Sleep and circadian rhythms in cardiovascular resilience: mechanisms, implications, and a Roadmap for research and interventions

Abstract

The interaction between sleep, circadian rhythms and cardiovascular resilience is a crucial yet underexplored research area with important public health implications. Disruptions in sleep and circadian rhythms exacerbate hypertension, diabetes mellitus and obesity, conditions that are increasingly prevalent globally and increase the risk of cardiovascular disease. A National Heart, Lung, and Blood Institute workshop examined these connections, as well as the emerging concept of cardiovascular resilience as a dynamic and multifaceted concept spanning molecular, cellular and systemic levels across an individual’s lifespan. The workshop emphasized the need to expand the focus from solely understanding whether and how sleep and circadian rhythm disturbances contribute to disease, to also exploring how healthy sleep and aligned circadian rhythms can increase cardiovascular resilience. To develop a Roadmap towards this goal, workshop participants identified key knowledge gaps and research opportunities, including the need to integrate biological, behavioural, environmental and societal factors in sleep and circadian health with cardiovascular research to identify therapeutic targets. Proposed interventions encompass behavioural therapies, chronotherapy, lifestyle changes, organizational policies and public health initiatives aimed at improving sleep and circadian health for better cardiovascular outcomes. Future cross-disciplinary research and translation of discoveries into public health strategies and clinical practices could improve cardiovascular resilience across the lifespan in all populations.

Introduction

Sleep and circadian rhythms are fundamental biological processes regulating human physiology, including metabolic pathways, inflammatory responses and neuroendocrine activities essential for cardiovascular health^1-5. Disruptions in these processes can increase the risk factors associated with cardiovascular diseases (CVDs), such as hypertension, diabetes mellitus and obesity^6-10. The strong link between sleep and circadian rhythm disruption and an increased risk of disease¹¹ is particularly concerning in modern society, in which many people do not get adequate sleep. In the USA, approximately one-third of adults do not obtain the recommended 7–9 h of sleep per night, and around 40% report poor sleep quality¹², with potentially worsening trends^13,14. Notably, minority populations are especially affected by poor sleep health¹⁵. Given the global rise in CVDs¹⁶, reducing sleep and circadian rhythm disturbances is vital to improving cardiovascular and overall health.

Research so far has primarily focused on how inadequate sleep might independently increase the risk of disease¹⁷. The emerging concept of resilience, particularly cardiovascular resilience, in the context of sleep and circadian rhythms presents new research opportunities. Resilience generally refers to the capacity to resist, adapt to, recover or grow in response to challenges^18,19. When applied to cardiovascular health, cardiovascular resilience could encompass various responses, from molecular and cellular processes that control inflammation and promote tissue regeneration, to systemic adaptations that maintain stable blood pressure and heart rate²⁰. The interaction between sleep, circadian rhythms and the promotion of cardiovascular resilience represents a promising area of research²¹ with substantial public health implications. To study this intersection, it is important to recognize the multifaceted nature of sleep and circadian health, as well as the challenge of quantifying metrics associated with biological resilience. A deeper understanding of the capacity of the cardiovascular system for resilience at all these levels in response to sleep and circadian disturbances is necessary to develop evidence-based public health interventions and clinical strategies. Such knowledge could lead to more effective approaches for preventing and managing CVDs and thereby reduce overall morbidity and mortality on a global scale.

This Roadmap offers a comprehensive overview of current research and identifies gaps in our understanding of the relationship between sleep, circadian rhythms and cardiovascular resilience. Disruptions in circadian rhythms and sleep disorders such as insomnia and obstructive sleep apnoea (OSA) are well documented to affect cardiovascular health²², but the protective mechanisms of healthy sleep and robust circadian rhythms are largely unexplored. Addressing these knowledge gaps through future research could reveal new strategies for improving cardiovascular health.

This Roadmap highlights potential therapeutic targets and intervention strategies aimed at optimizing sleep and circadian rhythms to improve cardiovascular function and prevent disease. The article underscores the importance of developing sleep and circadian rhythm interventions, such as behavioural therapies, pharmacological treatments, organizational policies and practices, and nutritional and lifestyle modifications that could improve cardiovascular resilience. Finally, the Roadmap outlines future research directions and opportunities, emphasizing the need for multidisciplinary collaboration among experts in sleep and circadian science, cardiovascular medicine, occupational health, nutrition and public health. Such collaborations are essential to advance our understanding of how sleep, circadian function and cardiovascular resilience are interconnected, which could lead to more effective strategies to promote cardiovascular health across populations.

NHLBI workshop

The Division of Cardiovascular Sciences and the National Center on Sleep Disorders Research of the National Heart, Lung, and Blood Institute (NHLBI), US National Institutes of Health (NIH), convened a 2-day virtual workshop entitled ‘Sleep and circadian rhythms in cardiovascular resilience: mechanisms, implications, and applications’ on 24 and 26 April 2024. Experts from multidisciplinary fields, including vascular biology, cardiology, sleep and circadian biology research, and allied health-care professions, convened via webinar to share insights and expertise on the relationship between sleep, circadian rhythms and cardiovascular health. Approximately 300 participants discussed methods to optimize sleep health, including quality, timing and duration of sleep, and circadian health, as well as strategies to bolster cardiovascular health and resilience through targeted sleep and circadian interventions. A culminating roundtable discussion provided an opportunity for speakers and attendees to identify key research gaps and opportunities for future collaborations. The objectives of the workshop are listed in Box 1. The executive summary of the workshop was published on the NHLBI website²³.

Box 1 ∣. Objectives of the NHLBI workshop.

• To delineate the contribution of sleep and circadian rhythms to cardiovascular resilience (briefly described as the ability of the cardiovascular system to maintain or return to homeostasis after a perturbation).

• To identify the potential mechanisms underlying these relationships.

• To explore strategies for improving cardiovascular resilience by optimizing sleep and circadian rhythms in general and at crucial points throughout the lifespan when the risk of cardiovascular disease might be particularly increased.

• To identify research gaps and opportunities, stimulate interdisciplinary research, and promote the development of novel interventions and technologies, as well as the potential for personalized medicine and precision health approaches.

