Circadian Mechanisms in Cardiovascular and Cerebrovascular Disease

HomeCirculation ResearchVol. 134, No. 6Circadian Mechanisms in Cardiovascular and Cerebrovascular Disease Free AccessReview ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessReview ArticlePDF/EPUBCircadian Mechanisms in Cardiovascular and Cerebrovascular Disease Eng H. Lo and Frank M. Faraci Eng H. LoEng H. Lo Correspondence to: Eng H. Lo, PhD, Departments of Radiology and Neurology, Massachusetts General Hospital, MGH E 149-2401, Charlestown, MA 02129, Email E-mail Address: [email protected] https://orcid.org/0000-0002-9327-2915 Departments of Radiology and Neurology, Massachusetts General Hospital, Charlestown (E.H.L.). and Frank M. FaraciFrank M. Faraci Frank M. Faraci, PhD, Department of Internal Medicine, Carver College of Medicine, University of Iowa, 3296 CBRB, Iowa City 52242, Email E-mail Address: [email protected] https://orcid.org/0000-0002-0203-1690 Department of Internal Medicine and Department of Neuroscience and Pharmacology, Francois M. Abboud Cardiovascular Center, Carver College of Medicine, University of Iowa (F.M.F.). Originally published14 Mar 2024https://doi.org/10.1161/CIRCRESAHA.124.324462Circulation Research. 2024;134:615–617All living organisms on Earth demonstrate rhythms in biological function, which are approximately tied to the 24-hour cycle of a single day and night. The term diurnal is commonly used to describe events that occur during the day. For example, a diurnal species is the one that is mainly active during the daylight. In contrast, the term circadian refers to a rhythm that has a period of ≈24 hours but is generated by a self-sustained oscillator. Thus, it persists in the absence of changes in the environment or behavior, such as dark/light or sleep/wake cycles. It is now clear that a full and integrated understanding of biology cannot be obtained without taking these elements of time into account.1 The fundamental importance of this concept has been recognized in multiple ways, including the 2017 Nobel Prize in Physiology or Medicine being awarded to Hall, Rosbach, and Young for their efforts in defining mechanisms that govern circadian rhythms. In this new Circulation Research compendium, we are honored to present a collection of reviews from thought leaders in this field, which provide a broad survey of the impact of circadian biology on cardiovascular and cerebrovascular function, in both health and disease.Tissue hypoxia comprises one of the most important sequelae of cardiovascular disease. Therefore, this compendium begins with a paper from Sator et al2 who introduce basic molecular mechanisms that connect genes that respond to hypoxia with select genes known to regulate circadian rhythms. Beyond a role in hypoxia responses per se, circadian genes and signaling pathways also interact with other mechanisms that mediate cardiovascular disorders. For example, sudden cardiac death is more prevalent in the morning,3 myocardial ischemia-reperfusion injury during the active phase leads to greater infarction,4 and disruptions of circadian rhythms increase the risk of cardiovascular disease.5 Hence, the compendium continues with a series of reviews that examine the heart as a key organ that is undeniably governed by circadian biology. Lal et al6 provide a molecular and physiological framework to understand how circadian and diurnal rhythms regulate cardiovascular metabolism. Delisle et al7 describe how daily rhythms in cardiac electrophysiology, cardiac ion channels, and expression of ion channel genes significantly influence myocardial contraction and function. If circadian rhythms govern heart function, then it is reasonable to expect that these mechanisms should also play a role in disease. Thus, Eckle et al8 provide a rigorous survey of circadian mechanisms that underlie ischemia and reperfusion injury in the development of heart damage, including heart failure.A growing literature suggests that circadian rhythms are central to cerebrovascular disease as well.9 In the context of ischemic stroke, risks of thrombosis may be greater during the early active phase (mornings for humans),10 whereas the progression of infarct growth may be higher during the inactive phase (nighttime for humans).11–13 