Circadian rhythms and the molecular clock in cardiovascular biology and disease


The Earth turns on its axis every 24 h; almost all life on the planet has a mechanism — circadian rhythmicity — to anticipate the daily changes caused by this rotation. The molecular clocks that control circadian rhythms are being revealed as important regulators of physiology and disease. In humans, circadian rhythms have been studied extensively in the cardiovascular system. Many cardiovascular functions, such as endothelial function, thrombus formation, blood pressure and heart rate, are now known to be regulated by the circadian clock. Additionally, the onset of acute myocardial infarction, stroke, arrhythmias and other adverse cardiovascular events show circadian rhythmicity. In this Review, we summarize the role of the circadian clock in all major cardiovascular cell types and organs. Second, we discuss the role of circadian rhythms in cardiovascular physiology and disease. Finally, we postulate how circadian rhythms can serve as a therapeutic target by exploiting or altering molecular time to improve existing therapies and develop novel ones.

Key points

  • Molecular clocks are found in all cardiovascular cell types.

  • Various cardiovascular functions, including endothelial function, thrombus formation, blood pressure and heart rate, are regulated by the circadian clock.

  • Disruption of 24-h rhythms leads to cardiovascular disease, including heart failure, myocardial infarction and arrhythmias.

  • 24-h rhythms are present in the development, risk factors, incidence and outcome of cardiovascular disease.

  • Cardiovascular disease leads to disrupted circadian rhythm and sleep problems.

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Fig. 1: Overview of the core molecular clockwork within the cardiovascular system.


  1. 1.

    Bargiello, T. A., Jackson, F. R. & Young, M. W. Restoration of circadian behavioural rhythms by gene transfer in Drosophila. Nature 312, 752–754 (1984).

  2. 2.

    Hardin, P. E., Hall, J. C. & Rosbash, M. Feedback of the Drosophila period gene product on circadian cycling of its messenger RNA levels. Nature 343, 536–540 (1990).

  3. 3.

    Siwicki, K. K., Eastman, C., Petersen, G., Rosbash, M. & Hall, J. C. Antibodies to the period gene product of drosophila reveal diverse tissue distribution and rhythmic changes in the visual system. Neuron 1, 141–150 (1988).

  4. 4.

    Zehring, W. A. et al. P-Element transformation with period locus DNA restores rhythmicity to mutant, arrhythmic Drosophila melanogaster. Cell 39, 369–376 (1984).

  5. 5.

    Brown, T. M. & Piggins, H. D. Electrophysiology of the suprachiasmatic circadian clock. Prog. Neurobiol. 82, 229–255 (2007).

  6. 6.

    Zhang, R., Lahens, N. F., Ballance, H. I., Hughes, M. E. & Hogenesch, J. B. A circadian gene expression atlas in mammals: implications for biology and medicine. Proc. Natl Acad. Sci. USA 111, 16219–16224 (2014).

  7. 7.

    Cajochen, C., Kräuchi, K. & Wirz-Justice, A. Role of melatonin in the regulation of human circadian rhythms and sleep. J. Neuroendocrinol. 15, 432–437 (2003).

  8. 8.

    Stokkan, K. A., Yamazaki, S., Tei, H., Sakaki, Y. & Menaker, M. Entrainment of the circadian clock in the liver by feeding. Science 291, 490–493 (2001).

  9. 9.

    Mistlberger, R. E. & Skene, D. J. Social influences on mammalian circadian rhythms: animal and human studies. Biol. Rev. Camb. Philos. Soc. 79, 533–556 (2004).

  10. 10.

    Damiola, F. et al. Restricted feeding uncouples circadian oscillators in peripheral tissues from the central pacemaker in the suprachiasmatic nucleus. Genes Dev. 14, 2950–2961 (2000).

  11. 11.

    Vitaterna, M. H., Takahashi, J. S. & Turek, F. W. Overview of circadian rhythms. Alcohol Res. Health 25, 85–93 (2001).

  12. 12.

    Beesley, S., Noguchi, T. & Welsh, D. K. Cardiomyocyte circadian oscillations are cell-autonomous, amplified by β-adrenergic signaling, and synchronized in cardiac ventricle tissue. PLOS ONE 11, e0159618 (2016).

  13. 13.

    Takeda, N. et al. Thrombomodulin is a clock-controlled gene in vascular endothelial cells. J. Biol. Chem. 282, 32561–32567 (2007).

  14. 14.

    Du Pré, B. C. et al. SCA1+ cells from the heart possess a molecular circadian clock and display circadian oscillations in cellular functions. Stem Cell Rep. 9, 762–769 (2017).

  15. 15.

    Lin, C. et al. The rhythmic expression of clock genes attenuated in human plaque-derived vascular smooth muscle cells. Lipids Health Dis. 13, 14 (2014).

  16. 16.

    Balsalobre, A., Damiola, F. & Schibler, U. A serum shock induces circadian gene expression in mammalian tissue culture cells. Cell 93, 929–937 (1998).

  17. 17.

    Kollias, G. E. et al. Diurnal variation of endothelial function and arterial stiffness in hypertension. J. Hum. Hypertens. 23, 597 (2009).