NHLBI, National Heart, Lung, and Blood Institute.

Conceptualizing cardiovascular resilience

Broadly, resilience refers to the ability of living systems to maintain or return to homeostasis, or to grow, in response to stressors or challenges^20,24,25. Some models divide resilience into three subcomponents: resistance, recovery and adaptation²¹ (Fig. 1). Resistance describes the capacity of a system to maintain function under stress (bend but not break). Recovery is the speed and effectiveness of returning to baseline function after damage. Adaptation is the capacity of a system to bolster against future stressors on the basis of past experiences. Each component is crucial in maintaining cardiovascular health over time.

Fig. 1 ∣. Conceptual model for defining resilience.

The graphs depict a model of resilience divided into three components: resistance (panel a), recovery (panel b) and adaptation (panel c) to stressors or challenges. The model can be applied to disturbances in aspects of circadian rhythm, such as misalignment of physiological timing with respect to clock time, amplitude of rhythms (such as temporary blunting of peak cortisol concentrations) and dysregulated internal synchrony of clocks (such as misalignment between peripheral and central clocks).

One of the challenges in cardiovascular resilience research is integrating outcomes across various biological levels and from different scales, ranging from molecular and cellular to organ and systemic responses. Cardiovascular resilience is characterized by the ability of the cardiovascular system to withstand physiological stressors, adapt to challenges, recuperate, or even grow, from injuries or disturbances. This resilience manifests across a spectrum of bodily responses, ranging from cellular activities such as inflammation moderation, tissue regeneration and response to hypoxia²⁶, to systemic adjustments that ensure the maintenance of normal blood flow, blood pressure, heart pumping and overall cardiovascular function. Historically measured through risk assessments, cardiovascular resilience is evident in individuals who maintain cardiovascular health despite high-risk genetic and/or environmental factors. Therefore, cardiovascular resilience is demonstrated not only by the capacity to recover and sustain homeostasis after adverse cardiovascular events, but also by the capacity to adapt and potentially thrive in the face of these challenges.

In cardiovascular epidemiology, resilience is often explored retrospectively by identifying individuals who maintain cardiovascular health despite having multiple adverse risk factors or a single severely adverse factor. These individuals are considered to be resilient because they do not develop CVD despite having risk factors. However, defining cardiovascular resilience prospectively is challenging owing to the complexity of stress responses. In 2010, the American Heart Association introduced the concept of ‘cardiovascular health’ as a construct intended to assess health status, rather than risk, in a measurable, monitorable and modifiable fashion at both individual and population levels²⁷. Originally termed Life’s Simple 7, this scoring system assessed diet, physical activity, smoking status, body mass index, blood cholesterol levels, blood glucose levels and blood pressure. In 2022, the cardiovascular health scoring system evolved into Life’s Essential 8 by adding sleep duration as a metric, acknowledging its importance for cardiovascular health²⁸. Research shows that a high or improved score of cardiovascular health as measured by the Life’s Essential 8 at any life stage correlates with greater longevity, reduced morbidity, lower health-care costs and improved quality of life compared with a low cardiovascular health score^29-31, making this cardiovascular health score a robust and temporally precise indicator of cardiovascular resilience as well as of general health resilience.

Endothelial cells, which line the blood vessels, have a crucial role in cardiovascular resilience at the tissue level³². Endothelial cells regulate blood flow, modulate blood–tissue exchanges, manage inflammation and respond to injury. Endothelial resilience (the capacity of endothelial cells to survive, regenerate, preserve their functions and recover after a stressor or challenge³³) is central to overall cardiovascular resilience and might be linked to cell-intrinsic ‘set points’ in blood-flow-mediated responses³⁴ and circadian regulation of vascular function and endothelial cell cycle³⁵. Healthy endothelial function is associated with better outcomes in patients with CVD, whereas endothelial dysfunction is often a precursor to atherosclerosis and other cardiovascular-related conditions, such as stroke³⁶.

Taken together, cardiovascular resilience can be considered a proactive, adaptive, dynamic and lifelong process, in which the cardiovascular system not only reacts to stressors but also anticipates and appropriately adjusts to them. Cardiovascular resilience results from the intricate interaction between cellular processes, lifestyle choices, social determinants and environmental influences. Cardiovascular resilience is unique to each individual, requiring tailored strategies for optimization.

Sleep and circadian rhythms in cardiovascular resilience

Characterization of sleep and circadian rhythms

Adequate and restorative sleep can be characterized by subjective satisfaction, appropriate timing, sufficient duration, high efficiency and sustained alertness during waking hours³⁷. However, the optimal sleep parameters for different physiological end points can vary.

Circadian rhythms are a multiscale biological timekeeping mechanism that synchronizes cellular physiology and behaviours with the environment. In mammals, the circadian timekeeper operates hierarchically. The suprachiasmatic nucleus of the hypothalamus functions as a central pacemaker consisting of both molecular and neural oscillators³⁸. Through both humoral and neural connections, the suprachiasmatic nucleus synchronizes body clocks, including those regulating temperature oscillations, feeding, thirst, aggression and sleep–wake cycles³⁹. The suprachiasmatic nucleus entrains to the environment cycle by integrating light input from the retina⁴⁰. Virtually every cell harbours a circadian timekeeping mechanism comprising the transcription factors basic helix–loop–helix ARNT-like protein 1 (BMAL1) and circadian locomotor output cycles kaput (CLOCK), which regulate the rhythmic expression of thousands of transcripts, including their own inhibitors, the Period genes (PER1–PER3) and Cryptochrome genes (CRY1 and CRY2)^41,42. This mechanistic clock architecture, known as a transcription–translation feedback loop, is conserved across species⁴³. Importantly, the rhythmic output of the transcription–translation feedback loop is tissue specific in both the genes affected and the rhythm phases of transcription–translation⁴⁴. In addition, circadian rhythms are also observed at the level of protein synthesis, phosphorylation and signalling dynamics, albeit with lower amplitude⁴⁵. These near-24-h molecular rhythms organize multiscale rhythmic processes that include metabolism, redox state and the timing of the sleep–wake cycle⁴⁶. These cellular circadian clocks, including those in the heart and the vasculature, are entrained by nutrients, redox state and neural inputs⁴⁷. Proper alignment of these internal circadian timekeepers, both within an organism and between an organism and its environment, probably extends lifespan and improves healthspan^48-50. Conversely, misalignment of these clocks is associated with increased inflammation, impaired proteostasis and redox dysfunction⁵¹.

