Sleep and Circadian Rhythms in Cardiovascular Resilience: Mechanisms, Implications, and Applications - Executive Summary

Overview

The National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health (NIH) convened a two-day virtual workshop titled "Sleep and Circadian Rhythms in Cardiovascular Resilience: Mechanisms, Implications, and Applications" on April 24th and 26th, 2024. Experts from diverse fields, including vascular biology, cardiology, sleep and circadian medicine, and allied healthcare professions, shared their insights and expertise, and discussed critical research gaps and opportunities for future collaborative endeavors.

Agenda

Workshop agenda

NIH Videocast

Day 1

Day 2

Background

The interplay between sleep, circadian rhythms, and cardiovascular (CV) resilience is a critical research area with significant public health implications. These biological processes govern metabolic pathways, inflammatory responses, and neuroendocrine activities, all crucial for maintaining CV health. Disruptions to sleep and circadian rhythms exacerbate risk factors for cardiovascular diseases (CVDs) such as hypertension, diabetes, and obesity. Given the global rise in these conditions, promoting sleep and circadian health is vital. Targeted public health interventions and clinical strategies can enhance CV resilience. This workshop explored the nexus of sleep, circadian rhythms, and CV resilience, framing future research directions, identifying therapeutic targets, and crafting innovative interventions for optimal CV function and disease prevention.

Summary

The workshop began by highlighting the importance of resilience—both generally and specifically within CV health—and underscoring the profound influence of sleep and circadian rhythms on CV health. Emphasis was placed on stimulating cross-discipline collaborations among these fields, essential for advancing our understanding of how sleep and circadian biology directly influence CV health and resilience. A working definition used across the NIH states that “resilience encompasses the capacity to resist, adapt to, recover, or grow from a challenge.” CV resilience includes responses ranging from molecular and cellular activities, like inflammation and tissue regeneration, to systemic adjustments that maintain stable blood pressure and heart rate. Workshop discussions addressed the intricacies of navigating CV resilience at various biological scales and synthesizing outcomes spanning molecular to systemic levels within these frameworks.

Mechanisms Connecting Sleep, Circadian Rhythms, and CV Resilience

This workshop provided insights into the critical role of sleep in CV health, focusing on the complex relationships between sleep, circadian rhythms, and CV resilience. Sleep, included in the "Life's Essential 8 " metrics, significantly influences CV function through various physiological and molecular mechanisms. Research has linked sleep and sleep disorders to physiological changes such as increased sympathetic nervous system (SNS) activity and inflammation, which are associated with endothelial dysfunction, metabolic disturbances, and blood pressure issues. This workshop explored multiple mechanisms linking sleep and CV health, including:

• Blood Pressure Regulation: Sleep significantly influences CV function by regulating blood pressure. Nocturnal dipping, a decrease in blood pressure during sleep, provides critical rest to the CV system. Sleep disruptions can prevent this dipping, increasing CV risk.
• Heart Rate Variability (HRV): HRV is an indicator of CV health. The ability of the heart to adapt in response to physical and mental challenges indicates better CV resilience, while disrupted sleep reduces HRV, increasing CV complications.
• Endothelial Function: The endothelium, the cell layer that lines all blood and lymph vessels, plays a vital role in vascular health by regulating vasoconstriction and dilation. Sleep supports endothelial function by promoting repair and reducing inflammation, preventing atherosclerosis.
• Sympathetic Nervous System: Circadian control of the SNS modulates CV responses to daily stressors. Disruptions elevate morning blood pressure and heart rate, increasing myocardial infarction risk.
• Gene Expression: Circadian genes like CLOCK (Circadian Locomotor Output Cycles Kaput) and BMAL1 (Basic Helix-Loop-Helix ARNT Like 1) regulate genes controlling blood pressure, heart rate, and vascular tone, aligning CV functions with environmental light-dark cycles.
• Metabolic Pathways: Circadian rhythms synchronize metabolic processes, including glucose metabolism and lipid homeostasis, which are essential for maintaining CV health.

