Appropriate Circadian-Circasemidian Coupling Protects Blood Pressure from Morning Surge and Promotes Human Resilience and Wellbeing

Plain Language Summary

Blood pressure measurements obtained every 30 minutes for 7 days from 239 adults, 23 to 74 years of age, are analyzed for their daily variation, with usually lower values during nightly sleep and higher values during the active daytime. The daily blood pressure pattern mostly stems from two components with periods of 24 and 12 hours (changes recurring every day and half a day). We define the concept of “circadian-circasemidian coupling” to capture the timing relation between these two components. We show how this relation affects the development of a morning or evening elevation in blood pressure, and how these features relate to a person’s physical health, resilience and wellbeing.

Introduction

Resilience, the ability to adapt to stress in daily life, is important for wellbeing, life satisfaction and health.^1–6 As often reported in previous investigations,^7–14 blood pressure (BP) variability is involved in the appraisal of threat and safety, and can serve as a potential marker of psychological resilience against stress. BP variability (BPV), including its circadian rhythm,^15–19 reflects the status of one’s continued adjustment to stress from daily life in response to constantly changing environmental demands. Claude Bernard enunciated this bidirectional heart-brain connection, which was confirmed by Thayer and Lane.²⁰

The circadian system plays a key role of resilience in the adaptation to a novel environment.^21–31 New evidence suggests that harmonic components of the 24-hour rhythm provided an evolutionary advantage for almost all life forms, from bacteria to humans.^32–34 In particular, the 12-hour (circasemidian) rhythm may be important for the rapid adaptation to a novel environment. We reported that the 12-hour response to the space environment appeared faster and was larger than the circadian response to it.³⁵ Prevalent 12-hour gene expression and metabolic rhythms were found by others in mouse liver, coupled with a physiological 12-hour unfolded protein response oscillation. Most 12-hour rhythms are reportedly regulated by a distinct and cell-autonomous pacemaker that includes the unfolded protein response (UPR) transcription factor spliced form of XBP1 (XBP1s) that can be entrained in vitro by metabolic and endoplasmic reticulum (ER) stress cues.^36–39 The ER functions to properly fold and process secreted and transmembrane proteins. ER stress refers to the accumulation of misfolded and unfolded proteins in the ER lumen, which occurs when ER function is disrupted by environmental and genetic factors.⁴⁰ The 12-hour rhythm could thus be first to respond to ER stress when faced to a novel environment to secure wellbeing and psychological resilience in humans. However, it is not clear yet whether coordination between circadian and cirasemidian rhythms plays an important role in the adaptation to a new environment, and, if so, how it contributes to human health. While recognizing the potential role of the circasemidian clock in regulating human diseases,³⁸ how to harness the temporal dynamics between circadian and circasemidian rhythms for chronodiagnosis and/or chronotherapy⁴¹ largely remains to be investigated.

Over the past 30 years, we have investigated the merits of long-term BP monitoring to assess human health, including wellbeing and vascular disease risk. We documented the predictive value of mapping chronomes (rhythms, chaos and age trends) based on 7-day/24-hour BP monitoring.^42–62 Since functional MRI showed that higher psychological resilience relates to harmonic oscillations with frequency-specific subcomponents of several brain regions,⁶³ harmonic 24-hour and 12-hour oscillations of BP may reflect human resilience and wellbeing, the topic of this investigation.

Subjects and Methods

Study Participants

Initially, 371 citizens were recruited to participate in a 7-day/24-hour chronobiologic BP screening as part of a community-based comprehensive medical assessment. All participants were residents of Tosa, a rural Japanese town in Kochi Prefecture. They took part in free health screening, counseling and educational services offered by the town’s office, from which we obtained their medical history, medications, and latest laboratory data. Among the 371 citizens, 239 (147 women), 23 to 74 years of age, satisfied the inclusion criteria for this study, as they did not take any anti-hypertensive medication and completed 7 days of BP monitoring. This study was approved by the Medical Ethics Committee of the Tokyo Women’s Medical University as Clinical Study #2912, titled “Health assessment of community-dwelling elderly in Japan”. A detailed explanation of the study protocol was given to the study participants before they gave written, informed consent. The study complies with the Declaration of Helsinki Principles.

