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Short-Term Disruption of Diurnal Rhythms After Murine Myocardial Infarction Adversely Affects Long-Term Myocardial Structure and Function
Abstract
Rationale: Patients in intensive care units are disconnected from their natural environment. Synchrony between environmental diurnal rhythms and intracellular circadian rhythms is essential for normal organ biology; disruption causes pathology. Whether disturbing rhythms after myocardial infarction (MI) exacerbates long-term myocardial dysfunction is not known. Objective: Short-term diurnal rhythm disruption immediately after MI impairs remodeling and adversely affects long-term cardiac structure and function in a murine model. Methods and Results: Mice were infarcted by left anterior descending coronary artery ligation (MI model) within a 3-hour time window, randomized to either a normal diurnal or disrupted environment for 5 days, and then maintained under normal diurnal conditions. Initial infarct size was identical. Short-term diurnal disruption adversely affected body metabolism and altered early innate immune responses. In the first 5 days, crucial for scar formation, there were significant differences in cardiac myeloperoxidase, cytokines, neutrophil, and macrophage infiltration. Homozygous clock mutant mice exhibited altered infiltration after MI, consistent with circadian mechanisms underlying innate immune responses crucial for scar formation. In the proliferative phase, 1 week after MI, this led to significantly less blood vessel formation in the infarct region of disrupted mice; by day 14, echocardiography showed increased left ventricular dilation and infarct expansion. These differences continued to evolve with worse cardiac structure and function by 8 weeks after MI. Conclusions: Diurnal rhythm disruption immediately after MI impaired healing and exacerbated maladaptive cardiac remodeling. These preclinical findings suggest that disrupted diurnal rhythms such as found in modern intensive care unit environments may adversely affect long-term patient outcome.
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“For instance, recovery from experimentally induced myocardial ischemia is impaired in mice by rapidly shifting light/dark cycles, suggesting that sleep and circadian rhythm disruption that occurs in intensive care units may compromise recovery (145).”
From Role of the circadian system in cardiovascular disease (2018) · cites this paper as [145]
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Circadian Dependence of the Acute Immune Response to Myocardial Infarction
Kilgallen, A. B., van den Akker, F., Feyen, D. A. M., Crnko, S., Blok, C. S., Gremmels, H., du Pré, B. C., Reijers, R., Doevendans, P. A., de Jager, S. C. A., et al. (2022) · Frontiers in Pharmacology · doi:10.3389/fphar.2022.869512 · Cited by 18
“Hence, it is reasonable to speculate that reducing environmental stressors, by implementing circadian lights in hospitals, could promote an improved healing of the myocardium after MI (Alibhai et al., 2014).”
BackgroundThe Impact of Sex, Circadian Disruption, and the ClockΔ19/Δ19 Genotype on Alcohol Drinking in Mice
Rizk, A. A., Jenkins, B. W., Al-Sabagh, Y., Hamidullah, S., Reitz, C. J., Rasouli, M., Martino, T. A., & Khokhar, J. Y. (2022) · Genes · doi:10.3390/genes13040701 · Cited by 19
“All experiments were approved by the University of Guelph Institutional Animal Care and Use Committee and performed in accordance with the guidelines set forth by the Canadian Council on Animal Care (1993).”
MethodSelf-citationKroetsch, J. T., Lidington, D., Alibhai, F. J., Reitz, C. J., Zhang, H., Dinh, D. D., Hanchard, J., Khatua, T. N., Heximer, S. P., Martino, T. A., et al. (2022) · Cardiovascular Research · doi:10.1093/cvr/cvac174 · Cited by 17
Self-citationCircadian medicine: a critical strategy for cardiac care
Sole, M. J., & Martino, T. A. (2023) · Nature Reviews Cardiology · doi:10.1038/s41569-023-00925-8 · Cited by 15
Self-citationSheng, M., Chen, X., Yu, Y., Wu, Q., Kou, J., & Chen, G. (2023) · Frontiers in Pharmacology · doi:10.3389/fphar.2023.1102567 · Cited by 14
“The mean arterial pressure and heart rate circadian phase of clock mutant mice were significantly delayed (Alibhai et al., 2014).”
BackgroundCircadian Disruption and the Molecular Clock in Atherosclerosis and Hypertension
Costello, H. M., Sharma, R. K., McKee, A. R., & Gumz, M. L. (2023) · Canadian Journal of Cardiology · doi:10.1016/j.cjca.2023.06.416 · Cited by 15
Giles, A. V., Sun, J., Femnou, A. N., et al. (2018) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00493.2018 · Cited by 14
Xue, G., Yang, X., Zhan, G., et al. (2022) · Frontiers in Pharmacology · doi:10.3389/fphar.2022.988408 · Cited by 14
“C57BL/6 mice underwent MI, as described previously (Alibhai et al., 2014).”