Linking Sleep Quality, Circadian Rhythm Disruption, and CVD Risk

Sleep health, characterized by subjective satisfaction, appropriate timing, adequate duration, high efficiency, and sustained alertness during waking hours, is essential for maintaining CV function. Poor sleep or circadian disruptions caused by changes in sleep duration, alterations in sleep quality, chronotype (circadian preferences) variability, or the presence of sleep disorders all play critical roles in modulating CVD risk. Numerous studies support the link between sleep quality, circadian rhythms, and CV outcomes. This workshop highlighted connections of poor sleep and circadian disruptions with physiological and psychological risk factors for CVDs, including:

• Oxidative Stress and Inflammation: Insufficient sleep increases oxidative stress, leading to vascular inflammation and endothelial dysfunction, both precursors to CVDs. Insufficient sleep suppresses antioxidant defenses and exacerbates oxidative damage in endothelial cells. Inflammatory markers such as C-reactive protein (CRP) and interleukin-6 (IL-6), associated with CVDs, are often elevated in individuals with inadequate sleep and high stress.
• Leukocyte Dynamics: Sleep fragmentation increases leukocyte production in the bone marrow, escalating systemic inflammation and accelerating atherosclerosis, contributing to CVD development and progression.
• Obesity and Diabetes: Poor sleep and circadian misalignment are linked to higher risks of obesity and diabetes, which exacerbate CVD risk. Metabolic health, inflammation, immune function, and behaviors like poor dietary choices prompted by sleep deprivation-related hormonal imbalances can increase caloric intake and preference for high-fat and high-sugar foods.
• Lipid Metabolism: Poor sleep is associated with dyslipidemia, characterized by elevated levels of triglycerides and low levels of high-density lipoprotein (HDL) cholesterol, and is a major risk factor for CVDs.
• Aging Processes: Sleep disturbances accelerate biological aging, including telomere shortening, epigenetic changes, and immune activation, impacting CV health. Aging alters sleep architecture, leading to shorter duration, more awakenings, less slow-wave sleep, lower levels of REM sleep, and a higher prevalence of obstructive sleep apnea (OSA), suggesting a bidirectional relationship where poor sleep accelerates aging and aging disrupts sleep.
• Stress, Depression, and Anxiety: Disrupted sleep increases stress and is strongly associated with depression and anxiety, all of which exacerbate CV risk through increased inflammation, altered HRV, and higher levels of stress hormones like cortisol.

Racial and ethnic disparities in sleep health and CVDs significantly impact risk factors and CV resilience. Workshop presentations highlighted that minoritized populations, particularly Black/African-Americans and Latinx/Hispanics, experience poorer sleep quality and shorter durations compared to White individuals, with women especially affected. Inadequate sleep increases risks of hypertension, obesity, diabetes, and psychological stress, undermining CV resilience. African-Americans have higher OSA prevalence and lower diagnosis and treatment rates, worsening CV risks. Socioeconomic factors like lower income, education levels, higher shift work rates, and polluted environments exacerbate these disparities. Cultural beliefs and historical distrust in healthcare further hinder diagnosis and treatment among minorities, perpetuating a cycle of sleep-related CV risk and health disparities.

Interventions Targeting Sleep Health to Optimize CV Resilience

The workshop underscored the importance of integrated strategies addressing biological, social, and behavioral determinants of sleep health to improve outcomes across all populations. Emphasis was placed on innovative biomedical and public health strategies to optimize sleep health and enhance CV resilience. Discussions highlighted the significance of direct interventions, including pharmacological aids and technological supports, as well as indirect approaches such as behavioral therapy and stress management programs.

