June/July 2024 Issue

Circadian Rhythms and CVD
By Carrie Dennett, MPH, RDN
Today’s Dietitian
Vol. 26 No. 6 P. 16

Could the “when” of nutrition and lifestyle behaviors matter as much as the “what”?

It’s well established that eating a nutrient-dense diet, engaging in appropriate types and amounts of physical activity, sleeping well, not smoking, and managing other sources of stress support cardiovascular health. But what about the rhythm of your daily life? A study published in the Journal of the American Heart Association found that an individual’s rest-activity rhythm may influence the risk of CVD,1 and this adds to existing research on the role of circadian rhythms and cardiometabolic health.

Circadian rhythms are the internal fluctuations in physiological and behavioral processes that evolved on a molecular level to synchronize our biological functions to the light-dark cycle of our environment.2 Rest-activity rhythms are the manifestation of circadian rhythms represented by someone’s daily 24-hour pattern of activity and rest, including sleep.1 The study included 4,521 adults, average age 49, who participated in one week of physical activity monitoring as part of the National Health and Nutrition Examination Survey (NHANES). The researchers found that 37% of those who had better-than-average rest-activity rhythms had high blood pressure and 6% had CVD, compared with 50% and 13%, respectively, for those who had lower-than-average rhythms.

Nour Makarem, PhD, an assistant professor of epidemiology at Columbia University’s Mailman School of Public Health in New York City, and the study’s lead author, says the findings suggest that a greater day-to-day variability in sleep-wake and rest-activity patterns and a later, less restful, and inefficient sleep period are associated with higher odds for heart disease and its risk factors. She also authored a 2021 study that analyzed data from the American Heart Association’s Go Red For Women Strategically Focused Research Network at Columbia University Irving Medical Center. This study, she says, was the first US study to show specifically that greater day-to-day variability in eating timing patterns and weekday-weekend differences (ie, “eating jet lag”) are also associated with increased cardiometabolic risk.3 “My research on eating timing patterns shows that a greater proportion of daily caloric intake consumed in the evening is associated with greater odds of cardiometabolic diseases such as hypertension, type 2 diabetes, and obesity,” she says.

In the last decade, evidence from several observational studies shows a link between circadian disruption and cardiometabolic diseases,4 and there’s been a similar increase in research on eating timing and health.5 How do the two intersect?

Circadian Alignment and Misalignment
The key to circadian rhythms are “clock genes,” which keep the central pacemaker clock in the suprachiasmatic nucleus (SCN) in the brain’s hypothalamus running according to an individual’s personal chronotype, or individual variation in the preferred timing of the sleep-wake cycle.2,6 Areas controlled by the central clock include the nervous system, core body temperature, blood pressure, secretion of melatonin, cortisol, growth hormones, and sleep/wake cycle. The central clock also drives the rhythmic activity of peripheral clocks—molecular clocks present in nearly all cells and tissues in the body—which determine daily variations in blood pressure, heart rate, insulin release and sensitivity, nutrient absorption, and exercise capacity, just to name a few physiological functions.2

Makarem says the primary mechanism linking the timing of eating and other behavioral factors to CVD risk is circadian misalignment, which refers to a mismatch between lifestyle behaviors and innate circadian rhythms, leading to a state of metabolic dysfunction characterized by glycemic dysregulation, higher blood pressure, hormonal imbalances, and greater risk for weight gain. She also says later irregular eating and sleeping patterns disrupt the synchrony of peripheral clocks in organs involved in metabolism with the central clock in the brain, which leads to impaired glucose control, increased insulin levels, insulin resistance, and a glucose response that mimics a prediabetic state. This can also elevate blood pressure by modulating the autonomic nervous system and reducing melatonin secretion.

Martin Young, DPhil, a professor of medicine and vice-director for research in the division of CVD at the University of Alabama, Birmingham, says circadian misalignment can happen when peripheral clocks are telling the wrong time of day relative to each other, or to the environment. “If you consider the body a little bit like a machine, you have to have all the components in alignment so that they work properly. If you have misalignment, then the whole thing kind of falls apart and the machine simply doesn’t work because the cogs don’t align. In biology, that’s true as well, because these organs talk to each other, and one organ will produce signals, nutrients, or hormones that the other organs have to respond to in a temporally appropriate manner.”

For example, Young says heart function dramatically increases upon waking in the morning, in terms of the speed and force of its contractions. “In the early hours of the morning before you’re successful in finding food, you have to meet that increased energetic demand,” he says. “Organs like the liver and the adipose tissue have to provide nutrients to the heart so it has the fuel that it needs at that time of the day. That’s an example of an alignment inside the body.”

In terms of alignment outside the body, exposure to light is the strongest factor for entraining, or synchronizing, the body with its environment. “It will reset your clock in your brain, then that clock sends out signals to help reset the rest of the clocks in your body,” Young says. “It’s a very nice system, but you can bypass this entire light system by changing your behavior.” He points to a second entrainment factor—food intake.