Furthermore, circadian biology may also affect the response to treatments. In preclinical models, neuroprotection was harder to achieve in active versus inactive phase strokes.14 Therefore, the next section of the compendium focuses on critical aspects related to brain health, beginning with a review from Webb et al15 who describe detailed phenotypes and mechanisms that mediate daily cycles in vascular regulation and the control of cerebral blood flow. For several reasons, including the fact that the brain is encased in a rigid skull, its physiology is dependent on the careful regulation of neurofluids and brain-fluid balance. Vizcarra et al16 describe how diurnal and circadian cycles are essential for the function of the choroid plexus, the blood-CSF (cerebrospinal fluid) barrier, and cerebrospinal fluid dynamics. This review is then complemented by a review prepared by Kim et al,17 who describe how diurnal variations in the blood-brain barrier function contribute to disease mechanisms and modulate drug delivery to the diseased brain. The central importance of circadian biology is perhaps best appreciated by understanding how daily rhythms seem to control function in all cell types in the mammalian brain. Hence, Li et al18 provide a review of how circadian rhythms may mediate and integrate function in various cells of the neurovascular unit. The section on the brain then concludes with a translational review from Mergenthaler et al19 who argue the case that because diurnal rhythms play such a fundamental role in brain health, any therapies for stroke cannot be optimized unless the impact of circadian time and the potential of chronotherapy are taken into account and leveraged to the greatest extent possible.A key concept in physiology is based on the recognition that organs do not operate in isolation, and cross talk between various organs contributes to function and dysfunction. Therefore, the compendium includes 2 reviews that summarize how circadian rhythms in systemic biology can profoundly affect brain, heart, and vascular disease. Daily oscillations within the immune system are well established. Zeng et al20 describe how rhythms in immune function may influence inflammatory pathways that contribute to disease in virtually all organs. Finally, the compendium includes a review that touches on an area of fundamental importance in relation to vascular biology and organ health. Among modifiable risk factors, the global leader for cardiovascular disease (eg, myocardial infarction, heart failure, atrial fibrillation), neurovascular disease (eg, stroke and cognitive decline), death, and disability-adjusted life years is hypertension.21,22 Faraci and Scheer23 review accumulating evidence about the impact of circadian mechanisms in relation to changes in daily rhythms in blood pressure (eg, the normal reduction in blood pressure that occurs at night, nocturnal hypertension, and so forth). They compare and contrast differences in blood pressure regulation between humans and the most common preclinical models that are naturally nocturnal. Finally, to complement other reviews within the compendium related to brain health, they discuss the impact of hypertension in relation to neurovascular disease, cerebral blood flow, and brain barriers (the blood-brain barrier and the blood-CSF-barrier).Diurnal and circadian mechanisms seem to influence virtually all aspects of mammalian physiology. Collectively, this series of reviews has highlighted several common themes, questions, and concepts that include the following: (1) additional work is needed to more fully define mechanisms that underlie cell-specific, intercellular, and organ cross talk in the context of daily biological rhythms; (2) differences between circadian and diurnal rhythms need to be more clearly distinguished; (3) currently, a majority of preclinical work is performed in species that are naturally nocturnal; studies of humans and other diurnal species, including large animal models, may provide additional benefit; (4) in both preclinical studies and within clinical trials, increased attention should be given to the timing of interventions, key measurements, and the potential benefit of chronotherapy; and (5) in relation to brain and heart, greater insight is needed for