A process is considered to be circadian if it is under the control of the molecular clock mechanism. By contrast, sleep loss refers to a diminution of a particular series of physiological states. Given that sleep is one of the primary behavioural and physiological outputs of the circadian clock, circadian disruption is often tightly intertwined with sleep loss. Distinguishing between processes that are purely ‘circadian’ versus those that are affected directly by the loss of sleep or specific sleep states is a major goal of future research. Sleep and circadian rhythms are linked to cardiovascular resilience through a variety of potential mechanisms, including those implicated in the physiological, molecular, behavioural and psychological aspects of cardiovascular function^52-54.

Sleep and cardiovascular function

Sleep influences cardiovascular function through systemic modulation of blood pressure, autonomic tone, inflammatory signalling and hormone release^55,56. Like circadian clocks⁵⁷, sleep can also directly influence local molecular physiology in cardiovascular tissues⁵⁸, including endothelial function⁵⁹. Nocturnal dipping, a natural reduction in blood pressure during sleep, is essential for cardiovascular health⁶⁰. Restricted sleep can lead to elevated daytime blood pressure⁶¹ and an increased risk of CVD⁶². Disrupted sleep architecture, such as in OSA or insomnia, can contribute to nocturnal non-dipping blood pressure⁶³ and reduced heart rate variability^64,65, which serves as an indicator of an increased risk of CVD⁶⁶. Higher heart rate variability indicates higher parasympathetic tone and is associated with greater cardiovascular resilience⁶⁷. Disrupted sleep patterns can reduce heart rate variability and potentially increase the risk of cardiovascular complications⁶⁸. Improving sleep quality by treating OSA at night can reduce nighttime and daytime resting heart rate and decrease sympathetic tone²². Healthy sleep supports endothelial function by regulating vessel tone, promoting vessel repair, reducing inflammation and mitigating oxidative stress, thereby reducing the risk of atherosclerosis⁶⁹ and other CVDs⁷⁰.

Circadian rhythms and cardiovascular function

Circadian rhythms influence the sympathetic nervous system to modulate cardiovascular responses to daily stressors. Disturbances in this rhythmic control can lead to elevated morning blood pressure and heart rate, possibly increasing the risk of cardiovascular events⁷¹. Circadian rhythms also influence metabolic processes and nutritional timing, such as glucose and lipid metabolism⁷², which are essential for cardiovascular health. In the heart and vasculature, the molecular clock regulates the expression patterns of genes related to blood pressure, heart rate and vascular tone, aligning these cardiovascular functions with light–dark cycles⁷³.

The interaction between the central and peripheral clocks, influenced by external signals, regulates various bodily processes, including muscle function⁷⁴ and metabolism^75,76. For example, skin homeostasis relies on the epidermal clock, which receives signals from the central clock in the brain⁷⁷. The timing of food intake also seems to have an important role in the synchronization of the skin clock and other peripheral tissue clocks^78,79. Changes in sleep patterns can similarly alter the rhythmicity in the expression of genes encoding core clock proteins or clock output proteins in peripheral tissues⁸⁰. Temperature is a potent cue for many peripheral osccilators⁸¹, and sleep-induced changes in body temperature are hypothesized to further desynchronize or shift body clocks^58,82,83.

Sleep and circadian disruptions increase CVD risk

Circadian rhythm disruptions, irregular sleep patterns, altered sleep quality, variability in chronotype (a person’s propensity for when they sleep) or sleep disorders all have crucial roles in modulating the risk of CVD^7,8,10,84-88. Numerous studies have shown that individuals with disrupted circadian rhythms, such as shift workers, have higher rates of CVD than those with regular sleep patterns⁸⁹. Disruptions such as shift work and jetlag are also linked to the development of metabolic syndrome⁹⁰. Poor sleep and circadian misalignment contribute to various CVD risk factors, including oxidative stress and inflammation^70,84,91, metabolic disturbances^92-94, obesity and diabetes^95-97, depression, stress and anxiety⁹⁸, and accelerated ageing^99-102.

Oxidative stress and systemic inflammation

Similar to other cardiovascular risk factors such as cigarette smoking and hypertension, insufficient sleep triggers oxidative stress¹⁰³. In animal models, sleep restriction amplifies oxidative stress and activates the antioxidant response via the nuclear factor erythroid 2-related factor 2 (NRF2), which stimulates the expression of genes that contain the antioxidant response element^104,105. Overexpression of genes encoding antioxidant enzymes promoted survival in severely sleep-deprived Drosophila melanogaster, highlighting the protective role of the NRF2–antioxidant response element pathway against the development of CVD^103,106. In a rigorous, randomized crossover study in healthy female individuals, mild, prolonged (6 weeks) sleep restriction mimicking real-life short sleep duration patterns increased endothelial oxidative stress, inflammation and dysfunction^59,70.

Elevated plasma levels of inflammatory markers, such as C-reactive protein and IL-6, are common in individuals with inadequate sleep and high stress^107,108, and are indicators of an increased risk of atherosclerosis and other CVDs¹⁰⁹. Inflammation can result from altered leukocyte dynamics related to poor sleep¹¹⁰. Sleep fragmentation alters leukocyte production in the bone marrow, escalating systemic inflammation and accelerating atherosclerosis^111,112. This heightened leukocyte activity can contribute to the development and progression of CVD¹¹³.

Circadian clock proteins that directly regulate molecular effectors of inflammation-related pathways, such as Period circadian protein homologue 1 in natural killer cells and REV-ERB nuclear receptors in macrophages, mediate many of the effects of sleep disruption on inflammatory pathways¹¹⁴. These pathways exhibit normal diurnal variation in circulation and activation of immune cells. Immune cell activity is regulated by the circadian-controlled expression of genes, and this activity is entrained systemically via the light-sensitive and food-sensitive suprachiasmatic nucleus in the brain^115,116. Genetic loss of circadian genes, such as Bmal1, in different immune cell types alters inflammatory responses independently of sleep disturbance^117,118. Therefore, alterations in the circadian rhythmicity of the innate and adaptive immune systems contribute to increased cardiovascular risk over time.

