Circadian Dependence of the Acute Immune Response to Myocardial Infarction

Aoife B. Kilgallen, Frederieke van den Akker, Dries A.M. Feyen, Sandra Crnko, Christian J.B. Snijders Blok, Hendrik Gremmels, Bastiaan C. du Pré, Robin Reijers, Pieter A. Doevendans, Saskia C.A. de Jager, Joost P.G. Sluijter, Vasco Sampaio-Pinto, Linda W. van Laake*

*Corresponding author for this work

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Abstract

Circadian rhythms influence the recruitment of immune cells and the onset of inflammation, which is pivotal in the response to ischemic cardiac injury after a myocardial infarction (MI). The hyperacute immune response that occurs within the first few hours after a MI has not yet been elucidated. Therefore, we characterized the immune response and myocardial damage 3 hours after a MI occurs over a full twenty-four-hour period to investigate the role of the circadian rhythms in this response. MI was induced at Zeitgeber Time (ZT) 2, 8, 14, and 20 by permanent ligation of the left anterior descending coronary artery. Three hours after surgery, animals were terminated and blood and hearts collected to assess the immunological status and cardiac damage. Blood leukocyte numbers varied throughout the day, peaking during the rest-phase (ZT2 and 8). Extravasation of leukocytes was more pronounced during the active-phase (ZT14 and 20) and was associated with greater chemokine release to the blood and expression of adhesion molecules in the heart. Damage to the heart, measured by Troponin-I plasma levels, was elevated during this time frame. Clock gene oscillations remained intact in both MI-induced and sham-operated mice hearts, which could explain the circadian influence of the hyperacute inflammatory response after a MI. These findings are in line with the clinical observation that patients who experience a MI early in the morning (i.e., early active phase) have worse clinical outcomes. This study provides further insight on the immune response occurring shortly after an MI, which may contribute to the development of novel and optimization of current therapeutic approaches.

Original languageEnglish
Article number869512
JournalFrontiers in Pharmacology
Volume13
DOIs
Publication statusPublished - 25 May 2022

Bibliographical note

Funding Information:
This work was supported by a grant from the Alexandre Suerman program for MD/PhD students of the University Medical Center Utrecht, Netherlands. This work was further supported by the HUSTCare grant from the Netherlands CardioVascular Research Initiative (CVON): the Dutch Heart Foundation, Dutch Federation of University Medical Centers, Netherlands Organization for Health Research and Development, the Royal Netherlands Academy of Sciences, Veni (ZonMW91612147), Netherlands Heart Foundation (2013T056), Dekker Senior Clinical Scientist 2019 (grant number 2019T056), and funding from the EU’s H2020 research and innovation programme under Marie S. Curie co-fund RESCUE Grant Agreement 801540.

Publisher Copyright:
Copyright © 2022 Kilgallen, van den Akker, Feyen, Crnko, Snijders Blok, Gremmels, du Pré, Reijers, Doevendans, de Jager, Sluijter, Sampaio-Pinto and van Laake.

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