Circadian Disruptions and Their Impact on Inflammatory Pathways, Neuroendocrine Dysregulation, and Cardiovascular Risk: A Systematic Review and Meta-Analysis

Abdul Rashid; Adil Mushtaq; Shaheera Raghib; Sumaiya Tarannum Shaik; Arun Kumar Maloth; Aima Asim Khan; Saja Saad; Mohammed Saad Saad; Shamsa Bin Bader Alaleeli; Shasliya Abdul Gafoor; Afrah Siraj Mujeeb Ali

doi:10.70749/ijbr.v3i2.754

Authors

Abdul Rashid Department of Cardiology, POF Hospital/ Wah Medical College, National University of Medical Sciences, Pakistan. https://orcid.org/0009-0002-4868-4483
Adil Mushtaq Akhtar Saeed Medical & Dental College, Lahore, Punjab, Pakistan.
Shaheera Raghib Baqai Medical University, Karachi, Pakistan. https://orcid.org/0009-0004-2303-3208
Sumaiya Tarannum Shaik Osmania Medical College, Hyderabad, India.
Arun Kumar Maloth Kakatiya Medical College, Warangal, India.
Aima Asim Khan Fazaia Medical College, Islamabad, Pakistan.
Saja Saad Jordan University Hospital, Jordan.
Mohammed Saad Jordan University Hospital, Jordan.
Shamsa Bin Bader Alaleeli Sheikh Shakhbout Medical City (SSMC), UAE.
Shasliya Abdul Gafoor Ras al Khaimah Medical and Health Centre10 (RAKMHSU), UAE
Afrah Siraj Mujeeb Ali RAK Medical & Health Sciences University, UAE

DOI:

https://doi.org/10.70749/ijbr.v3i2.754

Keywords:

Circadian Disruption, Shift Work, Inflammatory Markers, Neuroendocrine Dysregulation, Cardiovascular Risk

Abstract

Background: Circadian disruptions, such as shift work, sleep irregularity, and chronic circadian misalignment, have been increasingly linked to adverse health outcomes, particularly affecting cardiovascular health. These disruptions alter inflammatory and neuroendocrine pathways, which may accelerate cardiovascular disease risk. This meta-analysis aimed to synthesize evidence on the association between circadian misalignment, inflammatory markers, neuroendocrine dysregulation, and cardiovascular outcomes. Methods: A systematic literature search was conducted using PubMed, Web of Science, PsycINFO, Cochrane Library, and Scopus databases, covering studies published between 2015 and 2024. Eligible studies included observational and experimental designs assessing the impact of documented circadian disruptions on inflammatory markers (CRP, IL-6, TNF-α), neuroendocrine biomarkers (cortisol, melatonin), and cardiovascular outcomes (coronary heart disease, cardiovascular events, metabolic risk). Quality assessment was performed using the Cochrane Risk of Bias Tool for experimental studies and the Newcastle-Ottawa Scale (NOS) for observational studies. Due to substantial heterogeneity across studies, a narrative synthesis supported by descriptive statistics, correlation analysis, and visual comparative techniques was applied, rather than a formal pooled effect size calculation. Results: Eight studies (n=744) reported increased inflammatory markers (CRP, IL-6, TNF-α) in circadian disruptions (p < 0.05–0.01). Misalignment was linked to altered cortisol rhythms and increased secretion (p < 0.05). Correlation analysis showed a moderate positive association between neuroendocrine dysregulation and cardiovascular risk. Shift work and chronic misalignment had the highest cardiovascular risk, with stronger effects in longer studies. Most studies had low-to-moderate bias. Conclusions: Circadian disruptions contribute to inflammation, neuroendocrine dysregulation, and cardiovascular risk. Maintaining circadian stability is crucial, particularly for shift workers. High-quality studies are needed for targeted interventions.