Psychological factors

Disrupted sleep patterns often lead to increased psychological stress^119,120 and elevated levels of stress hormones (such as adrenocorticotropic hormone and cortisol)^121,122, exacerbating the risk of CVD through heightened sympathetic activity and inflammation^123,124. These effects also translate to sleep disorders, such as chronic insomnia, one of the most prevalent sleep disorders in the general population¹²⁵. Over time, as insomnia transitions from acute to chronic, the insomnia itself can become a chronic stressor. This ongoing stress can lead to chronic activation of physiological stress responses, resulting in a state of hyperarousal^126,127. The hypothalamic–pituitary–adrenal axis, the primary neuroendocrine system regulating hormonal responses to stress, might be a crucial link between insomnia and poor cardiovascular health^128,129. Poor sleep quality and insufficient sleep are also strongly associated with depression and anxiety¹³⁰, which can exacerbate cardiovascular risk via increased inflammation (as indicated by plasma C-reactive protein and IL-6 levels), altered heart rate variability and higher levels of cortisol^131-133.

Obesity, diabetes and dyslipidaemia

Disruptions in sleep and circadian rhythms substantially affect metabolic health, increasing the risk of obesity, diabetes and dyslipidaemia, all of which contribute to CVD^10,134. Short sleep duration and circadian misalignment are linked to obesity through hormonal imbalances affecting hunger and satiety^135,136. Circadian misalignment disrupts metabolic processes, leading to inefficient energy use and increased fat storage¹³⁷. Sleep disturbances also impair glucose metabolism¹³⁸, increasing the risk of type 2 diabetes. Sleep loss also elevates the plasma levels of inflammatory cytokines^139,140. Sleep disruptions induce dyslipidaemia by promoting changes in lipid metabolism that lead to elevated triglyceride and low HDL-cholesterol levels in plasma¹⁴¹, which in turn can promote the development of atherosclerosis. Addressing sleep and circadian health is crucial for preventing and managing these metabolic disorders and their cardiovascular complications¹⁴².

Accelerated ageing

Sleep disturbances can accelerate biological ageing processes, such as telomere shortening¹⁴³, epigenetic remodelling^144,145 and immune system activation^146,147, which in turn affect cardiovascular health¹⁴⁸. The risk of CVD increases with age¹⁴⁹. Similarly, sleep architecture and the prevalence of sleep disorders also change with age^150-153. Biological ageing relates to the cellular and molecular processes underlying age-related physiological changes, and these processes are starting to be identified. Sleep might directly affect biological ageing through numerous pathways¹⁴⁸. Cross-sectional data from observational studies indicate that participants with OSA are more likely to show signs of accelerated biological ageing, as evidenced by shorter leukocyte telomere length and greater epigenetic age (a measure of ageing that is based on DNA changes in cells and tissues rather than on chronological age)^101,144,154. Moreover, a higher number of insomnia symptoms has been associated with accelerated epigenetic ageing and an increase in late differentiated T cells, which are immune cells that have aged and might have lost some of their ability to fight off infections^155,156. Circadian rhythms also undergo age-related changes, which might have implications for cardiovascular resilience and risk^157,158. Taken together, ageing-related changes in sleep quality, quantity and timing might directly influence cardiovascular resilience and CVD risk.

Multiphenotype and multiomics studies in animal models have demonstrated that senolytic treatments (which selectively induce the death of senescent cells) can mitigate the cellular, molecular and physiological effects of intermittent exposure to hypoxia (which mimics OSA) across cardiovascular, metabolic and cognitive domains¹⁵⁹. These findings support the notion that sleep disorders promote systemic senescence, a condition that is reversible with treatment, and highlight the potential for personalized therapeutic interventions that are based on understanding the underlying cellular and molecular mechanisms.

Social determinants of sleep health and cardiovascular resilience

There are pervasive disparities in sleep health based on race and ethnicity that substantially affect the risk of CVD and the capacity for cardiovascular resilience¹⁶⁰. Chronic inflammation induced by poor sleep and chronic stress^4,161 undermines the body’s ability to repair and maintain cardiovascular health, reducing overall resilience. Race and ethnicity are social determinants (that is, how and where people are born, live, learn, work, play and worship influence health and health risk behaviours) of sleep health, and are social categories that are often used as a proxy for racism¹⁶². Racism continues to be an acute and prolonged stressor that is related to poor health in minority communities¹⁶³. Asian, Black and Hispanic or Latino individuals often experience poorer sleep quality, shorter sleep durations, irregular sleep patterns and more severe sleep disorders than their non-Hispanic white counterparts^164-168. This inadequate sleep contributes to higher risks of hypertension, obesity, diabetes and psychological stress^169,170, all of which undermine cardiovascular resilience¹⁷¹.

However, examining race as a social determinant of health in isolation could be misleading. Emerging research has demonstrated that substantial differences in sleep health persist for individuals at the intersection of multiple identities^172,173. Empirical evidence has also shown that discrimination, socioeconomic status and neighbourhood environment partially explain racial differences in sleep disorders (such as insomnia) and sleep health^174,175. Furthermore, neighbourhoods with high rates of crime, violence, disadvantage, pollution, inopportune light exposure and noise, where individuals from minority backgrounds are more likely to reside, are associated with adverse sleep health¹⁷⁶. Therefore, research suggests that intervening on the neighbourhood environment can improve sleep among minoritized populations. For example, adults living in neighbourhoods with higher neighbourhood social cohesion and safety have longer sleep duration than adults living in neighbourhoods with lower social cohesion and safety, and these associations are stronger in Black individuals¹⁷⁷.

Researchers need to take into account the social determinants of health and use an intersectional process approach that includes individuals with intersectional identities and social statuses, to identify what would otherwise be ‘invisible’ processes¹⁷⁸ and elucidate and understand differences in sleep health and how they might influence cardiovascular resilience and/or cardiovascular morbidity or mortality (Fig. 2).