MethodCircadian system and aging: where both times interact
Cobarro, C., Soares, L. I., Kutsenko, Y., & Tomás‐Loba, A. (2025) · Frontiers in Aging · doi:10.3389/fragi.2025.1646794 · Cited by 15
Hao, K., Zhai, Q., Gu, Y., Chen, Y.-Q., Wang, Y., Liu, R., Yan, S.-P., Wang, Y., Shi, Y., Lei, W., et al. (2023) · Acta Pharmacologica Sinica · doi:10.1038/s41401-023-01059-w · Cited by 12
“Despite evidence for the potential adverse effects of chronic disruption of the circadian clock [48, 49, 54, 55], very little is known about the role of the SCN in the response to acute stress including MI.”
BackgroundZhao, T., Liu, J.-J., Zhu, J., Li, H., Wang, Y.-C., Zhao, Y., Shao, S.-J., Guo, H.-D., & Mou, F.-F. (2022) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2022/4455183 · Cited by 11
“MI mice were established by ligature of the left anterior descending branch under isoflurane anesthetization [21].”
MethodOne Health: Circadian Medicine Benefits Both Non-human Animals and Humans Alike
Farag, H. I., Murphy, B. A., Templeman, J. R., Hanlon, C., Joshua, J., Koch, T. G., Niel, L., Shoveller, A. K. K., Bédécarrats, G. Y., Ellison, A., et al. (2024) · Journal of Biological Rhythms · doi:10.1177/07487304241228021 · Cited by 12
Self-citationBone Marrow Niche in Cardiometabolic Disease: Mechanisms and Therapeutic Potential
Kohutek, Z. A., Caslin, H. L., Fehrenbach, D. J., Heimlich, J. B., Brown, J. D., Madhur, M. S., Ferrell, P. B., & Doran, A. C. (2025) · Circulation Research · doi:10.1161/circresaha.124.323778 · Cited by 18
Sleep and Circadian Alterations and the Gut Microbiome: Associations or Causality?
Farré, N., Torres, M., Gozal, D., & Farré, R. (2018) · Current Sleep Medicine Reports · doi:10.1007/s40675-018-0100-0 · Cited by 10
The chronobiology of human heart failure: clinical implications and therapeutic opportunities
Gentile, F., Emdin, M., Passino, C., Montuoro, S., Tognini, P., Floras, J. S., O'Neill, J. M., & Giannoni, A. (2024) · Heart Failure Reviews · doi:10.1007/s10741-024-10447-1 · Cited by 9
Identification of the potential biomarkers associated with circadian rhythms in heart failure
Sun, Q., Zhao, J., Liu, L., Wang, X., & Gu, X. (2023) · PeerJ · doi:10.7717/peerj.14734 · Cited by 8
“, 2002), which may also perturb the delicate balance with severe repercussions on HF outcomes (Alibhai et al., 2014; Song et al., 2022).”
BackgroundImplications of Enteral and Parenteral Feeding Times
Rothschild, J. A., & Lagakos, W. (2014) · Journal of Parenteral and Enteral Nutrition · doi:10.1177/0148607114551026 · Cited by 9
Yan, X., Huang, Y., & Wu, J. (2018) · Journal of Computational Biology · doi:10.1089/cmb.2017.0254 · Cited by 8
“Long-term myocardial structure and function are adversely affected by circadian rhythm disorder after murine myocardial infarction (Alibhai et al., 2014).”
Circadian regulation of cardiac muscle function and protein degradation
Yoo, S. H. (2021) · Chronobiology International · doi:10.1080/07420528.2021.1957911 · Cited by 8
“In addition to GSK-3β, several other kinases have also been implicated in sarcomere protein modification and contractile function, including PKA, PKD, CamKII and calcineurin (Alibhai et al. 2014; Bray et al. 2008; Rotter et al. 2014; Sachan et al. 2011).”