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References

Reutrakul, S., & Knutson, K. L. (2015). Consequences of circadian disruption on cardiometabolic health. Sleep Medicine Clinics, 10(4), 455–468. https://doi.org/10.1016/j.jsmc.2015.07.005

Vetter, C., Devore, E. E., Wegrzyn, L. R., Massa, J., Speizer, F. E., Kawachi, I., Rosner, B., Stampfer, M. J., & Schernhammer, E. S. (2016b). Association between rotating night shift work and risk of coronary heart disease among women. JAMA, 315(16), 1726. https://doi.org/10.1001/jama.2016.4454

Morris, C. J., Purvis, T. E., Hu, K., & Scheer, F. a. J. L. (2016). Circadian misalignment increases cardiovascular disease risk factors in humans. Proceedings of the National Academy of Sciences, 113(10). https://doi.org/10.1073/pnas.1516953113

Huang, T., Mariani, S., & Redline, S. (2020). Sleep irregularity and risk of cardiovascular events. Journal of the American College of Cardiology, 75(9), 991–999. https://doi.org/10.1016/j.jacc.2019.12.054

Inokawa, H., Umemura, Y., Shimba, A., Kawakami, E., Koike, N., Tsuchiya, Y., Ohashi, M., Minami, Y., Cui, G., Asahi, T., Ono, R., Sasawaki, Y., Konishi, E., Yoo, S., Chen, Z., Teramukai, S., Ikuta, K., & Yagita, K. (2020). Chronic circadian misalignment accelerates immune senescence and abbreviates lifespan in mice. Scientific Reports, 10(1). https://doi.org/10.1038/s41598-020-59541-y

McHill, A. W., Melanson, E. L., Higgins, J., Connick, E., Moehlman, T. M., Stothard, E. R., & Wright, K. P. (2014). Impact of circadian misalignment on energy metabolism during simulated nightshift work. Proceedings of the National Academy of Sciences, 111(48), 17302–17307. https://doi.org/10.1073/pnas.1412021111

Vetter, C., Devore, E. E., Wegrzyn, L. R., Massa, J., Speizer, F. E., Kawachi, I., Rosner, B., Stampfer, M. J., & Schernhammer, E. S. (2016). Association between rotating night shift work and risk of coronary heart disease among women. JAMA, 315(16), 1726. https://doi.org/10.1001/jama.2016.4454

Lin, J., Kuang, H., Jiang, J., Zhou, H., Peng, L., Yan, X., & Kuang, J. (2023). Circadian rhythms in cardiovascular function: Implications for cardiac diseases and therapeutic opportunities. Medical Science Monitor, 29. https://doi.org/10.12659/msm.942215

Azmi, N. a. S. M., Juliana, N., Azmani, S., Effendy, N. M., Abu, I. F., Teng, N. I. M. F., & Das, S. (2021). Cortisol on circadian rhythm and its effect on cardiovascular system. International Journal of Environmental Research and Public Health, 18(2), 676. https://doi.org/10.3390/ijerph18020676

Bowles, N. P., Thosar, S. S., Butler, M. P., Clemons, N. A., Robinson, L. D., Ordaz, O. H., Herzig, M. X., McHill, A. W., Rice, S. P. M., Emens, J., & Shea, S. A. (2022). The circadian system modulates the cortisol awakening response in humans. Frontiers in Neuroscience, 16. https://doi.org/10.3389/fnins.2022.995452

Morris, C. J., Purvis, T. E., Hu, K., & Scheer, F. a. J. L. (2016). Circadian misalignment increases cardiovascular disease risk factors in humans. Proceedings of the National Academy of Sciences, 113(10). https://doi.org/10.1073/pnas.1516953113

Yang, H., Yang, L.-T., Liu, J., Tang, S., Zhao, X., Wang, Q., Zhang, S., Shi, M., Pan, W., & Yang, P.-C. (2018). Circadian protein CLK suppresses transforming growth factor-β expression in peripheral B cells of nurses with day-night shift rotation. PubMed, 10(12), 4331–4337.