  18. 18.

    Degaute, J. P., van de Borne, P., Linkowski, P. & Van Cauter, E. Quantitative analysis of the 24-hour blood pressure and heart rate patterns in young men. Hypertension 18, 199–210 (1991).

  19. 19.

    Portaluppi, F. & Hermida, R. C. Circadian rhythms in cardiac arrhythmias and opportunities for their chronotherapy. Adv. Drug Deliv. Rev. 59, 940–951 (2007).

  20. 20.

    Bulluck, H. et al. Circadian variation in acute myocardial infarct size assessed by cardiovascular magnetic resonance in reperfused STEMI patients. Int. J. Cardiol. 230, 149–154 (2017).

  21. 21.

    Manfredini, R. et al. Twenty-four-hour patterns in occurrence and pathophysiology of acute cardiovascular events and ischemic heart disease. Chronobiol. Int. 30, 6–16 (2013).

  22. 22.

    Bozek, K. et al. Regulation of clock-controlled genes in mammals. PLOS ONE 4, e4882 (2009).

  23. 23.

    Panda, S. et al. Coordinated transcription of key pathways in the mouse by the circadian clock. Cell 109, 307–320 (2002).

  24. 24.

    Storch, K.-F. et al. Extensive and divergent circadian gene expression in liver and heart. Nature 417, 78–83 (2002).

  25. 25.

    Shearman, L. P. et al. Interacting molecular loops in the mammalian circadian clock. Science 288, 1013–1019 (2000).

  26. 26.

    Preitner, N. et al. The orphan nuclear receptor REV-ERBα controls circadian transcription within the positive limb of the mammalian circadian oscillator. Cell 110, 251–260 (2002).

  27. 27.

    Solt, L. A., Kojetin, D. J. & Burris, T. P. The REV-ERBs and RORs: molecular links between circadian rhythms and lipid homeostasis. Future Med. Chem. 3, 623–638 (2011).

  28. 28.

    Akashi, M. & Takumi, T. The orphan nuclear receptor RORalpha regulates circadian transcription of the mammalian core-clock Bmal1. Nat. Struct. Mol. Biol. 12, 441–448 (2005).

  29. 29.

    Dierickx, P. et al. in Stem Cells and Cardiac Regeneration (ed. Madonna, R.) 57–78 (Springer International Publishing, 2016).

  30. 30.

    Mendoza-Viveros, L. et al. Molecular modulators of the circadian clock: lessons from flies and mice. Cell. Mol. Life Sci. 74, 1035–1059 (2017).

  31. 31.

    Du Pré, B. C. et al. Circadian rhythms in cell maturation. Physiology 29, 72–83 (2014).

  32. 32.

    Dierickx, P. et al. Circadian networks in human embryonic stem cell-derived cardiomyocytes. EMBO Rep. 18, 1199–1212 (2017).

  33. 33.

    Kowalska, E., Moriggi, E., Bauer, C., Dibner, C. & Brown, S. A. The circadian clock starts ticking at a developmentally early stage. J. Biol. Rhythms 25, 442–449 (2010).

  34. 34.

    Yagita, K. et al. Development of the circadian oscillator during differentiation of mouse embryonic stem cells in vitro. Proc. Natl Acad. Sci. USA 107, 3846–3851 (2010).

  35. 35.

    Weger, M., Diotel, N., Dorsemans, A.-C., Dickmeis, T. & Weger, B. D. Stem cells and the circadian clock. Dev. Biol. 431, 111–123 (2017).

  36. 36.

    Davidson, A. J., London, B., Block, G. D. & Menaker, M. Cardiovascular tissues contain independent circadian clocks. Clin. Exp. Hypertens. 27, 307–311 (2005).

  37. 37.

    McNamara, P. et al. Regulation of CLOCK and MOP4 by nuclear hormone receptors in the vasculature: a humoral mechanism to reset a peripheral clock. Cell 105, 877–889 (2001).

  38. 38.

    Nonaka, H. et al. Angiotensin II induces circadian gene expression of clock genes in cultured vascular smooth muscle cells. Circulation 104, 1746–1748 (2001).

  39. 39.

    Chalmers, J. A. et al. Vascular circadian rhythms in a mouse vascular smooth muscle cell line (Movas-1). Am. J. Physiol. Regul. Integr. Comp. Physiol. 295, R1529–R1538 (2008).

  40. 40.

    Welsh, D. K., Yoo, S.-H., Liu, A. C., Takahashi, J. S. & Kay, S. A. Bioluminescence imaging of individual fibroblasts reveals persistent, independently phased circadian rhythms of clock gene rxpression. Curr. Biol. 14, 2289–2295 (2004).

  41. 41.

    Durgan, D. J. The intrinsic circadian clock within the cardiomyocyte. Am. J. Physiol. Heart Circ. Physiol. 289, H1530–H1541 (2005).

  42. 42.

    Sato, F. et al. Smad3 and Bmal1 regulate p21 and S100A4 expression in myocardial stromal fibroblasts via TNF-α. Histochem. Cell Biol. 148, 617–624 (2017).