BackgroundKıvrak, A., & Yıldırım, A. (2023) · Kardiologia Polska · doi:10.33963/kp.a2023.0150 · Cited by 8
Cardiovascular research and the arrival of circadian medicine
Martino, T. A., & Delisle, B. P. (2023) · Chronobiology International · doi:10.1080/07420528.2022.2151862 · Cited by 7
“…relevant to clinical cardiology therapies, such as chronotherapy for hypertension, (Mistry et al. 2017) circadian lighting in intensive care units (Alibhai et al. 2014), and can influence morbidity and mortality following surgical procedures such as percutaneous coronary intervention, or…”
BackgroundSelf-citationReitz, C. J., Rasouli, M., Alibhai, F. J., Khatua, T. N., Pyle, W. G., & Martino, T. A. (2022) · JCI Insight · doi:10.1172/jci.insight.164700 · Cited by 8
Self-citationLin, J., Yao, H., Li, J., Hou, C., Song, X., An, K., Tian, S., Li, X., Wang, Y., Guo, Q., et al. (2023) · BMC Public Health · doi:10.1186/s12889-023-17077-6 · Cited by 6
“Recent studies reported that circadian rhythm disorder increases the risk of CHD and other CVDs [34, 35].”
BackgroundEdgar, R. S., O’Donnell, A. J., Zhuang, X. A., et al. (2025) · Philosophical Transactions of the Royal Society B Biological Sciences · doi:10.1098/rstb.2023.0336 · Cited by 5
Cheng, S., Wu, J., Pei, Y., Tong, H., Fan, M., Xiang, Q., Ding, Y., Xie, L., Zhang, H., Sun, W., et al. (2023) · Sleep And Breathing · doi:10.1007/s11325-023-02974-2 · Cited by 5
“Previous studies reported that short-term constant light exposure (24 h/day) had effects on cardiac response to ischemia–reperfusion [2] and VR after AMI [3].”
InfluentialZhang, T., Zhang, G., Liu, T., Gu, T., Yu, F., Xu, P., Mi, W., Zhao, X., Guo, Q., Zheng, H., et al. (2026) · Med Research · doi:10.1002/mdr2.70052 · Cited by 4
Effect of KLF15-Mediated Circadian Rhythm on Myocardial Infarction: A Narrative Review
Zhao, J., Chen, Z., Yang, J., Duan, L., Yang, H. Y., Cai, D., & Zhao, Z. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26104831 · Cited by 5
“A similar phenomenon can also affect the recovery of hospitalized patients [32].”
A brief history of circadian time in the heart
Young, M. E., Khanna, V., Metcalfe, M., Rameshkumar, N., Harington, S., Li, L. H., Doost, J. S., Taegtmeyer, H., & Martino, T. A. (2025) · Journal of Molecular and Cellular Cardiology · doi:10.1016/j.yjmcc.2025.08.005 · Cited by 5
Self-citationMyocardial Repair Around-The-Clock
Sharma, U. C., & Canty, J. M. (2014) · Circulation Research · doi:10.1161/circresaha.114.304102 · Cited by 4
Metadata
- Authors
- Alibhai, F. J., Tsimakouridze, E. V., Chinnappareddy, N., Wright, D. C., Billia, F., O’Sullivan, M. L., Pyle, W. G., Sole, M. J., & Martino, T. A.
- Affiliations
- University Health Network (CA)
- ORCID
- Venue
- Circulation Research
- Published
- 2014-05-23
- Volume
- 114
- Issue
- 11
- Pages
- 1713-1722
- ISSN
- 0009-7330 (ISSN-L)
- 1524-4571
- OpenAlex
- W2129546872
- Semantic Scholar
- 52dc76bbff6a1eb6aeaa8f8ad67a1849f7a682fe
- Cited by
- 122
- References
- 54
- Citations by year
- 2026: 3 · 2025: 9 · 2024: 9 · 2023: 18 · 2022: 13 · 2021: 8 · 2020: 11 · 2019: 11 · 2018: 9 · 2017: 10 · 2016: 5 · 2015: 10 · 2014: 6
- FWCI
- 5.03
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Circulation Research (publishedVersion)
- PubMed (publishedVersion)
- IslandScholar (University of Prince Edward Island) (submittedVersion)
- Funders
- Canadian Institutes of Health Research (MOP119518)
- Topics
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Circadian rhythm and melatonin
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Fibrosis and Remodeling
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Acute Myocardial Infarction Research
- Keywords
- myocardial infarction, circadian rhythm disruption, diurnal cycle, cardiac remodeling, myocardial fibrosis, innate immune response, macrophage infiltration, neutrophils, myeloperoxidase, infarct healing, coronary artery ligation, ICU environment, left ventricular dilatation, infarct expansion, Clock mutant mice
- MeSH terms
- Animals, Circadian Rhythm, Coronary Vessels, Disease Models, Animal, Heart, Ligation, Male, Mice, Inbred C57BL, Myocardial Infarction, Myocardium, Time Factors, Mice
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