Understanding the Determinants of Circadian Health Disparities and Cardiovascular Disease

Abstract

Emerging research suggests that sleep contributes to racial disparities in cardiovascular disease (CVD). Racial/ethnic minorities are disproportionately affected by poor cardiovascular outcomes including obesity, hypertension and diabetes. Although circadian rhythms affect sleep patterns, few studies have examined disparities in circadian health or the contribution of circadian disparities to CVD. In this paper, we provide an overview of the relation between circadian health and CVD in the context of health disparities. We discuss (1) the current knowledge on racial disparities in circadian health; (2) social and environmental determinants of circadian health disparities; (3) the cardiovascular consequences of circadian disparities; and (4) future opportunities to advance the field of circadian disparities. In brief, our findings demonstrated that among a small literature, racial minorities (mainly African American) were more likely to have a shorter circadian period, delayed phase shifts, and were more likely to be shift workers, which are associated with CVD risk factors. Given racial minorities are disproportionately affected by CVD and CVD risk factors, it is important to further understand circadian health as an intervention target and support more research among racial minorities to understand circadian health in these populations.

Introduction

The importance of sleep to health has become increasingly recognized over the past few decades. There is also a growing body of evidence pointing to the racial disparities in sleep health as a fundamental contributor to racial health disparities in cardiovascular disease (CVD) (Jackson, Redline et al., 2015). For example, research has shown that sleep partially mediates racial disparities in different cardiovascular outcomes (Knutson, Van Cauter et al., 2009; Rasmussen-Torvik, De Chavez et al., 2016; Curtis, Fuller-Rowell et al., 2017). However, like many other physiological processes, sleep occurs within the context of circadian rhythms, and is significantly impacted by disruptions to circadian rhythms. This is most apparent in the context of jet lag or shift work where there can be significant misalignment between the internal biological clock as the external schedule, either due to trans meridian travel or a non-traditional work schedule (e.g., night shifts). While emerging research points to the importance of circadian rhythms to health, very little research has examined disparities in circadian rhythms as a social determinant of health.

Among the most relevant morbidities significantly impacted by circadian rhythms — and thus impacted by disparities in circadian health — is CVD, which continues to be the leading cause of death in the United States (Mc Namara, Alzubaidi et al., 2019). Despite improvements in identifying risk factors for CVD and advances in treatment and prevention strategies, there are still striking and unexplained racial/ethnic disparities in cardiovascular morbidity and mortality (Mensah, Mokdad et al., 2005; Carnethon, Pu et al., 2017). In fact, a study conducted in 2013 demonstrated that disparities in cardiovascular health have persisted over the last decade, and there is limited evidence of narrowing disparities (Pool, Ning et al., 2017). Most strategies to address CVD disparities have included traditional approaches such as promoting health behaviors (weight-reducing diet, physical activity, limiting alcohol and salt intake) as well as medications (Chobanian, Bakris et al., 2003; Krousel-Wood, Thomas et al., 2004; Rippe, 2019). These strategies have largely ignored circadian biology. Many cardiovascular functions including blood pressure and heart rate are regulated by the circadian clock (Crnko, Du Pré et al., 2019). Consequentially, medical incidents related to cardiovascular functioning such as myocardial infarctions are affected by rhythm modifications that occur in the morning, resulting in increased adverse cardiovascular events during the morning hours (Muller, Stone et al., 1985; Marchant, Ranjadayalan et al., 1993; Suárez-Barrientos, López-Romero et al., 2011; Buurma, van Diemen et al., 2019). In fact, data demonstrate that patients who experience an adverse cardiovascular event in the morning compared to the evening have a worse prognosis (Suárez-Barrientos, López-Romero et al., 2011). Circadian rhythms are affected by environmental and behavioral factors, including ones that alter light exposure, such as shift work and artificial light at night. Due to social and structural inequities, racial minorities are more likely to be shift workers and reside in areas with more light pollution, which can lead to a disruption in circadian rhythms and the cardiovascular system. There is a clear need to understand racial/ethnic disparities in circadian health and how these disparities may contribute to cardiovascular disparities.

In this paper, we present the current scientific evidence on racial/ethnic disparities in circadian and cardiovascular health. Disparities in this context relate to inequities between groups such as race or ethnicity that are preventable and unfair/unjust (McGuire, Alegria et al., 2006). We adopt the definition of Duran et al. that defines a health disparity as “a health difference that adversely affects defined disadvantaged populations, based on one or more health outcomes” (Duran & Perez-Stable, 2019). Further, we are defining race as a social (not genetic) construct that is a proxy for experiences of racism. Race as a social construct has biological consequences that result from socio-economic and environmental factors that are differentially experienced across racial/ethnic groups as a result of historical and contemporary forms of discriminatory practices as well as policies on the basis of race/ethnicity (Smedley & Smedley, 2005). This paper will utilize a socio-ecological approach, which takes into account the complex interplay between individual, relationship, community, and societal-level factors to the discussion racial/ethnic disparities in CVD and circadian health.