  43. 43.

    Panza, J. A., Epstein, S. E. & Quyyumi, A. A. Circadian variation in vascular tone and its relation to α-sympathetic vasoconstrictor activity. N. Engl. J. Med. 325, 986–990 (1991).

  44. 44.

    Millar-Craig, M. W., Bishop, C. N. & Raftery, E. B. Circadian variation of blood-pressure. Lancet 311, 795–797 (1978).

  45. 45.

    Bastianini, S., Silvani, A., Berteotti, C., Lo Martire, V. & Zoccoli, G. Mice show circadian rhythms of blood pressure during each wake-sleep state. Chronobiol. Int. 29, 82–86 (2012).

  46. 46.

    Sei, H. et al. Diurnal amplitudes of arterial pressure and heart rate are dampened in Clock mutant mice and adrenalectomized mice. Endocrinology 149, 3576–3580 (2008).

  47. 47.

    Viswambharan, H. et al. Mutation of the circadian clock gene Per2 alters vascular endothelial function. Circulation 115, 2188–2195 (2007).

  48. 48.

    Curtis, A. M. et al. Circadian variation of blood pressure and the vascular response to asynchronous stress. Proc. Natl Acad. Sci. USA 104, 3450–3455 (2007).

  49. 49.

    Martino, T. et al. Day/night rhythms in gene expression of the normal murine heart. J. Mol. Med. 82, 256–264 (2004).

  50. 50.

    Leibetseder, V. et al. Clock genes display rhythmic expression in human hearts. Chronobiol. Int. 26, 621–636 (2009).

  51. 51.

    Martino, T. A. & Young, M. E. Influence of the cardiomyocyte circadian clock on cardiac physiology and pathophysiology. J. Biol. Rhythms 30, 183–205 (2015).

  52. 52.

    Young, M. E. The circadian clock within the heart: potential influence on myocardial gene expression, metabolism, and function. Am. J. Physiol. Heart Circ. Physiol. 290, H1–H16 (2006).

  53. 53.

    Paschos, G. K. & FitzGerald, G. A. Circadian clocks and vascular function. Circ. Res. 106, 833–841 (2010).

  54. 54.

    Bray, M. S. et al. Disruption of the circadian clock within the cardiomyocyte influences myocardial contractile function, metabolism, and gene expression. Am. J. Physiol. Heart Circ. Physiol. 294, H1036–H1047 (2008).

  55. 55.

    Durgan, D. J. & Young, M. E. The cardiomyocyte circadian clock: emerging roles in health and disease. Circ. Res. 106, 647–658 (2010).

  56. 56.

    Shostak, A. Circadian clock, cell division, and cancer: from molecules to organism. Int. J. Mol. Sci. 18, E873 (2017).

  57. 57.

    Scheiermann, C., Gibbs, J., Ince, L. & Loudon, A. Clocking in to immunity. Nat. Rev. Immunol. 18, 423–437 (2018).

  58. 58.

    Kondratova, A. A. & Kondratov, R. V. The circadian clock and pathology of the ageing brain. Nat. Rev. Neurosci. 13, 325–335 (2012).

  59. 59.

    Penev, P. D., Kolker, D. E., Zee, P. C. & Turek, F. W. Chronic circadian desynchronization decreases the survival of animals with cardiomyopathic heart disease. Am. J. Physiol. 275, H2334–H2337 (1998).

  60. 60.

    Martino, T. A. et al. Circadian rhythm disorganization produces profound cardiovascular and renal disease in hamsters. Am. J. Physiol. Regul. Integr. Comp. Physiol. 294, R1675–R1683 (2008).

  61. 61.

    Martino, T. A. et al. Disturbed diurnal rhythm alters gene expression and exacerbates cardiovascular disease with rescue by resynchronization. Hypertension 49, 1104–1113 (2007).

  62. 62.

    Lefta, M., Campbell, K. S., Feng, H.-Z., Jin, J.-P. & Esser, K. A. Development of dilated cardiomyopathy in Bmal1-deficient mice. Am. J. Physiol. Heart Circ. Physiol. 303, H475–H485 (2012).

  63. 63.

    Jeyaraj, D. et al. Circadian rhythms govern cardiac repolarization and arrhythmogenesis. Nature 483, 96–99 (2012).

  64. 64.

    Young, M. E. et al. Cardiomyocyte-specific BMAL1 plays critical roles in metabolism, signaling, and maintenance of contractile function of the heart. J. Biol. Rhythms 29, 257–276 (2014).

  65. 65.

    Cheng, B. et al. Tissue-intrinsic dysfunction of circadian clock confers transplant arteriosclerosis. Proc. Natl Acad. Sci. USA 108, 17147–17152 (2011).

  66. 66.

    Rüger, M. & Scheer, F. A. J. L. Effects of circadian disruption on the cardiometabolic system. Rev. Endocr. Metab. Disord. 10, 245–260 (2009).

  67. 67.

    Thosar, S. S., Butler, M. P. & Shea, S. A. Role of the circadian system in cardiovascular disease. J. Clin. Invest. 128, 2157–2167 (2018).