temporal aspects of integrated organ function in both health and disease. For example, loss of brain health is one of the most complex phenotypes in biology and medicine, yet our understanding of its pathophysiology is relatively meager. This includes the influence of diurnal and circadian mechanisms in relation to the regulation of global and regional cerebral blood flow, integrity and function of the blood-brain barrier, the blood-CSF barrier, the choroid plexus, and the impact of neurofluids under normal conditions and during disease. We respectfully hope that this new Circulation Research compendium may help stimulate these fields of investigation to identify novel mechanisms and therapeutic targets for cardiovascular and cerebrovascular disease and brain health.ARTICLE INFORMATIONAcknowledgmentsThis compendium arose in part from collaborations between 2 Networks of Excellence funded by the Leducq Foundation. The authors are grateful for ongoing discussions with all colleagues from both Networks.Sources of FundingThis work was supported in part by the National Institutes of Health (grant R01-NS108409) and the Leducq Foundation (Trans-Atlantic Network of Excellence on Circadian Effects in Stroke [grant 21CVD04] and an International Network of Excellence on Brain Endothelium [grant 22CVD01]).Disclosures None.FootnotesFor Sources of Funding and Disclosures, see page 616.The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.Correspondence to: Eng H. Lo, PhD, Departments of Radiology and Neurology, Massachusetts General Hospital, MGH E 149-2401, Charlestown, MA 02129, Email ehlo@mgh.harvard.eduFrank M. Faraci, PhD, Department of Internal Medicine, Carver College of Medicine, University of Iowa, 3296 CBRB, Iowa City 52242, Email frank-faraci@uiowa.eduREFERENCES1. Cederroth CR, Albrecht U, Bass J, Brown SA, Dyhrfjeld-Johnsen J, Gachon F, Green CB, Hastings MH, Helfrich-Forster C, Hogenesch JB, et al. Medicine in the fourth dimension.Cell Metab. 2019; 30:238–250. doi: 10.1016/j.cmet.2019.06.019CrossrefMedlineGoogle Scholar2. Sator F, Ferero-Bordera B, Haspel J, Sperandio M, Holloway PM, Merrow M. The circadian clock and hypoxia.Circ Res. 2024; 134:618–634. doi: 10.1161/CIRCRESAHA.124.323518LinkGoogle Scholar3. Delisle BP, George AL, Nerbonne JM, Bass JT, Ripplinger CM, Jain MK, Hermanstyne TO, Young ME, Kannankeril PJ, Duffy JF, et al. Understanding circadian mechanisms of sudden cardiac death: a report from the National Heart, Lung, and Blood Institute Workshop, Part 1: Basic and Translational Aspects.Circ Arrhythm Electrophysiol. 2021; 11:e010181. doi: 10.1161/CIRCEP.121.010181LinkGoogle Scholar4. Rabinovich-Nikitin I, Kirshenbaum LA. Circadian regulated control of myocardial ischemia-reperfusion injury.Trends Cardiovasc Med. 2024; 34:1–7. doi: 10.1016/j.tcm.2022.09.003CrossrefMedlineGoogle Scholar5. Morris CJ, Purvis TE, Hu K, Scheer FA. Circadian misalignment increases cardiovascular disease risk factors in humans.Proc Natl Acad Sci U S A. 2016; 113:E1402–E1411. doi: 10.1073/pnas.1516953113CrossrefMedlineGoogle Scholar6. Lal H, Verma SK, Wang Y, Xie M, Young ME. Circadian rhythms in cardiovascular metabolism.Circ Res. 2024; 134:635–658. doi: 10.1161/CIRCRESAHA.123.323520LinkGoogle Scholar7. Delisle BP, Prabhat A, Burgess DE, Ono M, Esser KA, Schroder EA. Circadian regulation of cardiac arrhythmias and electrophysiology.Circ Res. 2024; 134:659–674. doi: 10.1161/CIRCRESAHA.123.323513LinkGoogle Scholar8. Eckle T, Bertazzo J, Khatua TN, Tabatabaei SRF, Bakhtiari NM, Walker LA, Martino TA. Circadian influences on myocardial ischemia-reperfusion injury and heart failure.Circ Res. 2024; 134:675–694. doi: 10.1161/CIRCRESAHA.123.323522LinkGoogle Scholar9. Lo EH, Albers GW, Dichgans M, Donnan G, Esposito E, Foster R, Howells DW, Huang YG, Ji X, Klerman EB, et al. Circadian biology and stroke.Stroke. 2021; 52:2180–2190. doi: 10.1161/STROKEAHA.120.031742LinkGoogle Scholar10. Scheer FA, Shea SA. Human circadian system causes a morning peak in prothrombotic plasminogen activator inhibitor-1 (PAI-1) independent of the sleep/wake cycle.Blood. 