Fig. 2 ∣. Influence of social determinants on sleep, circadian rhythms and cardiovascular resilience.

A conceptual model showing the pathways through which life stressors and psychosocial factors might influence an individual’s resilience, sleep and cardiovascular morbidity and mortality. The model is based on information from ref. 282.

Sleep and circadian health interventions to optimize cardiovascular resilience

Integrated strategies that target biological, social and behavioural aspects of sleep and circadian rhythm health are necessary to improve cardiovascular resilience outcomes. These interventions include the use of light, melatonin or other zeitgebers (environmental or external cues that can synchronize an organism’s biological rhythms) to improve sleep and modify, consolidate or strengthen circadian rhythms¹⁷⁹. Alternatively, pharmacological and behavioural approaches could aim to alleviate symptoms of poor sleep, improve sleep quality and daytime functioning related to sleep health, or address sleep disorders. These sleep-related interventions have the potential to improve cardiovascular resilience^180,181 by addressing social, behavioural, environmental, and biological determinants of sleep and circadian health. These interventions could potentially focus on attitudes, health status and mental health; on community-level factors, such as workplace dynamics, family interactions and neighbourhood conditions; or on society-level influences, including health disparities, public policies and economic conditions⁵. Additionally, technology could have a crucial role in the development of intervention components (such as artificial intelligence)¹⁸², assessment tools (for example, sensors and behavioural inputs)¹⁸³ and the delivery of interventions (such as increasing interactivity or user engagement through real-time feedback and personalized recommendations, broadening dissemination of the interventions and reducing accessibility barriers)¹⁸⁴. Interventions can be targeted at various points along the causal chain by which sleep and circadian rhythms affect cardiovascular resilience (Fig. 3).

Fig. 3 ∣. Sleep and circadian rhythm targets to optimize cardiovascular resilience.

Interventions can target sleep and circadian rhythm factors at various points along the causal chain to optimize cardiovascular resilience.

Behavioural and psychosocial interventions

Chronotherapy and chrononutrition.

Chronotherapy involves adjusting the timing of interventions, such as medication, sleep, physical activity and dietary intake, to align with intrinsic circadian rhythms, thereby optimizing the effectiveness of treatments in the management of various health conditions¹⁸⁵. Chrononutrition focuses on meal timing in relation to circadian rhythms, with the hypothesis that metabolic health could be optimized by aligning food intake with metabolic processes, including glucose and lipid metabolism and insulin sensitivity¹⁸⁶. Eating earlier in the day, when metabolic efficiency is highest, might improve glycaemic control and lipid profiles, and meal composition could be tailored to the time of day to leverage insulin sensitivity and support satiety¹⁸⁷. Aligning meal times with circadian rhythms might also affect hormones such as insulin, ghrelin and leptin, thereby aiding in weight management and reducing the risk of CVD¹⁸⁸. Chrononutrition also emphasizes personalization, tailoring dietary interventions to individual genetic and metabolic profiles to increase effectiveness and optimize metabolic health.

Chrononutrition is an emerging field in clinical research, and strategies such as time-restricted eating (TRE) have yielded inconsistent findings in human studies. TRE has demonstrated substantial metabolic benefits in animal models¹⁸⁹. However, findings from studies in humans are more variable, with some studies reporting improvements in metabolic syndrome, obesity and cardiometabolic health with TRE compared with no TRE^190,191, whereas others did not find any effects¹⁹² or even adverse outcomes^193,194. The variability in outcomes might be attributable to several factors, including differences in the duration and timing of the eating window (such as early TRE versus late TRE), participant characteristics (for example, healthy individuals versus those with metabolic dysfunction) and the extent of caloric restriction achieved during the intervention^195,196.

Although sleep and circadian interventions can influence cardiometabolic health and resilience by aligning behaviours, such as sleep, dietary intake and physical activity, with relevant physiological processes^195,197, the field is in its infancy and research in this area represents the forefront of sleep and circadian science. Consequently, rigorously designed, controlled studies are urgently needed to elucidate the effects of behavioural timing and chronotherapeutic strategies on cardiometabolic health and resilience.

CBT-I.

Cognitive behavioural therapy for insomnia (CBT-I) focuses on improving sleep continuity (by targeting sleep continuity disturbances such as difficulty in initiating and maintaining sleep) with behavioural interventions, and is the first-line treatment for insomnia^198-200. Studies have demonstrated its effectiveness in reducing time awake at night and improving overall sleep efficiency^201,202. More recent adaptations of CBT-I have also included stress-reduction interventions that teach techniques such as mindfulness, meditation and cognitive behavioural stress reduction to manage elevated stress levels, which are common causes of sleep disturbances^203,204. Moreover, CBT-I and related therapies can be especially effective when culturally tailored to address specific stressors that are prevalent in underserved communities²⁰⁵. Future efforts should also focus on whether community engagement initiatives, which involve engaging communities through health education workshops that focus on the importance of sleep and its connection to heart health, can empower individuals to make informed health choices. Community support groups can provide a platform for sharing experiences and strategies for overcoming sleep-related challenges, thereby improving social support networks, which are crucial for mental and emotional wellbeing²⁰⁶. Interventions designed to increase social support and solidify social networks might be particularly beneficial for older populations, minority populations and those with high cardiovascular risk²⁰⁷. These support systems can improve coping mechanisms and encourage adherence to health-promoting behaviours, including consistent sleep schedules²⁰⁸.

Workplace interventions.

Workplace characteristics such as long working hours, commute time, job strain, shift work and noise levels have been associated with insomnia and CVD^209-212. However, the workplace can also offer benefits that increase quality of life, including social support, a sense of purpose, opportunities for development of skills and knowledge, and health insurance, all attributes that can improve cardiovascular resilience²¹³. Considering that a substantial portion of adults are employed and spend considerable time at work, leveraging and expanding these benefits through health promotion initiatives can help to mitigate poor health behaviours, improve safety and employees’ wellbeing, and consequently benefit the employer’s financial standing²¹⁴. To that end, organizational policies that cap the number of consecutive hours of a work shift, provide flexible working hours and implement fatigue-management approaches, as well as organizational policies and practices that promote mental health, can improve sleep, increase resilience and reduce cardiovascular risk^215-217. Initiatives that engage all stakeholders from the outset of programme development are more likely to be adopted and sustained. Additionally, programmes that adopt the hierarchy of controls and aim for strategies that eliminate occupational hazards or reorganize work through engineering or administrative controls tend to be most effective²¹⁸.