  68. 68.

    Portaluppi, F. et al. Circadian rhythms and cardiovascular health. Sleep Med. Rev. 16, 151–166 (2012).

  69. 69.

    Reutrakul, S. & Knutson, K. L. Consequences of circadian disruption on cardiometabolic health. Sleep Med. Clin. 10, 455–468 (2015).

  70. 70.

    Saxena, R. et al. Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels. Science 316, 1331–1336 (2007).

  71. 71.

    Zeggini, E. et al. Multiple type 2 diabetes susceptibility genes following genome-wide association scan in UK samples. Science 316, 1336–1341 (2007).

  72. 72.

    Woon, P. Y. et al. Aryl hydrocarbon receptor nuclear translocator-like (BMAL1) is associated with susceptibility to hypertension and type 2 diabetes. Proc. Natl Acad. Sci. USA 104, 14412–14417 (2007).

  73. 73.

    Scott, E. M., Carter, A. M. & Grant, P. J. Association between polymorphisms in the Clock gene, obesity and the metabolic syndrome in man. Int. J. Obes. 32, 658–662 (2008).

  74. 74.

    Fabbian, F. et al. Chronotype, gender and general health. Chronobiol. Int. 33, 863–882 (2016).

  75. 75.

    Laugsand, L. E., Strand, L. B., Platou, C., Vatten, L. J. & Janszky, I. Insomnia and the risk of incident heart failure: a population study. Eur. Heart J. 35, 1382–1393 (2014).

  76. 76.

    Laugsand, L. E., Vatten, L. J., Platou, C. & Janszky, I. Insomnia and the risk of acute myocardial infarction: A population study. Circulation 124, 2073–2081 (2011).

  77. 77.

    Vyas, M. V. et al. Shift work and vascular events: systematic review and meta-analysis. BMJ 345, e4800 (2012).

  78. 78.

    Esquirol, Y. et al. Shift work and cardiovascular risk factors: new knowledge from the past decade. Arch. Cardiovasc. Dis. 104, 636–668 (2011).

  79. 79.

    Kawachi, I. et al. Prospective study of shift work and risk of coronary heart disease in women. Circulation 92, 3178–3182 (1995).

  80. 80.

    Tepas, D. I. Do eating and drinking habits interact with work schedule variables? Work Stress 4, 203–211 (1990).

  81. 81.

    Lo, S. H. et al. Working the night shift causes increased vascular stress and delayed recovery in young women. Chronobiol. Int. 27, 1454–1468 (2010).

  82. 82.

    Pan, A., Schernhammer, E. S., Sun, Q. & Hu, F. B. Rotating night shift work and risk of type 2 diabetes: two prospective cohort studies in women. PLOS Med. 8, e1001141 (2011).

  83. 83.

    St-Onge, M.-P. et al. Sleep duration and quality: impact on lifestyle behaviors and cardiometabolic health: a Scientific Statement from the American Heart Association. Circulation 134, e367–e386 (2016).

  84. 84.

    Knutsson, A., Jonsson, B. G., Akerstedt, T. & Orth-Gomer, K. Increased risk of ischaemic heart disease in shift workers. Lancet 328, 89–92 (1986).

  85. 85.

    Paul, T. & Lemmer, B. Disturbance of circadian rhythms in analgosedated intensive care unit patients with and without craniocerebral injury. Chronobiol. Int. 24, 45–61 (2007).

  86. 86.

    Dessap, A. M. et al. Delirium and circadian rhythm of melatonin during weaning from mechanical ventilation an ancillary study of a weaning trial. Chest 148, 1231–1241 (2015).

  87. 87.

    Buchman, T. G., Stein, P. K. & Goldstein, B. Heart rate variability in critical illness and critical care. Curr. Opin. Crit. Care 8, 311–315 (2002).

  88. 88.

    Cornélissen, G., Halberg, F., Otsuka, K., Singh, R. B. & Chen, C.-H. Chronobiology predicts actual and proxy outcomes when dipping fails. Hypertension 49, 237–239 (2007).

  89. 89.

    Muller, J. E. et al. Circadian variation in the frequency of sudden cardiac death. Circulation 75, 131–138 (1987).

  90. 90.

    Viskin, S. et al. Circadian variation of symptomatic paroxysmal atrial fibrillation: data from almost 10000 episodes. Eur. Heart J. 20, 1429–1434 (1999).

  91. 91.

    Matsuo, K. et al. The circadian pattern of the development of ventricular fibrillation in patients with Brugada syndrome. Eur. Heart J. 20, 465–470 (1999).

  92. 92.

    Manfredini, R. et al. Chronobiology of rupture and dissection of aortic aneurysms. J. Vasc. Surg. 40, 382–388 (2004).

  93. 93.

    Muller, J. E. et al. Circadian variation in the frequency of onset of acute myocardial infarction. N. Engl. J. Med. 313, 1315–1322 (1985).

  94. 94.

    Shen, M. J. & Zipes, D. P. Role of the autonomic nervous system in modulating cardiac arrhythmias. Circ. Res. 114, 1004–1021 (2014).