7-Day/24-Hour Chronobiologic Blood Pressure Screening

Noninvasive ambulatory BP monitoring (ABPM) was performed using an oscillometric device (TM-2431, A&D Co., Tokyo, Japan) to record systolic (S) and diastolic (D) BP and heart rate (HR). As reported earlier,^50–52 BP was measured oscillometrically every 30 min from 07:00 to 22:00 and every 60 min from 22:00 to 07:00 for 7 consecutive days. At the town’s office, all participants were fitted with a monitor and asked to revisit the office 7 days later. Participants were taught how to attach and remove the recorder and were instructed to remove the recorder while taking a bath. They were asked to keep a diary noting the times they went to sleep and woke up. Stored data were retrieved on a personal computer using commercially available software (TM-2430-15, A&D Co., Tokyo, Japan). Bracketing the 7-day ABPM, home BP measurements were collected for 30 days, taken twice a day, in the morning upon getting-up and in the evening just before going to bed, in a sitting position after resting for 1 min.

Circadian Parameters of BP and HR

Each record was analyzed by the Maximum Entropy Method (MEM), using the MemCalc/Win software (Suwa Trust GMS, Tokyo, Japan)⁶⁴ to estimate the circadian period of SBP, DBP, and HR. The period was determined as the inverse of the frequency corresponding to a peak in the MEM spectrum located in the vicinity of 1/24 (h⁻¹). Missing data were linearly interpolated prior to analysis. Next, 24-hour and 12-hour cosine curves were fitted independently to each record by cosinor^61,65,66 to estimate the MESOR (Midline Estimating Statistic Of Rhythm, a rhythm-adjusted mean) and the amplitude and acrophase of each cosine curve. The acrophase is defined as the phase of the maximum assumed by the fitted cosine curve in relation to local midnight, used as reference time, as reported earlier.^57–61 The morning surge in SBP was defined as the difference between SBP at the time corresponding to the 12-hour morning acrophase and the SBP MESOR (24-hour average of the 7-day/24-hour record). Likewise, the evening surge in SBP was defined as the difference between SBP at the time corresponding to the 12-hour evening acrophase and the SBP MESOR.

Assessment of Citizens’ Resilience

Since circadian disruption could impair the health of citizens and lead to cardiovascular, metabolic and psychiatric disorders, cancer and cognitive decline in the aged, we examined whether circadian misalignment of BP, assessed by the circadian-circasemidian coordination of SBP, could account for the morning or evening surge in BP and the psychophysiological health status of the participants. ABPM results are associated with sleep duration and sleep quality, including time of getting-up and its variability over 30 consecutive days, time to fall asleep, and answer to the question “do you feel tired getting up in the morning?”. We also estimated wellbeing based on scores (0 to 15) from the Geriatric Depression Scale 15 (GDS15)^50,51,60,61 and on scores (0 to 100) from the Visual Analogue Scale (VAS),^50,51,60,61 which includes items such as subjective health, mood, good relation with family and friends, economic satisfaction, life satisfaction, and happiness. Finally, several laboratory examinations provided general health information, including fasting blood glucose, uric acid, total cholesterol, LDL-cholesterol, HDL-cholesterol, triglycerides, cardio-ankle vascular index (CAVI)⁶¹ and ankle brachial index (ABI).⁶¹

Classification of Citizens Based on Circadian-Circasemidian SBP Coupling

Circadian-circasemidian coupling is defined as the time difference between the circadian acrophase and the morning acrophase of the 12-hour component. The circadian-circasemidian coupling was individually determined for SBP by fitting to the 7-day/24-hour SBP data a two-component model consisting of cosine curves with periods of 24 and 12 hours by cosinor.^61,65,66 The 239 participants were equally divided into three groups: Group A had a short coupling; Group B an intermediate coupling; and Group C a long coupling.