Potential barriers to implementation.

Several important barriers need to be considered when implementing the proposed interventions in clinical practice and other health settings. Behavioural sleep interventions (such as CBT-I) are often time intensive and resource intensive for both the patient and the provider. Therefore, continued efforts to rescale these interventions to be compatible with different settings and patient populations are an important implementation consideration²¹⁹. Similarly, efforts to more broadly educate health-care providers on how to administer (or appropriately refer for) behavioural sleep interventions are still needed and should be the focus of future public health initiatives.

Physical and pharmacological interventions

Chronopharmacology.

Chronopharmacology is the investigation of how the effects of medications might vary based on the body’s biological rhythms. In the case of cardiovascular health, chronotherapeutic techniques can involve taking antihypertensive drugs at night^220,221 or using a controlled-release dosage that optimizes drug availability precisely in line with the natural circadian variation of blood pressure and heart rate²²². Several studies have assessed the differential effects of taking standard antihypertensive medications at bedtime versus exclusively in the morning on ambulatory blood pressure and/or prospective cardiovascular events (including non-fatal myocardial infarction, stroke and all-cause mortality), but the results have been mixed owing to several methodological differences and interpretative constraints. Positive results suggesting the superiority of bedtime dosing versus morning dosing were observed by the same Spanish research group in the MAPEC²²³ and Hygia²²⁴ trials. However, critics have raised questions about the external validity and generalizability of these findings, arguing that the recruitment processes, patient selection criteria and randomization procedures were not adequately transparent and were potentially biased^225-227.

Negative results suggesting no notable difference between evening and morning administration of antihypertensive medications on prospective cardiovascular end points could also be due to potentially flawed study designs (such as in the BedMed-Frail²²⁸ and TIME²²⁹ trials). In particular, the investigators in these pragmatic clinical trials did not incorporate ambulatory blood pressure monitoring to assess diurnal blood pressure variation (which prevented the inference of clear mechanistic insights linking dosing time to potential cardiovascular outcomes)²²⁹. In addition, many trial participants were individuals with well-controlled hypertension receiving stable therapy for hypertension, which constitutes a ‘low event rate’ population that might have reduced the statistical power to detect meaningful differences in cardiovascular outcomes on the basis of dosing time²²⁹. Finally, participant adherence to their assigned dosing schedule was not objectively verified and, when collected through subjective reporting, indicated large statistical differences in adherence (approximately 40% of the evening group in the TIME study reported non-adherence to the allocated dose timing and yet were included in primary analyses)²²⁹.

The limitations of the aforementioned investigations preclude making any definitive guidelines for when patients should take standard antihypertensive medication. By contrast, data regarding specialized antihypertensive formulations are clearer. By focusing on chemical and compounding strategies that tailor drug availability to coincide with early morning surges in heart rate and blood pressure, which are times of increased risk of stroke and myocardial infarction^230-232, researchers from two major pharmaceutical companies have developed proprietary ‘bedtime’ antihypertensive medications that control blood pressure across populations who are vulnerable to hypertension^233-235. These formulations, which were approved by the FDA and started to have widespread use in the mid-2000s in the USA and, subsequently, globally, exemplify practical and effective applications of circadian medicine. These advances provide valuable insights into improving cardiovascular resilience through the synchronized use of environmental interventions and CVD medications, and offer guidance on how to target other processes involved in CVD (such as cholesterol biosynthesis²³⁶) that might benefit from aligning treatment with the 24-h biological clock.

Molecular targets.

Targeting molecules involved in circadian function might improve cardiovascular resilience. Various toxic stressors can increase oxidative stress in endothelial cells and disrupt cellular homeostasis²³⁷ (Fig. 4). NRF2 is a transcription factor that responds to stress^237,238, and the capacity of NRF2-meditated detoxification and antioxidant defence is crucial for maintaining cellular homeostasis^239,240. The Nogo-B receptor (NgBR, also known as NUS1) is important for activating the survival pathway, a network of cellular mechanisms that protect endothelial cells against stress and promote continued function, and maintaining endothelial junctions through histone acetylation^241,242. Reduced expression of NRF2 and NgBR in endothelial cells is associated with increased oxidative stress and severe endothelial injury^239-242. Activators of NRF2, such as itaconate and fumarate, can protect against atherosclerosis development and endothelial injury by reducing inflammation and lipid peroxidation^243-245. In addition to NRF2, many other regulators, such as Krüppel-like factor 2 (KLF2) and BMAL1, also have important roles in cardiovascular resilience. KLF2 is a mechanosensitive transcription factor that helps to maintain resistance to shear stress in endothelial cells by activating endothelial nitric oxide synthase^246,247. Additionally, BMAL1 is crucial for resilience against oxidative stress caused by sleep deprivation, given that downregulation of BAML1 with ageing leads to the dysregulation of the expression of genes related to metabolism and antioxidant responses^248,249.

Fig. 4 ∣. Cellular pathways of cardiovascular resilience.

Signalling mediated by nuclear factor erythroid 2-related factor 2 (NRF2) is crucial for cellular resilience, that is, the capacity to maintain or return to cellular homeostasis. Disruptions in cellular homeostasis caused by sleep or metabolic disorders, toxic stress, ageing or diseases such as diabetes mellitus increase redox stress. As a stress-response factor, the functions of NRF2 in detoxification and antioxidant defence contribute to cellular resilience, together with other contributors such as Krüppel-like factor 2 (KLF2) and basic helix–loop–helix ARNT-like protein 1 (BMAL1), epigenetic regulation (such as chemical changes to DNA or histones, or small RNA molecules), survival pathway (a network of cellular mechanisms that help to prevent damage from stress and promote continued function), a healthy lifestyle, physical exercise and chronopharmacology.