1. Behavioral and Psychosocial Interventions

• Cognitive Behavioral Therapy for Insomnia (CBT-I): Utilizes cognitive and behavioral techniques to enhance sleep quality, duration, and efficiency, improving sleep architecture and reducing nighttime awakenings.
• Chronotherapy: Adjusts the timing of activities, meals (chrononutrition), and/or medication (chronopharmacology) to align with biological clocks, potentially improving metabolic outcomes, reducing circadian misalignment, and enhancing therapeutic effects.
• Sleep Hygiene Education: Promotes consistent sleep schedules, dark/quiet environments, and limited pre-bedtime screen exposure, fostering habits for restorative sleep, and encourages research into reversing biological aging from OSA.
• Stress Management Programs: Teach techniques such as mindfulness, meditation, and cognitive-behavioral stress reduction to manage elevated stress levels. These programs can be tailored for underserved communities or address workplace stress.
• Enhancing Social Support: Strengthens social networks, particularly for the elderly, those with high CVD risk, and other disadvantaged groups, which improve coping mechanisms and adherence to health-promoting behaviors, including consistent sleep schedules. Support groups share experiences and strategies for better sleep and enhancing social support.

2. Physical and Pharmacological Interventions

• Molecular Targets: Discussed targets include NRF2 and Nogo-B receptor (NgBR) in lung endothelial cells, whose decreased expression is linked to increased oxidative stress and lung injury. Additionally, BMAL1's interactions with the synaptic enzyme CaMKIIα may enhance cellular resilience and CV health.
• Vagal Nerve Stimulation (VNS): Delivers electrical impulses to the vagus nerve, regulating the parasympathetic nervous system, with potential benefits for sleep and CV health.
• Transcranial Magnetic Stimulation (TMS): Uses magnetic fields to stimulate nerve cells in the brain, targeting areas involved in sleep regulation and CV control.
• Continuous Positive Airway Pressure (CPAP) Therapy Management: Remote monitoring and management of CPAP use for OSA patients to provide better adherence and improve sleep quality and CV health.
• Bright Light Therapy Devices: Treat circadian disorders by offering controlled exposures to intense light, resetting the body's internal clock, facilitating earlier sleep times, and reducing CV risks.
• Close-Loop Auditory Stimulation: Enhances sleep by synchronizing auditory stimuli with the brain's slow-wave activity during deep sleep, delivering auditory cues at precise moments to boost slow-wave sleep.

Opportunities for Potential Public Health Initiatives

In further discussions, experts emphasized the necessity of holistic approaches that not only optimize individual health outcomes but also address broader societal factors influencing sleep and CV health. A potential roadmap for implementing interventions at various levels, ensuring improved sleep and circadian health benefits for all include the following key points:

• Sleep Assessments in CV Screenings: Incorporate sleep assessments and discussions of sleep disorders into routine CV health screenings to identify individuals at risk of CVDs, enabling early interventions and better management.
• Advanced Diagnostic Tools: Develop new diagnostic metrics incorporating physiological and molecular biomarkers to assess sleep health and disorders, including measures of hypoxemic burden, CV strain, and autonomic regulation.
• Personalized Medicine: Utilize machine learning and big data to develop personalized strategies for improving CV resilience through better sleep and circadian health, with an emphasis on individualized CPAP therapeutic strategies for OSA treatment.
• Healthcare Access and Equity: Expand affordable healthcare access, increase providers in underserved areas, promote training in cultural competency, and encourage diversity among healthcare professionals to enhance trust, communication, and reduce health disparities.

Conclusion

The workshop offered a thorough examination of the connections between sleep health, circadian rhythms, and CV resilience. Key discussions emphasized the importance of resilience in CV health and introduced refined definitions applicable across various health domains. Insights highlighted the reciprocal impacts of sleep and circadian rhythms on CV health, underscoring the urgent need for innovative research to bridge existing knowledge gaps. Efforts are required to bridge scales in sleep and CV resilience research and provide a mechanistic understanding of sleep, circadian rhythms, and CVD to identify additional therapeutic targets. Additionally, discussions stressed the integration of social determinants such as race and gender into CV resilience research to address sleep health disparities. Participants emphasized the importance of multidisciplinary research approaches and the translation of scientific discoveries into public health strategies and clinical practices, aiming to enhance understanding and promote CV resilience on a broader scale.