Statistical Analysis

Data are expressed in terms of the mean ± SD. Between-group differences for continuous variables are assessed using unpaired Student’s t-tests with Bonferroni correction for multiple comparisons. Categorical data are compared using the chi-squared test. Linear regression analysis was performed for assessing changes as a function of age and relations of psychophysiological variables as a function of the circadian-circasemidian coupling of SBP. The Stat Flex (Ver. 6) software (Artec Co., Ltd., Osaka, Japan) was used. Differences with P-values less than 0.05 are considered to indicate statistical significance.

Results

Example of 7-Day/24-Hour ABPM Record

Currently, 24-hour ABPM is considered a gold standard, reserved for special cases of high BP, but its time structure is only interpreted in terms of 24-hour, daytime and nighttime means. General reliance upon a single measurement, or even a single 24-hour profile of BP, however, was referred to as “flying blind”.⁶⁷ Long-term BP monitoring, analyzed time-structurally (chronomically, from chronome = time structure), detects physiological–physical interactions. Even within the conventionally accepted normal range, vascular variability disorders (VVDs) have been associated with a statistically significant increase in risk. Long-term chronobiologically interpreted ABPM (C-ABPM) records help to “know ourselves”, serving for relief of psychological and other strain once transient VVDs are linked to the source of a load, prompting adjustment of one’s lifestyle for strain reduction.⁶⁸

One study participant’s record of SBP, DBP and HR is shown in Figure 1. He did not take any anti-hypertensive medication. His office BP was 155/94 mmHg and his home BP measurements averaged over 30 days were 113.4/70.8 mmHg (morning) and 105.7/58.5 mmHg (evening). The 7-day/24-hour MESOR (midline estimating statistic of rhythm) estimates of SBP, DBP, and HR were 114.6 mmHg, 71.4 mmHg and 74.1 bpm, respectively. The MEM spectrum showed a prominent circadian component with a period of 24.51 hours, together with three smaller peaks at periods of 11.43 (circasemidian), 92.74, and 142.66 hours.

Figure 1 Example of 7-day/24-hour ABPM. Time plots of the 7-day/24-hour records of systolic blood pressure (SBP, thick continuous line), diastolic blood pressure (DBP, thin continuous line), and heart rate (HR, dashed line) of a 40-year old man with white-coat hypertension. When the 7-day/24-hour ABPM was started at 11:00 in front of a doctor, high SBP on the first day of monitoring can readily be seen. Measurements dropped thereafter within the normal range, where they fluctuated periodically, following a circadian rhythm, suggesting a regular rest-activity schedule.

Changes with Age in Circadian and Circasemidian Rhythm Characteristics Assessed by 7-Day/24-Hour ABPM

The MESOR of SBP increased with age (P = 0.0014), while the MESOR of HR decreased with age (P = 0.0082). While the circadian and circasemidian amplitudes of SBP did not change with age, the circasemidian amplitude of DBP decreased with age (P = 0.0033). The circadian amplitude of HR increased (P = 0.0060) but its circasemidian amplitude decreased (P = 0.0002) with age. The period of the circadian, circasemidian, and circaoctohoran components of SBP, estimated by MEM, averaged 24.03±0.49, 12.08±0.85, and 8.13±0.68 hours, respectively, and did not change statistically significantly with advancing age in either gender.

Noteworthy are phase advances of the circadian rhythm in SBP (P < 0.0001), DBP (P = 0.0001) and HR (P = 0.0060) with increasing age. A similar phase advance with age characterizes the circasemidian component of SBP (P = 0.0081) and DBP (P = 0.0138), but not that of HR.