Racial Disparities in CVD

Racial minorities have a higher prevalence of CVD, and in particular African Americans have the highest prevalence of CVD in comparison to White adults (Benjamin, Muntner et al., 2019). From 1999 – 2017, the prevalence of heart disease among White adults decreased, while the trend for African American, Hispanic, and Asian adults remained stable – no observed improvements. Traditional CVD risk factors (e.g., hypertension, diabetes) are contributing to the CVD disparities. African Americans have the highest prevalence of hypertension, and Hispanic and African Americans are most likely to have obesity and diabetes (Zhang, Wang et al., 2009; Whelton, Carey et al., 2018). Ideal cardiovascular health includes health behaviors (diet quality, physical activity, smoking, body mass index) and health factors (blood cholesterol, blood pressure, blood glucose) (Lloyd-Jones, Hong et al., 2010). African American and Hispanic/Latino adults tend to have fewer cardiovascular health metrics at ideal levels than White adults (Benjamin, Muntner et al., 2019). While studies have shown that Asian American adults are less likely to have heart disease as well as a lower prevalence of overweight/obesity and hypertension, this varies by ethnicity. Asian Indians have an earlier onset of coronary artery disease, and South Asians have more nontraditional risk factors of CVD such as insulin resistance (Graham, 2015). This underscores the importance of conducting within group analyses and identifying subgroups. The burden of CVD among racial/ethnic minorities presents a pressing public health need to identify modifiable targets to begin to tackle and reduce these health disparities. Disparities in CVD may be driven in part by disparities in circadian health.

Important Factors in Circadian Health

Because all organisms on earth have evolved in an environment that changes predictably by day and night over a 24-hour period, almost all physiological functions have also adapted to these changes, and as such are often regulated or influenced by the endogenous clock. When considering evaluating circadian health, there are three parameters that are relevant: 1) the circadian phase (i.e. timing of a physiological event), 2) the amplitude (i.e. the range of intensity of the physiological event), and 3) the period (i.e. the time it takes for a physiological event to complete a full cycle). Because the period functionally impacts circadian phase, this paper will focus predominantly on factors that impact phase and amplitude. Additionally, because the human circadian system is regulated primarily by light, the most influential factors will impact light exposure.

One main component of circadian health is how well aligned the phase (i.e. timing) of a physiological event is with the desired phase. For example, someone who works from 9am to 5pm may need to sleep from 11pm to 7am to achieve optimal health and functioning. This desired schedule would require the individual’s endogenous clock to be physiologically prepared for sleep between 11pm and 7am (e.g., time the onset and offset of melatonin secretion to align with this sleep schedule). A misalignment between the endogenous timing and desired timing of sleep result in negative health and performance consequences. For example, those with a late chronotype often exhibit a later circadian phase of melatonin onset and offset, which can cause the individual to have trouble falling asleep and waking up at the desired schedule, which often results in chronic sleep loss. Another mechanism by which this type of misalignment can occur is through exposure to light at inopportune times. Because light at night can delay circadian phase, people who are exposed to bright artificial light in the evening are more likely to exhibit a delayed circadian phase of melatonin onset and offset, thus causing a circadian misalignment resulting in chronic sleep loss (Cho, Ryu et al., 2015).

Shift workers, particularly those who work the night shift, often experience severe circadian disruption (James, Honn et al., 2017). First, workers on the night shift must sleep during day following their night shift in order to achieve adequate rest for their next night shift. However, because the human circadian system is strongly entrained by daylight, most individuals do not secrete melatonin during the day. As such, night shift workers often report an inability to achieve restful and consolidated sleep during the day. Additionally, many night shift workers are also exposed to artificial light at night, which may displace the phase of melatonin secretion. As such, many night shift workers also report disrupted nocturnal sleep on their off-work periods, when they may have social or familial obligations that require them to be awake and functioning during the day.