Key Gaps and Opportunities

• Foster integration of sleep science, circadian biology, and cardiovascular (CV) research through shared platforms and interdisciplinary research groups aiming to investigate the molecular and systemic effects of sleep health and circadian rhythms on CV health, resilience, and disease.
• Uncover the molecular foundations of sleep and circadian medicine in enhancing CV resilience, integrate findings across multiple biological scales to understand their influence on metabolic health, inflammation, and immune function, and assess whether these mechanisms are viable therapeutic targets for bolstering CV resilience.
• Develop and validate new diagnostic metrics that incorporate physiological metrics and molecular biomarkers to better assess sleep health and related sleep disorders, including measures of hypoxemic burden, CV strain, and autonomic regulation.
• Use machine learning algorithms and big data analytics to enhance the analysis of extensive epidemiological datasets aiming to identify patterns and forecast risks linked to sleep disorders and CV diseases.
• Standardize protocols for measuring sleep health and circadian rhythm disruptions, and data collection methods across different research to ensure consistency and enhance meta-analytical research capabilities.
• Develop and validate diagnostic tools and therapeutic interventions that are effective across different racial, ethnic, and socioeconomic groups to address health disparities and promote equitable health outcomes.
• Develop practical guidelines across various settings to implement evidence-based sleep interventions in workplaces, schools, and healthcare facilities, considering contextual factors such as cultural norms, economic barriers, and accessibility issues to ensure effective implementation.
• Further support the development of public health initiatives and educational programs to raise awareness about the critical role of sleep and circadian rhythms in CV health and resilience to improve preventative care and management strategies.

Workshop Organizers and Contacts

• Yunling Gao, PhD, MD, Program Director, Vascular Biology and Hypertension Branch, DCVS, NHLBI
• Alfonso Alfini, PhD, MS, Program Director, NCSDR, DLD, NHLBI

Workshop Co-Chairs and Moderators

• Brooke Aggarwal, EdD, MS, FAHA, Columbia University
• Michael Grandner, PhD, MTR, CBSM, FAASM, University of Arizona
• Donald Lloyd-Jones, MD, ScM, FACC, FAHA, Northwestern University

Workshop Speakers

• Ron Anafi, MD, PhD, University of Pennsylvania
• Ali Azarbarzin, PhD, Harvard University
• Kelly Baron, PhD MPH, DBSM, University of Utah
• Victoria Bautch, PhD, University of North Carolina at Chapel Hill
• Nicole Bowles, PhD, Oregon Health and Science University
• Josiane Broussard, PhD, Colorado State University
• Marishka Brown, PhD, Director of the NCSDR, DLD, NHLBI
• Philip Cheng, PhD, Henry Ford Health
• Stephanie Cook, DrPH, New York University
• Rene Cortese, PhD, ATSF, University of Missouri
• Fabian Fernandez, PhD, University of Arizona
• Zorina Galis, PhD, Chief of Vascular Biology and Hypertension Branch, DCVS, NHLBI
• David Goff, MD, PhD, FACP, FAHA, Director of the DCVS, NHLBI
• Sanja Jelic, MD, Columbia University Medical Center
• Jonathan Lipton, MD, PhD, Harvard University
• Dayna Johnson, PhD, MPH, Emory University
• Pamela Lutsey, PhD, MPH, University of Minnesota
• Qing Miao, PhD, New York University Long Island School of Medicine
• Jose Ordovas, PhD, Tufts University
• Aric Prather, PhD, University of California, San Francisco
• Filip Swirski, PhD, Icahn School of Medicine at Mount Sinai
• Esra Tasali, MD, University of Chicago
• Ivan Vargas, PhD, University of Arkansas

Disclaimer

The findings, knowledge gaps, and opportunities described here represent a summary of individual opinions and ideas expressed during the workshop. The summary does not represent a consensus opinion or directive made to or by NHLBI or NIH.