In mammals, rhythmic interactions between BMAL1 and the enzyme calcium–calmodulin-dependent protein kinase type IIα (CaMKIIα) in brain synapses regulates rhythms of synaptic plasticity in the brain, thereby potentially promoting behavioural resilience independently of the transcription–translation feedback loop²⁵⁰. Loss of rhythmicity in the BMAL1–CaMKIIα interaction is associated with impaired long-term memory in animal models²⁵⁰. Given that BMAL1 also interacts with CaMKIIδ, which is highly expressed in the heart, similar rhythmic biochemical interactions in the heart might promote cellular resilience and cardiovascular health through non-canonical, post-transcriptional mechanisms^251,252.

Devices.

Devices have been developed to improve sleep neurophysiology, including transcutaneous vagal nerve stimulation, closed-loop sensory stimulation and transcranial magnetic stimulation. These tools might be used to improve cardiovascular resilience through their positive effects on sleep health. Transcutaneous vagal nerve stimulation delivers electrical impulses through the auricular branch of the vagus nerve and can affect sleep directly by changing the activity of sleep–wake brain regions (locus coeruleus and nucleus of the solitary tract) or indirectly by attenuating hyperarousal via the parasympathetic nervous system^253,254. Vagal nerve stimulation has shown promise for the treatment of other conditions such as epilepsy and depression^255-257, and is now being investigated for its potential to improve sleep and cardiovascular health^258,259. Closed-loop auditory stimulation uses sound to improve the quality of sleep by synchronizing auditory stimuli with the brain’s natural slow-wave activity during deep sleep. This technology monitors sleep-related electrophysiology in real time and delivers acoustic cues at precise moments to boost slow-wave oscillations and fast spindle activity, which has been shown in some, but not all, studies to improve memory consolidation and modulate neuroendocrine output^260-262. Transcranial magnetic stimulation uses magnetic fields to stimulate nerve cells in the brain. This non-invasive method has been successfully used to treat depression²⁶³, and there is increasing interest in its efficacy to treat sleep disturbance, including insomnia, by targeting specific brain areas involved in sleep regulation and cardiovascular control, such as the prefrontal cortex²⁶⁴.

Sleep optimization interventions.

Conceptually, interventions aimed at sleep optimization can promote cardiovascular resilience²⁶⁵ (Box 2). In short-term studies in individuals with habitual short sleep duration, prescribing sleep schedules with longer time in bed and interventions using wearable sleep trackers and brief coaching have been successful at increasing sleep duration, which improves quality of life²⁶⁶. In real-life settings, short-term sleep extension strategies have been shown to reduce hunger and appetite^267,268, improve blood pressure and reduce insulin sensitivity²⁶⁹, as well as reduce objectively assessed energy intake, resulting in a negative energy balance²⁷⁰. In the longer-term, interventions aimed at optimizing sleep duration could increase weight loss and promote the maintenance of a healthy weight^266,270 and, therefore, have great potential to be used as a behavioural strategy to improve cardiometabolic health and promote cardiovascular resilience. In these interventions, sleep trackers can provide detailed insights into nightly sleep patterns and circadian rhythms over long monitoring periods in real-life settings and enable the tailoring of personal sleep-optimization strategies, as well as provide feedback and accountability during the intervention²⁷¹.

Box 2 ∣. Sleep optimization to promote cardiovascular resilience.

An interaction exists between sleep and circadian rhythms.

To optimize sleep, multiple aspects of sleep health should be considered, including:

• Sleep timing

• Sleep duration

• Sleep quality

• Sleep regularity

• Sleep continuity

These components of sleep are biologically tightly linked together and, therefore, an intervention targeted at one component can influence another (for example, a sleep-extension intervention can also affect the timing, regularity, continuity and quality of sleep).

Technologies to improve sleep quality.

Given that poor sleep quality and sleep disorders such as OSA are strongly associated with an increased risk of cardiometabolic disease^272,273, improving sleep quality can promote cardiovascular resilience. For example, new technologies can improve adherence to continuous positive airway pressure therapy in OSA and result in better treatment outcomes, contributing to better sleep quality and potentially improving cardiovascular health^273,274. These strategies might also increase access to these treatments for various populations, thereby helping to reduce sleep health disparities.

Mechanistic pathways.

Several potential mechanistic pathways might explain how sleep interventions affect cardiovascular health, including alterations in sympathovagal balance, slow-wave sleep, insulin sensitivity, fat metabolism, inflammatory pathways and neuroendocrine regulation of appetite signals (changes in ghrelin levels and changes in brain regions related to reward-seeking behaviour)^272,275,276. These mechanisms can be direct or indirect (for example, improved dietary patterns). These pathways are interrelated and could collectively improve cardiometabolic health after sleep interventions. However, most research has been focused on sleep-deprivation studies; therefore, future research is needed to explore these potential mechanisms in the context of sleep and circadian interventions.

Knowledge gaps and research opportunities

Workshop participants identified ten crucial knowledge gaps and research opportunities to integrate sleep, circadian rhythms and cardiovascular resilience across various research, health-care and community settings (Box 3). Together, these opportunities, which are intersecting and potentially synergistic strategies, represent a Roadmap for future steps for researchers, funding agencies and policymakers.

Box 3 ∣. Research gaps and opportunities in sleep, circadian rhythm and cardiovascular resilience.

Interdisciplinary research models

Foster the integration of sleep science, circadian biology and cardiovascular research by developing shared platforms and interdisciplinary research groups, aimed to investigate the molecular and systemic effects of sleep health and circadian rhythms on cardiovascular health, resilience and disease.

Integrative mechanism research

Investigate the molecular, cellular, and systemic mechanisms of sleep and circadian medicine in cardiovascular resilience, to identify their effects on cardiometabolic health, inflammation and immune function, and aimed to assess whether these mechanisms could serve as viable therapeutic targets for improving cardiovascular resilience.

