Cardiovascular diseases (CVDs) are one of the leading causes of death worldwide, and one of the most significant risk factors for CVD is high blood pressure (1, 2). Blood pressure exhibits a circadian rhythm, rising from morning to afternoon and dipping at night (3). Mammals are under the control of this circadian rhythm, a rhythm of ~24 h, and the circadian clock mechanism plays an important role in physiological functions such as sleep/wakefulness, hormone secretion, and metabolism (4–6). In organs such as the kidney, peripheral clocks generate physiological rhythms (7). The circadian rhythm of blood pressure is driven by a complex molecular network of clock genes, and alterations in blood pressure rhythm from genetic manipulation of various clock genes have been reported in rodent studies (8). Mice lacking one of the core clock genes, Cryptochrome-1 and Cryptochrome-2, show salt-sensitive hypertension due to abnormally high synthesis of the mineral corticoid aldosterone, indicating a potential link between disturbances in the circadian rhythm and hypertension (9). Individuals with disrupted clocks, such as shift workers, showed higher blood pressure and a higher prevalence of CVDs (10). In patients with hypertension, loss of the day-night rhythm of blood pressure has been reported (11).

The blood pressure is well-controlled by urine and sodium excretion through the Na/K reuptake mechanism located in the renal tubule (12). Excess sodium intake and insufficient potassium intake have been shown to result in high blood pressure (13, 14). To observe the joint effects of sodium intake and potassium intake, the use of the sodium-to-potassium ratio (Na/K ratio) has been proposed in various studies. The Na/K ratio has been reported to show a stronger association with blood pressure than with sodium or potassium alone (15). Other nutrients have also been reported to be associated with hypertension. High cholesterol levels are known to cause arterial stiffness and arteriosclerosis, and systolic pressure is influenced by arterial stiffness (16). In addition, the benefits of dietary fiber intake on blood pressure have been reported (17). Reducing alcohol consumption lowers the blood pressure in a dose-dependent manner (18). Therefore, it is important to focus on various nutrients to prevent high blood pressure.

From transcriptome and metabolome analyses of human blood and tissue samples, it has been reported that circadian rhythms also exist in food digestion, absorption, and metabolism (8, 19). “Chrono-nutrition” is the study focusing on the intake timing of nutrients. There have been reports showing that nutrients show more health benefits depending on the intake timing (20). Catechin suppressed the elevation of postprandial glucose more effectively when taken in the evening than in the morning (21). Continuous beginning of the active phase administration of sesamin and episesamin improved lipid metabolism compared to administration at the end of the active phase (22). Morning intake of fish oil, which is abundant in docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), suppressed serum triglyceride levels and decreased serum total saturated fatty acids and serum n-6 polyunsaturated fatty acids (23). Thus, it is important to consider not only what to eat but also when.

As previously stated, the association between blood pressure and the circadian clock has been suggested in various studies. Furthermore, the metabolism and excretion of nutrients associated with blood pressure exhibit a circadian rhythm. The excretion of sodium and potassium by the kidneys is controlled by the circadian timing system (24). Cholesterol metabolism also exhibits a 24-h rhythm (25). The influence of eating patterns and meal timings on blood pressure has also been suggested. Consuming meals irregularly has been suggested to be adversely associated with cardiometabolic risk, including blood pressure (26). Later lunch compared to the conventional Australian mealtime pattern showed higher blood pressure in women (27). Compared to breakfast eaters, elevated blood pressure was observed among female chronic breakfast skipping groups (28). Reversed feeding completely reversed the blood pressure rhythm in mice (29). These finding suggest that considering the prevention of high blood pressure from a “chrono-nutrition” point of view may be important.

According to the National Nutrition Survey in Japan (NNSJ) in 2019, compared to the estimated average requirement, the average intake of sodium and saturated fat is excessive, while that of potassium and dietary fiber is insufficient (30). Proposing the intake timing would be an effective way to approach the discrepancy between the actual and recommended intake of these nutrients. However, research focusing on blood pressure and the timing of intake of various nutrients has not been conducted. In this study, we aimed to investigate the relationship between dietary data of nutrient intake in three meals and blood pressure among ~2,400 users of “Asken,” a mobile health application for dietary management.