Another core component of circadian health is the clear delineation of physiological functioning between day and night, which is often reflected in the amplitude of the physiological event. For example, for those who live a diurnal schedule (i.e. awake during the day and asleep during the night), it is desirable for alertness to be robustly upregulated during the day and significantly downregulated during the night. However, when the amplitude of the alertness rhythm is blunted, the individual may experience inadequate alertness during the day that impairs functioning (i.e. sleepiness), and subsequently experience excessive alertness during the night that interferes with sleep. Another example is the ‘dipping’ of blood pressure at night during sleep; individuals who are “non-dippers” are at increased risk for poor cardiovascular health outcomes (Cicconetti, Donadio et al., 2007). A blunted amplitude can occur when there is inadequate contrast in light exposure during the day and night. The prior has been observed in nursing homes where residents (especially those with restricted mobility) may receive inadequate exposure to bright light during the day and/or have excessive exposure to bright artificial light in the evening. When light interventions were implemented to increase the contrast of light exposure to better align with the day-night differences, residents exhibited significant improvements in their level or alertness and sleep quality (Ancoli-Israel, Martin et al., 2002; Ancoli-Israel, Gehrman et al., 2003).

Racial Disparities in Circadian Health

A growing literature supports evidence of racial/ethnic disparities in sleep (Johnson, Jackson et al., 2019), yet few studies have focused on racial/ethnic disparities in circadian health (Table 1). Laboratory data suggest that African Americans have a shorter endogenous circadian period and more difficult and complex responses to phase shifts than White adults (Smith, Burgess et al., 2009; Eastman, Molina et al., 2012; Eastman, Suh et al., 2015; Paech, Crowley et al., 2017). Phase shifts are a necessity for adapting to changes in time zones and work schedules, for example. Lack of adaptation/phase shifts can result in circadian misalignment, which is a mismatch between the internal circadian system and behavioral or environmental cycles, which is, in turn, associated with adverse cardiometabolic health (Scheer, Hilton et al., 2009).

Table 1.

Racial differences in circadian factors among Black, Asian, and Hispanic/Latino in comparison to White individuals.

Race	Circadian factors
	Circadian period	Sleep timing	Sleep regularity	Circadian disruption or misalignment	Chronotype – preference
Black	↓ (Smith, Burgess et al., 2009; Eastman, Molina et al., 2012; Paech, Crowley et al., 2017)	↑ (Smith, Burgess et al., 2009; Bailey, Combs et al., 2019; Combs, Hsu et al., 2020; Huang, Mariani et al., 2020)	↓ (Lunsford-Avery, Engelhard et al., 2018)	No data	Morning type (Eastman, Molina et al., 2012; Malone, Zemel et al., 2016)
Asian	No data	↑ (Huang, Mariani et al., 2020)	↓ (Lunsford-Avery, Engelhard et al., 2018)	No data	No data
Hispanic/Latino	No data	↑ (Paech, Crowley et al., 2017)	↓ (Lunsford-Avery, Engelhard et al., 2018)	No data	No data

Note: A downward arrow indicates a shorter period or less regular sleep; an upward arrow indicates a later sleep timing.

Racial disparities in chronotype are mixed. A cross-sectional study of 439,933 White (95%) and Black (5%) adults from the UK Biobank, found that morning type was 1.4 times more prevalent in Black individuals than White (Malone, Patterson et al., 2016). While a large cohort study in the U.S., the Multi-Ethnic Study of Atherosclerosis (MESA) study, reported no difference in chronotype between African American and White adults (Combs, Hsu et al., 2020). However, the MESA study did find that African Americans were more likely to report a delayed sleep phase (i.e. going to sleep after midnight) (Combs, Hsu et al., 2020). This is supported by data from a community-based sample that also found African Americans were more likely to have a delayed sleep phase (Bailey, Combs et al., 2019). If African Americans do not have a later chronotype, or even an earlier chronotype, but are going to sleep later, then this could lead to circadian misalignment. Emerging research suggests specific sleep dimensions such as sleep timing and sleep regularity are indicative of circadian misalignment. These measures also have existing racial disparities. African Americans, Asian and Latinx adults have later sleep timing and more irregular sleep (Huang & Redline, 2019; Johnson, Jackson et al., 2019; Combs, Hsu et al., 2021). Given these sleep disparities, and the negative consequences of delayed sleep phase, it is important to identify determinants of circadian disparities.