Prioritize research on social determinants of sleep health

Future research on cardiovascular resilience should prioritize integrating social determinants of sleep and circadian health in research to develop targeted interventions to improve cardiovascular health, particularly for groups with substantial social and economic barriers. Social determinants, such as early childhood development, community context (social cohesion and safety), social support and socioeconomic status, are important targets. Future research should leverage mixed methods to integrate community perspectives through both qualitative and quantitative research, to better understand the complex interaction between social factors and cardiovascular resilience. Additionally, qualitative research can help to identify cultural factors that might benefit sleep and circadian health, and thereby cardiovascular health.

Advanced diagnostic tools

Develop and validate new diagnostic metrics that incorporate physiological parameters and molecular biomarkers to better assess sleep and circadian health and related sleep disorders.

Artificial intelligence and big data

Use machine learning algorithms and big data analytics to analyse extensive epidemiological datasets to identify disease patterns and forecast risks linked to sleep and circadian disorders and cardiovascular disease, thereby improving risk stratification, disease prevention, early diagnosis and intervention strategies, leading to better health-care outcomes.

Standardization of research initiatives

Establish universal protocols for measuring sleep health and circadian health, standardizing data collection, data sharing and data nomenclature methods across different research settings to ensure consistency and improve meta-analytical research capabilities.

Research and health-care approaches across populations

Focus on developing and validating diagnostic tools and therapeutic interventions that are effective across diverse racial, ethnic and socioeconomic groups, address health disparities and promote equitable health outcomes.

Practical translation and community implementation

Develop practical guidelines for implementing evidence-based sleep and circadian interventions in various settings, including workplaces, schools, and community and other health-care facilities. Consider contextual factors, such as lifestyle, economic barriers and accessibility issues, to ensure effective implementation.

Public health strategies and education

Develop comprehensive public health initiatives and educational programmes to raise awareness about the crucial role of sleep and circadian rhythms in cardiovascular health and resilience, targeting both the general public and health-care professionals to improve preventative care and management strategies.

Improved academic and clinical training

Integrate sleep and circadian rhythm education into medical and graduate curricula to cultivate a new generation of researchers and clinicians who are well versed in these areas, fostering a holistic approach to patient care and research, empowering health-care professionals to address the crucial role of sleep and circadian rhythms in cardiovascular resilience.

Public health and clinical strategies to address gaps

In addition to optimizing individual health outcomes through targeted interventions, a holistic approach addressing broader societal factors influencing sleep and cardiovascular health is crucial. The following public health and clinical strategies and future directions offer guidance for implementing these interventions at various levels, ensuring that the benefits of improved sleep and circadian health are accessible to all.

• Sleep and circadian rhythm assessments in cardiovascular health screenings. Integrating systematic sleep and circadian rhythm assessments into routine cardiovascular health screenings (such as sleep quantity and quality, sleep variability and circadian rhythms) can help to identify individuals at risk of CVD. For example, health-care professionals could incorporate at least one basic sleep question in patient evaluations (such as, ‘how is your sleep?’), enquire about any symptoms of sleep or circadian rhythm disorders, and refer for further testing if needed. This proactive approach facilitates earlier interventions and better management of cardiovascular risk.

• Advanced diagnostic tools. Develop and validate new diagnostic metrics that incorporate physiological measures and molecular biomarkers to better assess sleep and circadian health and related disorders. For example, moving beyond traditional methods such as the apnoea–hypopnoea index, which might not fully capture the heterogeneity of OSA and its physiological consequences²⁷⁷, and using novel metrics of hypoxic burden²⁷⁸ and cardiac response to respiratory events might be useful²⁷⁹. Additionally, the variability observed in clinical trials in the cardiovascular benefits of continuous positive airway pressure for the secondary prevention of CVD underscores the need for personalized diagnostic and treatment strategies^280,281.

• Personalized medicine and precision nutrition. Develop personalized medicine approaches aimed at improving cardiovascular resilience through improved sleep and circadian rhythm health by leveraging machine learning algorithms and big data analytics to predict risks associated with sleep disorders and CVD. Precision nutrition, which tailors dietary interventions to individual needs on the basis of genetic, metabolic and environmental factors, could increase the effectiveness of these personalized approaches.

• Employer guidelines. Employers should adopt guidelines that align work schedules with natural circadian rhythms and sleep needs. This approach can improve employee health and productivity and reduce long-term health-care costs. Flexible work hours and policies that support sleep and circadian rhythm health can contribute to overall wellbeing and cardiovascular resilience.

• Health-care access. Address issues impeding health-care access that prevent many from receiving timely diagnoses and adequate treatments for sleep disorders. Expand access to affordable health care and telemedicine and increase the number of health-care providers in underserved areas. Training providers in cultural competency and increasing the pool of health-care professionals, including those from communities where health disparities are greatest, can increase trust and improve communication between providers and patients.

• Built environment improvements. The quality of the built environment, including housing quality, noise levels and light pollution, substantially influences sleep duration and quality. Improvements in urban planning and housing regulations can create environments conducive to better sleep. Initiatives could include noise controls, improved street lighting, and programmes promoting safer and quieter neighbourhoods. Improving public transport options and reducing commute times through better urban planning can also improve sleep health and overall wellbeing. These improvements will target environmental determinants of sleep health, thereby potentially reducing sleep disparities.

Conclusions

Most research so far has focused on sleep and circadian rhythms in relation to CVD outcomes, presenting an opportunity to expand the focus towards their effects on cardiovascular resilience, rather than primarily on disease. This Roadmap highlights the bidirectional effects of sleep and circadian rhythms on cardiovascular health and emphasizes the need for innovative research to bridge existing knowledge gaps. Efforts are required to connect various scales, including biological, behavioural, environmental and social factors, in research on sleep and cardiovascular resilience. This approach will improve our mechanistic understanding of how sleep and circadian rhythms influence cardiovascular health and help to identify resilience factors that could be potential therapeutic targets. Integrating social determinants into research on cardiovascular resilience is also crucial for addressing differences in sleep health. Finally, multidisciplinary approaches in sleep, circadian rhythm and cardiovascular research are urgently needed to ensure that scientific discoveries can be translated into public health strategies and clinical practices. Such a synthesis could facilitate a broader understanding and promotion of cardiovascular resilience, ultimately leading to improved health outcomes for communities around the world.