Young says in studies where researchers force the misalignment of these entrainment signals—participants are exposed to light and then eat 12 hours later—they find that some organs get confused because they perceive both signals and get pulled in opposite directions, resulting in lower amplitude oscillations, or variations, in the organ’s daily rhythmic pattern.

He gives the example of skipping breakfast and lunch, and then eating dinner at 8 or 9 pm. The brain will still be entrained with the light-dark cycle, he says, but many of the peripheral clocks won’t be. “If you eat at the wrong time of the day, those clocks will ignore, to a certain extent, the light signal and instead will entrain or reset to the food intake pattern,” he says. “That’s a big problem because your brain thinks it’s one time of day, but the other organs in your body think it’s a different time of day. And so now you have this internal misalignment of your biological clocks.”

A 2023 study used repeated 24-hour dietary records to estimate meal timing and number of eating occasions for 103,389 adults in the NutriNet-Santé study, which was set up to investigate the relationship between nutrition and health. Researchers found that having a later first meal of the day, a later last meal, and/or a shorter overnight fast were associated with a higher risk of CVD, especially among women. Each hour of delay in having the first meal of the day was associated with a 6% higher risk of overall CVD. Compared with having a last meal before 8 pm, eating a last meal after 9 pm was associated with a 28% higher risk of cerebrovascular disease. Each hour of additional nighttime fasting was associated with a 7% lower risk of cerebrovascular disease. Participants eating later meals also tended to consume more alcohol—and have more binge drinking episodes—as well as report later bedtimes and have more erratic meal timings across the week.7

The Role of Robust Rhythms and Anticipation
One of the factors that Makarem’s study looked at was the robustness of individuals’ daily and weekly rhythms. A robust rhythm has greater amplitude in its oscillations, and Young says we can encourage this by pairing light exposure with food and activity. Specifically, by eating something within two hours—within 60 to 90 minutes would be ideal—of waking and becoming exposed to light. “If you can try your best to align the light signal, the activity signal, and also the food signal after you’ve had this period of sleep when you had no light, no food intake, and no physical activity—other than moving around in your sleep—the body won’t get confused. You’ll now have all of these signals telling the body it’s time to wake up. That will help to make sure all the clocks in the body are aligned and that you’re also aligned with the environment. It really ensures that you get robust high amplitude transitions in all the organs and that their timing is the same.”

When the body’s internal clocks become desynchronized from the light-dark cycle, it can have negative effects on health. Many people experience this in a short-term way when they travel across multiple time zones and experience jet lag—their central clock takes time to entrain to a new light-dark cycle, and until that happens, they’re in circadian misalignment. Tightly controlled studies in laboratory settings have demonstrated that forcing people into circadian misalignment affects how their bodies use energy and increases blood pressure.1 Irregular sleep and eating schedules can also affect how the body uses calories, contributing to weight gain, type 2 diabetes, and CVD.2

For instance, “Shift workers are exposed to light at night and they eat at night, therefore the robustness of their oscillation decreases,” Young says. “Unfortunately these individuals have increased risk of all kinds of cardiometabolic diseases. They also have increased risk of cancer and increased gastrointestinal problems and cognitive dysfunction. It’s terrible circadian misalignment.”

The clock system runs on a 24-hour cycle that prepares the brain and other tissues to perform very different and often incompatible functions at appropriate times by anticipating the light-dark cycles and shifting the body’s energy consumption and expenditure accordingly.2,8 Young says the body’s ability to correctly anticipate events such as sleep/wake, light/dark, and feeding/fasting cycles is critical.

“What would your life be like if you didn’t know what time of day it was? It would be very dysfunctional, and the same is true biologically. Biologically, these clocks in the body allow cells to prepare before a major daily event happens,” Young says. “Our biological processes won’t just adapt to these events. It’s not that you wake up and then your metabolism changes—metabolism changes before you wake up to prepare the organs in advance.” He says when someone wakes up, eats, engages in physical activity, or has a stressful work conversation at a time of day when the heart and other organs aren’t anticipating those behaviors, they respond inappropriately. This can force organs out of alignment with each other or with the environment, and trigger an increase in blood pressure, nutrients, or hormone secretion that is unhealthy simply because of its timing. “That’s probably why circadian misalignment is extremely detrimental in terms of cardiovascular disease.”

Recommendations for RDs
What the growing body of research on circadian rhythms and cardiometabolic health suggests is that certain aspects of modern life—increased freedom to work remotely and access to on-demand streaming entertainment 24/7—may contribute to circadian misalignment through their potential to destabilize our rest-activity rhythms. The freedom to work in the evening, stay up late binge-watching our favorite streaming show, and keep irregular mealtimes may ultimately not be in patients’ or clients’ best interests.

It’s also important to note that a 2021 study using NHANES data on 8,200 adults found that rest-activity rhythm patterns vary significantly based on sex, age, and race/ethnicity. For example, women had a stronger, more stable, and less-fragmented rest-activity rhythm than men, Hispanic participants had the strongest, most stable, and least fragmented rhythm pattern, while Black participants had the weakest and most unstable rhythms.9 This means that awareness of client demographics may likely play an additional role.