Cuesta, M., Boudreau, P., Dubeau-Laramée, G., Cermakian, N., & Boivin, D. B. (2016). Simulated night shift disrupts circadian rhythms of immune functions in humans. The Journal of Immunology, 196(6), 2466–2475. https://doi.org/10.4049/jimmunol.1502422

Damasceno, A., Moraes, A. S., Farias, A., Damasceno, B. P., Santos, L. M. B. D., & Cendes, F. (2015). Disruption of melatonin circadian rhythm production is related to multiple sclerosis severity: A preliminary study. Journal of the Neurological Sciences, 353(1–2), 166–168. https://doi.org/10.1016/j.jns.2015.03.040

Cannizzaro, E., Cirrincione, L., Mazzucco, W., Scorciapino, A., Catalano, C., Ramaci, T., Ledda, C., & Plescia, F. (2020). Night-Time Shift Work and Related Stress Responses: A Study on Security Guards. International journal of environmental research and public health, 17(2), 562. https://doi.org/10.3390/ijerph17020562

Wright, K. P., Jr, Drake, A. L., Frey, D. J., Fleshner, M., Desouza, C. A., Gronfier, C., & Czeisler, C. A. (2015). Influence of sleep deprivation and circadian misalignment on cortisol, inflammatory markers, and cytokine balance. Brain, behavior, and immunity, 47, 24–34. https://doi.org/10.1016/j.bbi.2015.01.004

Leproult, R., Copinschi, G., Buxton, O., & Van Cauter, E. (1997). Sleep loss results in an elevation of cortisol levels the next evening. Sleep, 20(10), 865–870. https://pubmed.ncbi.nlm.nih.gov/9415946/

Chapotot, F., Buguet, A., Gronfier, C., & Brandenberger, G. (2001). Hypothalamo-pituitary-adrenal axis activity is related to the level of central arousal: effect of sleep deprivation on the association of high-frequency waking electroencephalogram with cortisol release. Neuroendocrinology, 73(5), 312–321. https://doi.org/10.1159/000054648

Von Treuer, K., Norman, T. R., & Armstrong, S. M. (1996). Overnight human plasma melatonin, cortisol, prolactin, TSH, under conditions of normal sleep, sleep deprivation, and sleep recovery. Journal of pineal research, 20(1), 7–14. https://doi.org/10.1111/j.1600-079x.1996.tb00232.x

Weibel, L., Follenius, M., Spiegel, K., Ehrhart, J., & Brandenberger, G. (1995). Comparative effect of night and daytime sleep on the 24-hour cortisol secretory profile. Sleep, 18(7), 549–556. https://doi.org/10.1093/sleep/18.7.549

Weitzman, E. D., Zimmerman, J. C., Czeisler, C. A., & Ronda, J. (1983). Cortisol secretion is inhibited during sleep in normal man. The Journal of clinical endocrinology and metabolism, 56(2), 352–358. https://doi.org/10.1210/jcem-56-2-352

Scheer, F. A., Hilton, M. F., Mantzoros, C. S., & Shea, S. A. (2009). Adverse metabolic and cardiovascular consequences of circadian misalignment. Proceedings of the National Academy of Sciences of the United States of America, 106(11), 4453–4458. https://doi.org/10.1073/pnas.0808180106

Vetter, C., Devore, E. E., Wegrzyn, L. R., Massa, J., Speizer, F. E., Kawachi, I., Rosner, B., Stampfer, M. J., & Schernhammer, E. S. (2016). Association between rotating night shift work and risk of coronary heart disease among women. JAMA, 315(16), 1726. https://doi.org/10.1001/jama.2016.4454

Kervezee, L., Kosmadopoulos, A., & Boivin, D. B. (2018). Metabolic and cardiovascular consequences of shift work: The role of circadian disruption and sleep disturbances. European Journal of Neuroscience, 51(1), 396–412. https://doi.org/10.1111/ejn.14216