Determinants of Circadian Disparities

Inopportune Light:

Circadian rhythms are entrained by external environmental cues (e.g., light) and regulate the wake-sleep cycles and metabolism (Maury, Ramsey et al., 2010; Stothard, McHill et al., 2017). Therefore, light exposure is a key determinant of circadian misalignment. Bright artificial lights are common in low socio-economic status (SES) neighborhoods, where racial minorities are more likely to live, to reduce crime; which can lead to inopportune light exposure. Light is the primary signal that the central clock uses to synchronize the internal clock to the external light-dark cycle. Light at night also delays the circadian rhythm and it suppresses melatonin, a hormone produced in the pineal gland that regulates sleep and wakefulness (Vollmer, Michel et al., 2012; Obayashi, Saeki et al., 2014; Koo, Song et al., 2016). It is likely that racial minorities are at increased risk for circadian disruptions due to environmental features (e.g. light at night) that are more prevalent in urban areas, where this population is more likely to reside: ~80% of African Americans in the U.S. live in urban neighborhoods. These features of the urban environment (brighter street lighting, traffic noise) (Stevens, 2011) may cause phase shifts of circadian rhythms, leading to later chronotype and bedtimes, thus resulting in shorter sleep duration and more irregular sleep, which is associated with adverse cardiovascular health (Wright, McHill et al., 2013).

There may also be social determinants that influence exposure to bright light. For example, those living in neighborhoods with higher crime rates may be incentivized to increase light in and around the home as a mechanism to deter crime (Rottapel, Zhou et al., 2020); however, the trade-off may be unintended shifts in circadian phase that may have deleterious effects on sleep and health. Additionally, there may also be differences in indoor light exposure (e.g., large windows that are architecturally placed to maximize natural light) that may also influence circadian amplitude.

Shift work:

Racial minorities are more likely to work non-traditional shifts with non-standard work schedules, such as rotating or night shifts. The Nurses’ Health Study II, a prospective study with 16 years of follow-up among 95,652 White (98%) and Black (1.5%) adults, found rotating night shift work to be more prevalent in Black individuals than White individuals (33% vs 23%) (Lieu, Curhan et al., 2012). Further, there was a significant risk of hypertension associated with working rotating shifts in the Black nurses, but no association in the White nurses, suggesting a differential effect by race. Certain racial groups, such as African Americans tend to have a biological predisposition to morning chronotype (i.e., “larks” rather than “owls”) (Eastman, Molina et al., 2012), but due to socio-occupational demands they are more likely to be shift-workers or work multiple jobs impacting sleep schedules. This not only increases the circadian misalignment, it also reduces the odds of circadian alignment to the night shift over time. The discrepancy in the biological need vs. social demands results in circadian misalignment and sleep patterns that are counter to their endogenous biological rhythms (Malone, Patterson et al., 2016). Indications of circadian disruptions on CVD can be seen among shift workers (Gu, Han et al., 2015), during shifts of circadian phase (e.g. daylight saving) (Janszky & Ljung, 2008), periods of social jetlag (Wong, Hasler et al., 2015), and among later sleep timing or evening chronotypes (Wong, Hasler et al., 2015; Yu, Yun et al., 2015).

Link between Circadian disruption and CVD

Circadian disruption can lead to CVD through different pathways. There can be an indirect association through sleep disturbances, which is associated with adverse cardiovascular health (Rüger & Scheer, 2009). There could be damage to the suprachiasmatic nucleus, which can result in CVD outcomes such as coronary heart disease, diabetes, obesity or metabolic syndrome (Rüger & Scheer, 2009). Shift work and circadian misalignment can increase systemic inflammation, which is an underlying cause of many CVDs (Rana, Prabhu et al., 2020).

There are few studies that have examined circadian health in relation to CVD (Table 2), and even fewer focus on disparities. There is evidence supporting sleep regularity, a measure of circadian biology as a contributor to CVD. A longitudinal study of 1,978 White, Chinese-American, Black and Hispanic adults found that sleep irregularity was associated with an increased 10-year risk of CVD, and greater obesity, hypertension, fasting glucose, hemoglobin A1C, and diabetes (Lunsford-Avery, Engelhard et al., 2018). This study provides evidence that circadian biology may contribute to cardiovascular health.

Table 2.

Studies on disparities in circadian disruption and cardiovascular outcomes, N=11.