  95. 95.

    Manfredini, R., Gallerani, M., Portaluppi, F. & Fersini, C. Relationships of the circadian rhythms of thrombotic, ischemic, hemorrhagic, and arrhythmic events to blood pressure rhythms. Ann. NY Acad. Sci. 783, 141–158 (1996).

  96. 96.

    Shea, S. A., Hilton, M. F., Hu, K. & Scheer, F. A. J. L. Existence of an endogenous circadian blood pressure rhythm in humans that peaks in the evening. Circ. Res. 108, 980–984 (2011).

  97. 97.

    Dashti, H. S. et al. Clock genes explain a large proportion of phenotypic variance in systolic blood pressure and this control is not modified by environmental temperature. Am. J. Hypertens. 29, 132–140 (2016).

  98. 98.

    Scheer, F. A. J. L. & Shea, S. A. Human circadian system causes a morning peak in prothrombotic plasminogen activator inhibitor-1 (PAI-1) independent of the sleep/wake cycle. Blood 123, 590–593 (2014).

  99. 99.

    Eckle, T. et al. Adora2b-elicited Per2 stabilization promotes a HIF-dependent metabolic switch crucial for myocardial adaptation to ischemia. Nat. Med. 18, 774–782 (2012).

  100. 100.

    Reiter, R., Swingen, C., Moore, L., Henry, T. D. & Traverse, J. H. Circadian dependence of infarct size and left ventricular function after ST elevation myocardial infarction. Circ. Res. 110, 105–110 (2012).

  101. 101.

    Fournier, S. et al. Circadian variations of ischemic burden among patients with myocardial infarction undergoing primary percutaneous coronary intervention. Am. Heart J. 163, 208–213 (2012).

  102. 102.

    Ammirati, E., Maseri, A. & Cannistraci, C. V. Still need for compelling evidence to support the circadian dependence of infarct size after ST-elevation myocardial infarction. Circ. Res. 113, e43–e44 (2013).

  103. 103.

    Durgan, D. J. et al. Short communication: Ischemia/reperfusion tolerance is time-of-day-dependent: mediation by the cardiomyocyte circadian clock. Circ. Res. 106, 546–550 (2010).

  104. 104.

    Bennardo, M. et al. Day-night dependence of gene expression and inflammatory responses in the remodeling murine heart post-myocardial infarction. Am. J. Physiol. Regul. Integr. Comp. Physiol. 311, R1243–R1254 (2016).

  105. 105.

    Alibhai, F. J. et al. Short-term disruption of diurnal rhythms after murine myocardial infarction adversely affects long-term myocardial structure and function. Circ. Res. 114, 1713–1722 (2014).

  106. 106.

    Kung, T. A. et al. Rapid attenuation of circadian clock gene oscillations in the rat heart following ischemia-reperfusion. J. Mol. Cell. Cardiol. 43, 744–753 (2007).

  107. 107.

    Mohri, T. et al. Alterations of circadian expressions of clock genes in Dahl salt-sensitive rats fed a high-salt diet. Hypertension 42, 189–194 (2003).

  108. 108.

    Young, M. E., Razeghi, P. & Taegtmeyer, H. Clock genes in the heart: characterization and attenuation with hypertrophy. Circ. Res. 88, 1142–1150 (2001).

  109. 109.

    Maruo, T. et al. Circadian variation of endothelial function in idiopathic dilated cardiomyopathy. Am. J. Cardiol. 97, 699–702 (2006).

  110. 110.

    Dhaun, N. et al. Diurnal variation in blood pressure and arterial stiffness in chronic kidney disease: the role of endothelin-1. Hypertension 64, 296–304 (2014).

  111. 111.

    Floras, J. S. Sleep apnea and cardiovascular risk. J. Cardiol. 63, 3–8 (2014).

  112. 112.

    Kaneko, Y. et al. Cardiovascular effects of continuous positive airway pressure in patients with heart failure and obstructive sleep apnea. N. Engl. J. Med. 348, 1233–1241 (2003).

  113. 113.

    Vacas, S. et al. The feasibility and utility of continuous sleep monitoring in critically ill patients using a portable electroencephalography monitor. Anesth. Analg. 123, 206–212 (2016).

  114. 114.

    Tsimakouridze, E. V. et al. Chronomics of pressure overloadinduced cardiac hypertrophy in mice reveals altered day night gene expression and biomarkers of heart disease. Chronobiol. Int. 29, 810–821 (2012).

  115. 115.

    Tsimakouridze, E. V., Alibhai, F. J. & Martino, T. A. Therapeutic applications of circadian rhythms for the cardiovascular system. Front. Pharmacol. 6, 77 (2015).

  116. 116.

    Podobed, P. et al. The day/night proteome in the murine heart. Am. J. Physiol. Regul. Integr. Comp. Physiol. 307, R121–R137 (2014).

  117. 117.

    Dominguez-Rodriguez, A., Abreu-Gonzalez, P., Garcia-Gonzalez, M. & Reiter, R. J. Prognostic value of nocturnal melatonin levels as a novel marker in patients with ST-segment elevation myocardial infarction. Am. J. Cardiol. 97, 1162–1164 (2006).