Effects of the Circadian-Circasemidian Coupling on Citizens’ Resilience

Resilience to daily life stress, wellbeing, and life satisfaction may be reflected in BPV, notably in the coordination between circadian and circasemidian rhythms, akin to the bidirectional heart-vessel-brain connection proposed by Claude Bernard and Thayer and Lane.²⁰ To check this proposition, we evaluated citizens’ resilience by assessing their circadian-circasemidian coupling of SBP. We found that, as compared to citizens of Group B, the average morning SBP surge was larger in citizens of Group A (14.29 vs 10.82 mmHg, P < 0.001), who had a shorter coupling interval (example shown in Figure 2, left). Likewise, as compared to citizens of Group B, the average evening SBP surge was larger in citizens of Group C (15.21 vs 11.86 mmHg, P < 0.001), who had a longer coupling interval (example shown in Figure 2, right) (Table 1). Moreover, a shorter circadian-circasemidian coupling of SBP is associated with a larger morning SBP surge in the 183 participants in Groups A-C for whom a morning surge was detected (Table 1, Figure 3, left). A longer circadian-circasemidian coupling of SBP is also associated with a larger evening SBP surge in 187 participants in Groups A-C for whom an evening BP surge was detected (Table 1, Figure 3, right).

Table 1 Effects of Circadian-Circasemidian Coupling of Systolic Blood Pressure on Results from 7-Day/24-Hour ABPM, Wellbeing and Psychological Resilience

Figure 2 Examples of 7-day/24-hour ABPM from one citizen in Group A and one in Group C. Left: record from Group A citizen who has a short phase difference of about 4.5 hours between the circasemidian morning acrophase and the circadian acrophase of systolic blood pressure. Right: record from Group C citizen who has a long phase difference of about 7.0 hours between the circasemidian morning acrophase and the circadian acrophase of systolic blood pressure. Corresponding 2-component models show the presence of a morning BP surge in Group A citizen (left bottom), and of an evening BP surge in Group C citizen (right bottom).

Figure 3 Relation between circadian-circasemidian coupling of SBP and morning SBP surge (left), or evening SBP surge (right). Left: Shorter circadian-circasemidian couplings of SBP are associated with larger morning SBP surges. Right: Longer circadian-circasemidian couplings of SBP are associated with larger evening SBP surges.

No statistically significant differences were found among Groups A, B and C in terms of sleep duration, time of getting-up and its variability over 30 consecutive days (assessed by the standard deviation, SD), time to fall asleep, or answer to the question “do you feel tired getting up in the morning?”. These results indicate that the circadian-circasemidian coupling of SBP did not affect sleep quality in this population. Comparing all three groups, we found that a short circadian-circasemidian coupling of SBP (Group A) was associated with a lower score of wellbeing on the GDS15 and VAS scales (good relation with friends, P = 0.0278). Moreover, a long circadian-circasemidian coupling of SBP (Group C) was also associated with lower scores of wellbeing on the GDS15 and VAS scales (life satisfaction, P = 0.0164; happiness, P = 0.0302). Considering all eight wellbeing variables listed in Table 1, scores of Group B citizens who had an intermediate coupling are on average higher than scores of Group A (short coupling; paired t = 2.862, P = 0.024) or Group C (long coupling; paired t = 2.377, P = 0.049) citizens. Measures of wellbeing in Groups A-C show a bell-shaped distribution in response to the circadian-circasemidian coupling of SBP, where responses appear only in a certain range of stimuli (so-called “windows”), as proposed by Murase⁶⁹ (see Figure 4).

Figure 4 Bell-shaped distribution of resilience measures follows grouping by circadian-circasemidian coupling of SBP (Groups A, B, and C). An intermediate circadian-circasemidian coupling interval of systolic blood pressure (SBP) (Group B) corresponds to the distribution peak, suggesting that it may promote psychological resilience, as gauged by life satisfaction (left) and subjective happiness (right).

