation, oxidative stress, and chemoattraction in the vessel wall. Altogether, this is the first study to show that circadian disruption by shifting light\u2010dark cycles directly aggravates atherosclerosis development.<\/jats:p>","DOI":"10.1111\/jpi.12614","type":"journal-article","created":{"date-parts":[[2019,10,10]],"date-time":"2019-10-10T05:45:57Z","timestamp":1570686357000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":64,"title":["Disruption of circadian rhythm by alternating light\u2010dark cycles aggravates atherosclerosis development in APOE*3\u2010Leiden.CETP mice"],"prefix":"10.1111","volume":"68","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8597-7675","authenticated-orcid":false,"given":"Maaike","family":"Schilperoort","sequence":"first","affiliation":[{"name":"Division of Endocrinology Department of Medicine Leiden University Medical Center Leiden The Netherlands"},{"name":"Einthoven Laboratory for Experimental Vascular Medicine Leiden The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7677-1336","authenticated-orcid":false,"given":"Rosa","family":"van den Berg","sequence":"additional","affiliation":[{"name":"Division of Endocrinology Department of Medicine Leiden University Medical Center Leiden The Netherlands"},{"name":"Einthoven Laboratory for Experimental Vascular Medicine Leiden The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura A.","family":"Bosmans","sequence":"additional","affiliation":[{"name":"Department of Medical Biochemistry Amsterdam Cardiovascular Sciences Amsterdam University Medical Centre University of Amsterdam Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bram W.","family":"van Os","sequence":"additional","affiliation":[{"name":"Department of Medical Biochemistry Amsterdam Cardiovascular Sciences Amsterdam University Medical Centre University of Amsterdam Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martijn E. 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