  118. 118.

    Cornelissen, G. et al. Chronobiologically interpreted ambulatory blood pressure monitoring: past, present, and future. Biol. Rhythm Res. 50, 46–62 (2019).

  119. 119.

    Fournier, S. et al. Circadian rhythm of blood cardiac troponin T concentration. Clin. Res. Cardiol. 106, 1026–1032 (2017).

  120. 120.

    du Pre, B. C. et al. Analysis of 24-h rhythm in ventricular repolarization identifies QT diurnality as a novel clinical parameter associated with previous ventricular arrhythmias in heart failure patients. Front. Physiol. 8, 590 (2017).

  121. 121.

    Oldham, M. A., Lee, H. B. & Desan, P. H. Circadian rhythm disruption in the critically ill: an opportunity for improving outcomes. Crit. Care Med. 44, 207–217 (2016).

  122. 122.

    Van Rompaey, B. et al. Risk factors for delirium in intensive care patients: a prospective cohort study. Crit. Care 13, R77 (2009).

  123. 123.

    Perras, B., Meier, M. & Dodt, C. Light and darkness fail to regulate melatonin release in critically ill humans. Intensive Care Med. 33, 1954–1958 (2007).

  124. 124.

    Carden, S. M. Entrainment of free-running circadian rhythms by melatonin in blind people: melatonin, circadian rhythms and sleep (Editorial). Surv. Ophthalmol. 46, 299–300 (2001).

  125. 125.

    Al-Aama, T. et al. Melatonin decreases delirium in elderly patients: a randomized, placebo-controlled trial. Int. J. Geriatr. Psychiatry 26, 687–694 (2011).

  126. 126.

    de Jonghe, A. et al. Effect of melatonin on incidence of delirium among patients with hip fracture: a multicentre, double-blind randomized controlled trial. Can. Med. Assoc. J. 186, E547–E556 (2014).

  127. 127.

    Purnell, M. T., Feyer, A. M. & Herbison, G. P. The impact of a nap opportunity during the night shift on the performance and alertness of 12-h shift workers. J. Sleep Res. 11, 219–227 (2002).

  128. 128.

    Neil-Sztramko, S. E., Pahwa, M., Demers, P. A. & Gotay, C. C. Health-related interventions among night shift workers: a critical review of the literature. Scand. J. Work Environ. Health 40, 543–556 (2014).

  129. 129.

    Sarafidis, P. et al. Prevalence and control of hypertension by 48-h ambulatory blood pressure monitoring in haemodialysis patients: a study by the European Cardiovascular and Renal Medicine (EURECA-m) working group of the ERA-EDTA. Nephrol. Dial. Transplant. 33, 1872 (2018).

  130. 130.

    Culleton, B. et al. Effect of frequent nocturnal hemodialysis versus conventional hemodialysis. J. Am. Med. Assoc. 298, 1291–1299 (2007).

  131. 131.

    Boggia, J. et al. Prognostic accuracy of day versus night ambulatory blood pressure: a cohort study. Lancet 370, 1219–1229 (2007).

  132. 132.

    Svensson, P., de Faire, U., Sleight, P., Yusuf, S. & Ostergren, J. Comparative effects of ramipril on ambulatory and office blood pressures: a HOPE substudy. Hypertension 38, E28–E32 (2001).

  133. 133.

    Hermida, R. C. & Ayala, D. E. Chronotherapy with the angiotensin-converting enzyme inhibitor ramipril in essential hypertension: improved blood pressure control with bedtime dosing. Hypertension 54, 40–46 (2009).

  134. 134.

    Hermida, R. C., Ayala, D. E., Mojón, A. & Fernández, J. R. Decreasing sleep-time blood pressure determined by ambulatory monitoring reduces cardiovascular risk. J. Am. Coll. Cardiol. 58, 1165–1173 (2011).

  135. 135.

    De Giorgi, A., Mallozzi Menegatti, A., Fabbian, F., Portaluppi, F. & Manfredini, R. Circadian rhythms and medical diseases: does it matter when drugs are taken? Eur. J. Intern. Med. 24, 698–706 (2013).

  136. 136.

    Manfredini, R., Gallerani, M., Salmi, R. & Fersini, C. Circadian rhythms and the heart: Implications for chronotherapy of cardiovascular diseases. Clin. Pharmacol. Ther. 56, 244–247 (1994).

  137. 137.

    Zhao, P., Xu, P., Wan, C. & Wang, Z. Evening versus morning dosing regimen drug therapy for hypertension. Cochrane Database Syst. Rev. 10, CD004184 (2011).

  138. 138.

    Scheer, F. A. J. L. et al. The human endogenous circadian system causes greatest platelet activation during the biological morning independent of behaviors. PLOS ONE 6, e24549 (2011).

  139. 139.

    Bonten, T. N. et al. Time-dependent effects of aspirin on blood pressure and morning platelet reactivity: a randomized cross-over trial. Hypertension 65, 743–750 (2015).