A 2023 study using NHANES data found that eating fewer than three times per day and having a nighttime fasting duration of less than 10 hours or more than 14 hours were each associated with an increased risk of cardiovascular and all-cause mortality. Participants with a longer fasting duration tended to eat their last meal of the day earlier, which could be positive, but they also tended to eat their first meal later, which could be detrimental. Those with a short overnight fast ate breakfast early and dinner late. Participants who ate fewer than three meals per day tended to have irregular mealtimes, which could make it difficult for the body to prepare for nutrient influx.10

Makarem says later-day and irregular eating and sleeping timing patterns have been linked to systemic inflammation and alterations in gene expression and the microbiome, which could predispose patients to cardiometabolic disease. These patterns have also been linked to poorer mental health, including depression and unhealthful eating behaviors such as higher intake of fats and sugar. She says her team’s research hasn’t found the timing of physical activity influences cardiometabolic risk, but there’s emerging evidence that earlier timing of physical activity may be beneficial. Her study noted that a more active wake period is related to lower cardiovascular risk consistent with the results of studies aimed at increasing daytime physical activity. This includes “formal” exercise as well as reducing sitting time and incorporating small bouts of movement into daily routines.

If a patient or client’s daily rhythms are irregular, and they have the capacity within their work-life schedule to make changes, behavioral counseling could involve adding more activity during the day and improving sleep habits. If a client struggles with sleep and circadian rhythm disruptors such as insomnia or night eating syndrome, you can refer them to appropriate providers. That’s in addition to counseling on nutrition and a consistent eating schedule.

In a 2023 review, Young wrote that when making nutrition recommendations for prevention or treatment of cardiovascular conditions, it might be that it’s not only the foods and nutrients that matter, but also the timing of their delivery. Our biological clocks determine how the body responds to food intake, and research is finding that shifting caloric intake to earlier in the day may help reduce the risk of hypertension, dyslipidemia, type 2 diabetes, and adverse cardiovascular events.11

“Clinicians should, of course, emphasize the importance of eating a heart-healthy diet, getting enough sleep, and being physically active,” Makarem says. “Based on research so far, it does seem that recommending earlier and consistent eating and sleep timing schedules throughout the week could have important heart health benefits. Therefore, addressing the ‘when’ to eat and sleep could enhance the effectiveness of interventions addressing the ‘what or how much’ to eat or sleep, but more research is needed.”

— Carrie Dennett, MPH, RDN, is the nutrition columnist for The Seattle Times, owner of Nutrition By Carrie, and author of Healthy for Your Life: A Non-Diet Approach to Optimal Well-Being.

References
1. Makarem N, German CA, Zhang Z, et al. Rest-activity rhythms are associated with prevalent cardiovascular disease, hypertension, obesity, and central adiposity in a nationally representative sample of US adults. J Am Heart Assoc. 2024;13(1):e032073.

2. Allada R, Bass J. Circadian mechanisms in medicine. N Engl J Med. 2021;384(6):550-561.

3. Makarem N, Sears DD, St-Onge MP, et al. Variability in daily eating patterns and eating jetlag are associated with worsened cardiometabolic risk profiles in the American Heart Association Go Red for Women Strategically Focused Research Network. J Am Heart Assoc. 2021;10(18):e022024.

4. Ansu Baidoo V, Knutson KL. Associations between circadian disruption and cardiometabolic disease risk: a review. Obesity (Silver Spring). 2023;31(3):615-624.

5. Mentzelou M, Papadopoulou SK, Psara E, et al. Chrononutrition in the prevention and management of metabolic disorders: a literature review. Nutrients. 2024;16(5):722.

6. Zou H, Zhou H, Yan R, Yao Z, Lu Q. Chronotype, circadian rhythm, and psychiatric disorders: recent evidence and potential mechanisms. Front Neurosci. 2022;16:811771.

7. Palomar-Cros A, Andreeva VA, Fezeu LK, et al. Dietary circadian rhythms and cardiovascular disease risk in the prospective NutriNet-Santé cohort. Nat Commun. 2023;14(1):7899.

8. Hastings MH, Maywood ES, Brancaccio M. Generation of circadian rhythms in the suprachiasmatic nucleus. Nat Rev Neurosci. 2018;19(8):453-469.

9. Li J, Somers VK, Lopez-Jimenez F, Di J, Covassin N. Demographic characteristics associated with circadian rest-activity rhythm patterns: a cross-sectional study. Int J Behav Nutr Phys Act. 2021;18(1):107.

10. Cheng W, Meng X, Gao J, et al. Relationship between circadian eating behavior (daily eating frequency and nighttime fasting duration) and cardiovascular mortality. Int J Behav Nutr Phys Act. 2024;21(1):22.

11. Young ME. The cardiac circadian clock: implications for cardiovascular disease and its treatment. JACC Basic Transl Sci. 2023;8(12):1613-1628.