Aging effects on the circadian or circasemidian acrophase of SBP differed among the three groups. As shown in Figure 5 (top), the circadian acrophase of SBP advanced with age statistically significantly in all three groups. The circasemidian acrophase, however, only advanced with age in Group B (P = 0.00021) and even more so in Group C (P = 0.00032) (Figure 5, bottom). As a result, aging effects on the circadian-circasemidian coupling interval of SBP differed among the three groups (Figure 6, top). In Group A, the circadian-circasemidian coupling interval shortened with age (P < 0.00001), whereas in Group B it did not change, and in Group C it tended to lengthen with age (P = 0.18618). When participants of Groups A, B and C were classified into young (<50 years), middle-aged (50~65 years) and elderly (>65 years), the morning SBP surge in Group A was less pronounced in younger participants than in middle-aged (P = 0.0444) and the elderly (P = 0.0463) (Figure 6, bottom left). No difference with age in the extent of the evening SBP surge was found in either group.

Figure 5 Effect of age on circadian and circasemidian acrophases of systolic blood pressure (SBP) in Groups A, B and C. The circadian acrophase of SBP advances with age statistically significantly in all three groups. The circasemidian morning acrophase of SBP also advances with age statistically significantly in Groups B and C, but not in Group A.

Figure 6 Effect of age on circadian-circasemidian coupling interval of SBP (top) and extent of morning and evening SBP surge (bottom) in Groups A, B and C. Top: The circadian-circasemidian coupling interval of SBP becomes even shorter with advancing age in Group A, and it tends to become even longer with advancing age in Group C, thereby exacerbating the morning or evening SBP surge. By contrast, there is no change with age in the circadian-circasemidian coupling interval of SBP in Group B. Bottom: Participants of each Group were further subdivided into three age groups: Young (<50 years), Middle-aged (50~65 years) and Old (>65 years). Whereas there was no significant change in evening SBP surge as a function of age in any of the three groups, the morning SBP surge increased in middle-aged (P = 0.0444) and elderly (P = 0.0463) as compared to young participants, observed only in Group A (bottom left).

State of Health Influencing Citizens’ Resilience

Among Group A participants (with a short circadian-circasemidian SBP coupling), those with a longer coupling interval are closer to citizens of Group B and have a less pronounced morning SBP surge (Figure 3, left and Table 1, left), suggesting that they may also have a better resilience. As seen from Table 2 (left), we indeed found by linear regression that Group A citizens with a longer coupling interval have a larger circadian amplitude of SBP (r = 0.2984, P = 0.0068) and DBP (r = 0.4112, P = 0.0001), a lower nighttime SBP (r = −0.4152, P = 0.0003), and a deeper SBP nightly dip (r = 0.4319, P = 0.0001). They also have higher HDL-cholesterol (r = 0.2819, P = 0.0473), lower CAVI (r = −0.5574, P = 0.0001), and lower fasting blood glucose (r = −0.3621, P = 0.0325). Their longer circadian period of SBP (r = 0.2467, P = 0.0274) and larger circadian phase delay of SBP (r = 0.5251, P < 0.0001) and DBP (r = 0.3148, P = 0.0042) may have contributed to promote resilience, as seen from their higher score of happiness (r = 0.2319, P = 0.04380). Increasing age, however, is associated with a shorter coupling interval (r = −0.5231, P < 0.0001).