  140. 140.

    Watanabe, Y., Halberg, F., Otsuka, K. & Cornelissen, G. Toward a personalized chronotherapy of high blood pressure and a circadian overswing. Clin. Exp. Hypertens. 35, 257–266 (2013).

  141. 141.

    Shinagawa, M. et al. Impact of circadian amplitude and chronotherapy: relevance to prevention and treatment of stroke. Biomed. Pharmacother. 55, 125s–132s (2001).

  142. 142.

    Montaigne, D. et al. Daytime variation of perioperative myocardial injury in cardiac surgery and its prevention by Rev-Erbα antagonism: a single-centre propensity-matched cohort study and a randomised study. Lancet 391, 59–69 (2017).

  143. 143.

    Madonna, R. et al. Position Paper of the European Society of Cardiology Working Group Cellular Biology of the Heart: cell-based therapies for myocardial repair and regeneration in ischemic heart disease and heart failure. Eur. Heart J. 37, 1789–1798 (2016).

  144. 144.

    Van Laake, L. W., Passier, R., Doevendans, P. A. & Mummery, C. L. Human embryonic stem cell-derived cardiomyocytes and cardiac repair in rodents. Circ. Res. 102, 1008–1010 (2008).

  145. 145.

    Woldt, E. et al. Rev-erb-α modulates skeletal muscle oxidative capacity by regulating mitochondrial biogenesis and autophagy. Nat. Med. 19, 1039–1046 (2013).

  146. 146.

    Chen, Z., Yoo, S. H. & Takahashi, J. S. Small molecule modifiers of circadian clocks. Cell. Mol. Life Sci. 70, 2985–2998 (2013).

  147. 147.

    Eastman, C. I., Suh, C., Tomaka, V. A. & Crowley, S. J. Circadian rhythm phase shifts and endogenous free-running circadian period differ between African-Americans and European-Americans. Sci. Rep. 5, 8381 (2015).

  148. 148.

    Chen, X. et al. Racial/ethnic differences in sleep disturbances: the Multi-Ethnic Study of Atherosclerosis (MESA). Sleep 38, 877–888 (2015).

  149. 149.

    Santhi, N. et al. Sex differences in the circadian regulation of sleep and waking cognition in humans. Proc. Natl Acad. Sci. USA 113, E2730–E2739 (2016).

  150. 150.

    Jarczok, M. N. et al. The heart’s rhythm ‘n’ blues: sex differences in circadian variation patterns of vagal activity vary by depressive symptoms in predominantly healthy employees. Chronobiol. Int. 35, 896–909 (2018).

  151. 151.

    Hood, S. & Amir, S. The aging clock: circadian rhythms and later life. J. Clin. Invest. 127, 437–446 (2017).

  152. 152.

    López, F. et al. Are there ethnic differences in the circadian variation in onset of acute myocardial infarction? A comparison of 3 ethnic groups in Birmingham, UK and Alicante. Spain. Int. J. Cardiol. 100, 151–154 (2005).

  153. 153.

    Donat, M. et al. Linking sleep duration and obesity among black and white US adults. Clin. Pract. (2013).

  154. 154.

    Yamasaki, F., Schwartz, J. E., Gerber, L. M., Warren, K. & Pickering, T. G. Impact of shift work and race/ethnicity on the diurnal rhythm of blood pressure and catecholamines. Hypertension 32, 417–423 (1998).

  155. 155.

    Manfredini, R. et al. Sex and circadian periodicity of cardiovascular diseases: are women sufficiently represented in chronobiological studies? Heart Fail. Clin. 13, 719–738 (2017).

  156. 156.

    Berry, J. D. et al. Lifetime risks of cardiovascular disease. N. Engl. J. Med. 366, 321–329 (2012).

  157. 157.

    Forman, D. E., Cittadini, A., Azhar, G., Douglas, P. S. & Wei, J. Y. Cardiac morphology and function in senescent rats: gender-related differences. J. Am. Coll. Cardiol. 30, 1872–1877 (1997).

  158. 158.

    Alibhai, F. J. et al. Female ClockΔ19/Δ19 mice are protected from the development of age-dependent cardiomyopathy. Cardiovasc. Res. 114, 259–271 (2018).

  159. 159.

    Halberg, F. et al. Diagnosing vascular variability anomalies, not only MESOR-hypertension. Am. J. Physiol. Heart Circ. Physiol. 305, H279–H294 (2013).

  160. 160.

    Smolensky, M. H., Hermida, R. C., Ayala, D. E., Tiseo, R. & Portaluppi, F. Administration-time-dependent effects of blood pressure-lowering medications: basis for the chronotherapy of hypertension. Blood Press. Monit. 15, 173–180 (2010).

  161. 161.

    Racca, C. et al. Aspirin intake in the morning is associated with suboptimal platelet inhibition, as measured by serum thromboxane B2, during infarct-prone early-morning hours. Platelets (2018).

  162. 162.

    Smolensky, M. H. et al. Diurnal and twenty-four hour patterning of human diseases: acute and chronic common and uncommon medical conditions. Sleep Med. Rev. 21, 12–22 (2015).