2014; 123:590–593. doi: 10.1182/blood-2013-07-517060CrossrefMedlineGoogle Scholar11. Ryu WS, Hong KS, Jeong SW, Park JE, Kim BJ, Kim JT, Lee KB, Park TH, Park SS, Park JM, et al. Association of ischemic stroke onset time with presenting severity, acute progression, and long-term outcome: a cohort study.PLoS Med. 2022; 19:e1003910. doi: 10.1371/journal.pmed.1003910CrossrefMedlineGoogle Scholar12. Reidler P, Brehm A, Sporns PB, Burbano VG, Stueckelschweiger L, Broocks G, Liebig T, Psychogios MN, Ricke J, Dimitriadis K, et al. Circadian rhythm of ischaemic core progression in human stroke.J Neurol Neurosurg Psychiatry. 2023; 94:70–73. doi: 10.1136/jnnp-2021-326072CrossrefMedlineGoogle Scholar13. Seners P, Mlynash M, Sreekrishnan A, Ter Schiphorst A, Arquizan C, Costalat V, Henon H, Bretzner M, Heit JJ, Olivot JM, et al; Infarct-Growth collaborators. Infarct core growth during interhospital transfer for thrombectomy is faster at night.Stroke. 2023; 54:2167–2171. doi: 10.1161/STROKEAHA.123.043643LinkGoogle Scholar14. Esposito E, Li W, Mandeville E T, Park JH, Şencan I, Guo S, Shi J, Lan J, Lee J, Hayakawa K, et al. Potential circadian effects on translational failure for neuroprotection.Nature. 2020; 582:395–398. doi: 10.1038/s41586-020-2348-zCrossrefMedlineGoogle Scholar15. Webb AJS, Klerman EB, Mandeville ET. Circadian and diurnal regulation of cerebral blood flow.Circ Res. 2024; 134:695–710. doi: 10.1161/CIRCRESAHA.123.323049LinkGoogle Scholar16. Vizcarra VS, Fame RM, Hablitz LM. Circadian mechanisms in brain fluid biology.Circ Res. 2024; 134:711–726. doi: 10.1161/CIRCRESAHA.123.323516LinkGoogle Scholar17. Kim M, Keep RJ, Zhang SL. Circadian rhythms and the blood-brain barrier and drug delivery.Circ Res. 2024; 134:727–747. doi: 10.1161/CIRCRESAHA.123.323521LinkGoogle Scholar18. Li W, Tiedt S, Lawrence JH, Harringtom ME, Musiek ES, Lo EH. Circadian biology and the neurovascular unit.Circ Res. 2024; 134:748-769. doi: 10.1161/CIRCRESAHA.124.323514LinkGoogle Scholar19. Mergenthaler P, Balami JS, Neuhaus AA, Motthahedin A, Albers GW, Rothwell P, Saver JL, Young ME, Buchan AM. Stroke in the time of circadian medicine.Circ Res. 2024; 134:770–790. doi: 10.1161/CIRCRESAHA.124.323508LinkGoogle Scholar20. Zeng Q, Oliva VM, Moro MA, Scheiermann C. Circadian effects on vascular immunopathologies.Circ Res. 2024; 134:791–809. doi: 10.1161/CIRCRESAHA.123.323619LinkGoogle Scholar21. Martin SS, Aday AW, Almarzooq ZI, Anderson CAM, Arora P, Avery CL, Baker-Smith CM, Barone Gibbs B, Beaton AZ, et al. 2024 heart disease and stroke statistics: a report of US and global data from the American Heart Association.Circulation. 2024; 149:e347. doi: 10.1161/CIR.0000000000001209LinkGoogle Scholar22. Yusuf S, Joseph P, Rangarajan S, Islam S, Mente A, Hystad P, Brauer M, Kutty VR, Gupta R, Wielgosz A, et al. Modifiable risk factors, cardiovascular disease, and mortality in 155,722 individuals from 21 high-income, middle-income, and low-income countries (PURE): a prospective cohort study.Lancet. 2020; 395:795–808. doi: 10.1016/S0140-6736(19)32008-2CrossrefMedlineGoogle Scholar23. Faraci FM, Scheer FAJL. Hypertension: causes and consequences of circadian rhythms in blood pressure.Circ Res. 2024; 134:810–832. doi: 10.1161/CIRCRESAHA.124.323515LinkGoogle Scholar eLetters(0)eLetters should relate to an article recently published in the journal and are not a forum for providing unpublished data. Comments are reviewed for appropriate use of tone and language. Comments are not peer-reviewed. Acceptable comments are posted to the journal website only. Comments are not published in an issue and are not indexed in PubMed. Comments should be no longer than 500 words and will only be posted online. References are limited to 10. Authors of the article cited in the comment will be invited to reply, as appropriate.Comments and feedback on AHA/ASA Scientific Statements and Guidelines should be directed to the AHA/ASA Manuscript Oversight Committee via its Correspondence page.Sign In to Submit a Response to This Article Previous Back to top Next FiguresReferencesRelatedDetails March 15, 2024Vol 134, Issue 6 Advertisement Discover CircRes March 2024 March 21, 2024 Article InformationMetrics © 2024 American Heart Association, Inc.https://doi.org/10.1161/CIRCRESAHA.124.324462PMID: 38484030 Originally publishedMarch 14, 2024 KeywordsEditorialsbrainchronotherapycircadian rhythmheartPDF download Advertisement SubjectsBasic Science ResearchIschemic Stroke