Table 2 Difference in Resilience Assessed by 7-Day/24-Hour ABPM, Sleep, Wellbeing and Laboratory Examinations Related to Circadian-Circasemidian Interval of Systolic Blood Pressure (SBP) Between Group A and Group C Participants

Among Group C participants (with a long circadian-circasemidian SBP coupling), those with a shorter coupling interval are closer to citizens of Group B and have a less pronounced evening SBP surge (Figure 3, right and Table 1, right), suggesting that they may also have a better resilience. As seen from Table 2 (right), we indeed found by linear regression that Group C citizens with a shorter coupling interval have a larger circadian amplitude of DBP (r = −0.2600, P = 0.0169), a lower nighttime SBP (r = 0.3671, P = 0.0013) and a deeper SBP nightly dip (r = −0.4770, P < 0.0001). Their shorter circadian phase delay of SBP (r = 0.3293, P = 0.0022) and DBP (r = 0.2401, P = 0.0278) may have contributed to promote resilience, as seen from their higher score of economic satisfaction (r = −0.2637, P = 0.0338), life satisfaction (r = −0.3158, P = 0.0110), and happiness (r = −0.3234, P = 0.0059).

Discussion

We previously found that an amplified 12-hour (circasemidian) rhythm could help consolidate the circadian system and contribute to a rapid adaptation to microgravity in space.³⁵ Namely, we reported that spaceflight upregulated the 12-hour rhythm, closely cross-talking with the circadian clock, contributing to an amplified circadian rhythm, and switching to an “alerted mode” in space, which also amplified 8-hour, 6-hour, 3-hour and 90-min harmonics, extending adaptive reactions up to 12-months in space.³⁵ Most life on Earth is governed by biological rhythms that are defined as self-sustained oscillations, cycling with a specified period.^70–75 Circadian disruption can lead to cancer, cardiovascular, metabolic, and psychiatric disorders, and to cognitive decline in the aged. Alteration of the 12-hour component related to cardiovascular dysfunction⁷⁶ indicates that the 12-hour component may be important for human health.

Following the pioneering study by Hughes et al,³² a series of studies by Pittsburgh’s group identified a cell-autonomous 12-hour oscillator of nuclear speckle liquid–liquid phase separation dynamics in mammals,^39,41,77 which regulates 12-hour rhythms of systemic gene expression and metabolism, independently from the 24-hour circadian clock. These studies enabled the formulation of novel hypotheses that the biological 12-hour component could play an important role not only in the adaptation to space,³⁵ but also in the adaptation to everyday physiology by adjusting to recurring daily changes in the external environment.^74,77

Herein, we investigated how the biological 12-hour rhythm of SBP can help citizens in a community adapt to recurring daily changes in the external environment with help from the circadian clock. The relationship between BP rhythms and citizens’ resilience was cross-sectionally assessed by a 7-day/24-hour chronobiologic screening of a rural Japanese community, focusing on the 12-hour component and the circadian-circasemidian coupling of SBP. The 239 residents ranging in age from 23 to 74 years who participated in the study were free of anti-hypertensive medication and fully completed their 7-day/24-hour ABPM. We showed that both a morning and an evening SBP surge stemmed from an inappropriate coordination between the 24-hour and 12-hour rhythmic components of SBP. Citizens of Group A who had a short coupling interval had a circasemidian morning acrophase preceding the circadian acrophase by about 4.5 hours, which induced a morning BP surge in all 81 citizens. Moreover, the shorter the circadian-circasemidian coupling of SBP was, the larger was the morning SBP surge in 183 participants from all three groups (Figure 3). These findings may be relevant to residents’ resilience in terms of both health and wellbeing, as suggested from associations summarized in Table 2. These results are in agreement with those of many other investigations. An abrupt and dramatic morning BP surge is a predictor of cardiovascular events, including chronic kidney disease independently of ambulatory BP values and nocturnal BP falls. They also indicate that a larger morning BP surge is associated with an exaggerated risk of cardiovascular diseases and mortality.^{52,55,78–84}

Results herein suggest that a circadian-circasemidian SBP coupling interval of about 6.0 hours (ranging from 5.67 to 6.5 hours) may be optimal, protect from a morning or evening BP surge, and promote resilience and wellbeing. Indeed, when the circadian-circasemidian coordination is appropriate, the biological clock is reinforced and the SBP surge in the morning or evening is less pronounced (morning surge in Group B vs Group A: 10.82 vs 14.29, P < 0.0001; evening surge in Group B vs Group C: 11.86 vs 15.21 mmHg, P < 0.0001). The incidence of a morning or evening SBP surge was also less frequent in Group B than in Group A (P < 0.0001) or in Group C (P < 0.0001) (Table 1). Overall, wellbeing and psychological resilience assessed by good relation with friends (P < 0.05), life satisfaction (P < 0.05), and subjective happiness (P < 0.05) were also highest for citizens of Group B than for citizens in Group A or Group C (Table 1).