Study	Sample	Study design	Circadian Measure	Findings
Eastman et al. (2012)	21% Black, 58% White	Experimental laboratory study	Circadian periods and melatonin levels. Melatonin was measured by a saliva swab every 30 minutes.	Black individuals experienced a shorter circadian period than White counterparts and were more likely to exhibit morning chronotype.
Combs et al. (2020)	41% Black, 59% White	Secondary analysis of a national dataset	Delayed sleep phase	No difference in chronotype between Black individuals and Whites. But Black individuals were 80% more likely to report a delayed sleep phase.
Bailey et al. (2019)	9% Black, 91% White	Secondary analysis of a community-based sample	Delayed sleep time	After adjusting for confounders, Black individuals had delayed sleep time compared to Whites. Depression was independently associated with sleep time.
Malone et al. (2016)	5% Black, 95% White	Cross-sectional	Sleep duration and chronotype both measured by self-report	Black ethnicity emerged as the strongest predictor of sleep behavior. Morning type was 1.4 times more prevalent in Black individuals than White.
Lambert et al. (2020)	49% Black, 51% White	Secondary analysis of a prospective cohort study	24- hour blood pressure	Black individuals had higher BP during the day and night than Whites, but the morning surge in BP was lower because of a slower morning rate of increase. Black individuals, had an increased prevalence of undiagnosed hypertension.
Smith et al. (2009)	n=60, percentages not given	Laboratory study	Circadian period/phase measured by circadian phase assessments	Black individuals had a significantly shorter circadian period than people of other races/ethnicities.
Lunsford-Avery et al. (2018)	39% White, 10% Chinese-American, 28% Black, 23% Hispanic	Secondary analysis of a longitudinal observational study	Sleep regularity	Sleep irregularity was associated with 10-year risk of CVD, and greater obesity, hypertension, fasting glucose, hemoglobin A1C, and diabetes status.
Muntner et al. (2015)	63% Black, 37% White	Observational laboratory study	24-hour blood pressure	Black individuals were more likely than Whites to have nocturnal hypertension. ABPM variability was higher among Black individuals compared with Whites.
Paech et al. (2017)	51% Black, 49% White	Experimental laboratory study	Circadian misalignment	The circadian period was shorter in Black individuals than Whites. Cognitive performance during baseline or misaligned days did not differ between the two groups.
Huang et al. (2020)	28% Black, 38% White, 22% Hispanic, 12% Chinese-American	Secondary data analysis	Sleep regularity measured by 7 days of wrist actigraphy	Irregular sleep duration and timing were associated with CVD.
Lieu et al. (2012)	1.5% Black, 98% White	Prospective study with 16 years of follow-up	Rotating night shift	Rotating night shift was independently associated with an increased risk of hypertension in blacks but not in whites.

Blood pressure, which is disproportionately higher among racial minorities, has a circadian rhythm. A prospective cohort study with 406 Black and White adults demonstrated that Black individuals have a higher daytime blood pressure than whites, but a lower morning surge in blood pressure as a result of a slower morning rate of increase (Lambert, Head et al., 2020). Studies have also shown that ambulatory blood pressure variability, which may be a marker of circadian disruption was higher among Black individuals compared with Whites (Muntner, Lewis et al., 2015). Given hypertension is a main contributor to CVD, it is important to further understand the role of circadian biology in hypertension disparities.

Summary

In summary, there are few studies that examine circadian health among racial minorities, or examine circadian disruption as a contributor to CVD disparities. Among the limited literature, most studies compared White adults to African American or Black adults, with no study to our knowledge that included other racial minorities such as Hispanic/Latinx, Asian, Native Hawaiian or Pacific Islanders. Based on the existing literature, African Americans have a shorter circadian period, delayed phase shifts, and are more likely to be a shift worker, which are associated with CVD risk factors. Given racial minorities are disproportionately affected by CVD and CVD risk factors, it is important to further understand circadian health as an intervention target. Based on the current literature, we recommend the following in order to improve circadian health among racial minorities, and reduce the burden of CVD:

1. Conduct real-world studies to understand circadian health among racial minorities, particularly those that are understudied including, American Indian/Alaska Native, Asian, Black, Hispanic/Latino, and Native Hawaiian/Pacific Islander. There are newer and novel techniques that can be employed to measure circadian biology in the home (Burgess, Wyatt et al., 2015), that can be utilized to conduct studies in the natural environment.

2. Identify the social determinants of circadian disruption, which are likely contributing to circadian disparities. We provided data demonstrating inopportune light exposure, which is more common in lower SES environments where minorities are more likely to live and occupation as determinants. Studies should confirm these findings in studies intentionally designed to assess these associations. For example, we suggest multi-level studies that examine light pollution at a neighborhood-level, as well as identify household factors or individual behaviors that increase light pollution.

3. Design prospective studies that can test circadian disruption as a contributor to racial disparities in CVD. The sleep field can be used an example. There are a few studies that have tested and found that sleep partially mediates racial disparities in CVD risk factors (Knutson, Van Cauter et al., 2009; Rasmussen-Torvik, De Chavez et al., 2016; Curtis, Fuller-Rowell et al., 2017).

4. Develop acceptable, feasible and effective interventions to improve circadian health in racial/ethnic minorities.

All of the steps above are necessary to address circadian and associated health disparities. Conducting research on the link between circadian and CVD disparities can inform culturally relevant interventions that may reduce the CVD societal burden.