  163. 163.

    Bruguerolle, B. & Labrecque, G. Rhythmic pattern in pain and their chronotherapy. Adv. Drug Deliv. Rev. 59, 883–895 (2007).

  164. 164.

    Lévi, F., Altinok, A., Clairambault, J. & Goldbeter, A. Implications of circadian clocks for the rhythmic delivery of cancer therapeutics. Phil. Trans. R. Soc. A 366, 3575–3598 (2008).

  165. 165.

    de Mairan, J.-J. Observation botanique [French]. Hist. Acad. R. Sci. 1729, 35 (1729).

  166. 166.

    Konopka, R. J. & Benzer, S. Clock mutants of Drosophila melanogaster. Proc. Natl Acad. Sci. USA 68, 2112–2116 (1971).

  167. 167.

    Sehgal, A. et al. Rhythmic expression of timeless: a basis for promoting circadian cycles in period gene autoregulation. Science 270, 808–810 (1995).

  168. 168.

    Price, J. L. et al. double-time is a novel Drosophila clock gene that regulates PERIOD protein accumulation. Cell 94, 83–95 (1998).

  169. 169.

    Stujanna, E. N. et al. Rev-erb agonist improves adverse cardiac remodeling and survival in myocardial infarction through an anti-inflammatory mechanism. PLOS ONE 12, e0189330 (2017).

  170. 170.

    Van Beek, M. H. C. T. et al. The prognostic effect of physical health complaints with new cardiac events and mortality in patients with a myocardial infarction. Psychosomatics 58, 121–131 (2017).

  171. 171.

    Anea, C. B. et al. Vascular disease in mice with a dysfunctional circadian clock. Circulation 119, 1510–1517 (2009).

  172. 172.

    Wang, Q., Maillard, M., Schibler, U., Burnier, M. & Gachon, F. Cardiac hypertrophy, low blood pressure, and low aldosterone levels in mice devoid of the three circadian PAR bZip transcription factors DBP, HLF, and TEF. Am. J. Physiol. Regul. Integr. Comp. Physiol. 299, R1013–R1019 (2010).

  173. 173.

    Durgan, D. J. et al. Evidence suggesting that the cardiomyocyte circadian clock modulates responsiveness of the heart to hypertrophic stimuli in mice. Chronobiol. Int. 28, 187–203 (2011).

  174. 174.

    Schroder, E. A. et al. The cardiomyocyte molecular clock, regulation of Scn5a, and arrhythmia susceptibility. Am. J. Physiol. Cell Physiol. 304, C954–C965 (2013).

  175. 175.

    Xie, Z. et al. Smooth-muscle BMAL1 participates in blood pressure circadian rhythm regulation. J. Clin. Invest. 125, 324–336 (2015).

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The authors acknowledge support from Innovation and the Netherlands CardioVascular Research Initiative (CVON): the Dutch Heart Foundation, the Dutch Federation of University Medical Centers, the Netherlands Organization for Health Research and Development and the Royal Netherlands Academy of Science. S.C. receives support from the Jacob Jongbloed Talent Society Grant (Circulatory Health, University Medical Centre Utrecht). J.P.G.S. receives support from Horizon2020 ERC-2016-COG EVICARE (725229).

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Nature Reviews Cardiology thanks G. Cornelissen, R. Manfredini and K. Otsuka for their contribution to the peer review of this work.

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All the authors researched data for the article, discussed its content, wrote the manuscript and reviewed and/or edited the manuscript before submission.

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Correspondence to Linda W. Van Laake.

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Circadian rhythms

Endogenous biorhythms with a period of approximately 24 h; self-sustainable but can be entrained.


Duration of one circadian cycle.

Central or primary clock

Group of neurons in the suprachiasmatic nucleus (part of the hypothalamus) of the brain, which orchestrates rhythmicity within the body.

Peripheral clocks

Molecular mechanism within individual cells that regulates circadian rhythm.


External or environmental cue (such as light, food intake or exercise) that synchronizes or entrains circadian rhythms; also known as Zeitgeber (‘time giver’).

24-h rhythms

Patterns re-occurring every 24 h.


Scheduling of treatment in relation to 24-h rhythms to increase effectiveness of the therapy and/or reduce adverse effects.

Clock-controlled genes

Genes whose transcription is controlled by the molecular circadian clock.

Core clock genes

Genes that form a basis for generation and regulation of circadian rhythms by encoding BMAL1, CLOCK, CRY and PER proteins.


Difference between mesor and peak of the sinusoidal-shaped circadian rhythm.


Mean value of a (circadian) cycle or rhythm.

Serum shock

Acute exposure to a high concentration of serum (50% fetal bovine serum for 2 h) to align desynchronized circadian phases in a multicellular system.


Propensity to be active, inactive or asleep at a specific time during a 24-h cycle.


Time at which the peak of the rhythm occurs.

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Crnko, S., Du Pré, B.C., Sluijter, J.P.G. et al. Circadian rhythms and the molecular clock in cardiovascular biology and disease. Nat Rev Cardiol 16, 437–447 (2019).

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