The biological 12-hour rhythm reflects both the function of “endogenous endoplasmic reticulum (ER) stress and unfolded protein response (UPR^ER) cycle” and the reaction of “mitochondrial stress response pathway and unfolded protein response (UPR^mt)”, which can protect cells from widespread proteome stress in both central and peripheral tissues.^{32,37–39,41,77,85–87} An XBP1s-SON axis implies a cell-autonomous 12-hour rhythm of nuclear speckle liquid–liquid phase separation (LLPS) dynamics.^41,88 A large protein called Son is essential for appropriate subnuclear organization of pre-mRNA splicing factors and for promoting normal cell cycle progression.^89,90 An evolutionarily conserved XBP1s-SON axis coordinates a rapidly functioning feedforward loop connecting nuclear speckle LLPS and proteostasis, resulting in a highly efficient genetic information transfer functioning at multiple temporal scales. At the molecular level, it modulates the rates of chemical reactions; at the mesoscale, it organizes large structures within cells; and at the cellular level, it facilitates the localization of cellular materials and homeostatic responses.^41,88,91 Previously, we noted that both ER hormesis and mitohormesis are known to positively associate with adaptation to novel environments, stress resistance, anti-aging and longevity,^92–96 and that this may be why the biological 12-hour rhythm was first activated, to consolidate a stronger circadian system in space. Whether a similar mechanism may account for results herein that relate to the adaptation to everyday physiology responding to the challenges of everyday life requires further investigation.

Several factors are associated with a BP surge, such as neurohormonal changes, notably the activation of the sympathetic nervous system,^54,61 a depressive mood,^50,51,60 acceleration of physical activity, sleep problems, smoking, bathing⁶¹ or drinking habits.^{52,62,81–83} Baross et al⁸⁴ reported that practical lifestyle interventions are effective in markedly reducing the morning BP surge that might lower the incidence of adverse cardiovascular events, which often occur in the morning. Our results herein also suggest that practical lifestyle interventions to lower BP, dyslipidemia, arteriosclerosis and a depressive mood (Table 2) could counteract adverse effects from disrupted biological rhythms, a sub-optimal circadian-circasemidian coupling in particular.

Conclusion

The 12-hour rhythm may provide an evolutionary advantage^{34,36,41,67–69} as it may be even more ancient and having evolved earlier than the circadian clock: 12-hour clock genes are conserved in even more divergent species.⁸⁹ Hence, assessing whether the circadian-circasemidian coupling is optimal or not, ie, dynamically balancing interactions with circadian and ultradian oscillations could play an important role in improving the health of citizens. The idea of Dion et al⁴¹ to prepare an atlas at the molecular level of four-dimensional (spatial and temporal) maps of biological processes to improve human health could detect unidentified chronotherapeutic targets for pathologies associated with disrupted biological rhythms. Our results herein support Dion’s idea of four-dimensional integrative medicine. It could be achieved by means of precision medicine based on chronomodecine and chronomics medicine, including an assessment of the circadian-circasemidian coupling in concert with 8-hour, 6-hour, 3-hour, and 90-min harmonics of the circadian rhythm^{23,27,35,38,41,68,74} to optimize their constellation. Devising a new approach focused at least on circadian-circasemidian coordination could be the first step as it offers great promise for achieving properly timed rhythms and lead to overall resilience as part of a precision chronomics medicine.^{15,18,19,21,22,31,61,97}