In this study, we investigated the association between blood pressure and different nutrient intake timing among mobile health app “Asken” male and female users. Our findings confirm previous findings that high Na/K ratio, high lipid intake, high alcohol intake, and low dietary fiber are associated with high blood pressure (15, 17, 18). However, little is known about the influence of intake timing. Our research provides new perspectives on the prevention of hypertension and has shown that various nutrients are associated with blood pressure at different meal timings. In both males and females, lunch and snack Na/K ratio, dinner energy, dinner lipid, and dinner saturated fatty acids showed a meal-specific positive association with blood pressure, and breakfast protein, lunch potassium and lunch dietary fiber showed a meal-specific negative association with blood pressure after eliminating the confounding factors.

From previous studies, dietary records collected by Asken have been reported to be an effective method for estimating the energy and nutrient intakes of Japanese women (31). As stated, the nutrition amount resembles the data calculated from the NNSJ (30) (Supplementary Figure 1 and Shinto et al.). Focusing on sodium and potassium, dinner sodium intake was lower and potassium intake was higher, resulting in a lower dinner Na/K ratio than that of NNSJ (Supplementary Figure 2). This can be explained by the characteristics of the Asken users. With the aim of losing weight, Asken users have higher health consciousness and high self-efficacy (38).

Our results showed that blood pressure had a strong positive association with the Na/K ratio, especially the lunch and snack Na/K ratio. In addition, the negative correlation of lunch potassium shows that promoting excretion of sodium is important for lowering blood pressure at lunch time. Sodium and potassium urine excretion has been previously reported to exhibit circadian rhythm, which is explained by the rhythm of aldosterone (24). Aldosterone, a mineralocorticoid that through ENaC is responsible for the reabsorption of Na and the increase in K secretion through K channels in the distal nephron, has also been reported to exhibit rhythm, low at nighttime and high in the morning (39). Therefore, intake of sodium at dinner time may be excluded in urine, even though sodium intake and the Na/K ratio were high in the dinner. Several previous studies have demonstrated higher excretion of sodium and an increase of Na/K ratio in the evening than in the morning and afternoon (24).

Potassium and dietary fiber are both rich in vegetables. Lunch fiber and potassium intake showed a negative correlation with blood pressure in the current experiment, suggesting the intake of more vegetables at lunch and snack time to protect higher blood pressure. Higher blood pressure has been reported to be associated with lower gut microbiota alpha diversity in many human cross-sectional studies (40). A low intake of dietary fiber leads to reduced microbial diversity (41). Inulin, a water-soluble dietary fiber, has been reported to have greater positive effects on the microbiota in the morning than in the evening (42). Taken together, these results suggest that dietary fibers, especially at lunch and breakfast time, may be more helpful than at dinner time to protect higher blood pressure through an increase in microbial diversity. These results have suggested the importance of vegetables in the prevention of hypertension in a time-specific manner. Vegetables are also known to include many dietary polyphenols such as flavonoids, and their treatment or prevention of hypertension (43). As previously stated, catechin, a type of flavonoid, suppressed the elevation of postprandial glucose more effectively when taken in the evening than in the morning, suggesting that the metabolic response of polyphenols may depend on their intake timing (21). Dietary polyphenols' health promoting effects are reported to be in a hormetic dose-response manner, partly via the upregulation of Nrf2 pathway (44–47). Therefore, in addition to the analysis of nutrients that we have conducted, analysis of the intake timing and volume of dietary polyphenols may provide a clearer view.

Furthermore, breakfast protein was negatively correlated with blood pressure. The beneficial effect of proteins on blood pressure is small, according to previous studies (48). However, a high-protein breakfast has been suggested to accelerate overloading-induced skeletal muscle hypertrophy in mice and have greater skeletal muscle volume in human studies (49). It has also been revealed that breakfast and lunch proteins have a strong positive association with daily physical activity (unpublished observation), and recent studies have supported the role of physical activity in the prevention of hypertension (50). Therefore, the relationship between morning protein intake and exercise may explain its negative correlation with blood pressure. As clinical trials of food-protein-derived peptides in the management of hypertension have been published (51), we should examine the detailed information of protein compositions (cereals, beans, vegetables, fruits, meat, fish milk, egg, etc.) in future experiment.

Dinner cholesterol and saturated fatty acids were positively correlated with blood pressure. A high dinner energy also showed a positive correlation. It is well-known that a high intake of cholesterol and saturated fatty acids causes progression of arteriosclerosis and higher blood pressure (52, 53). However, we do not know the true reason why dinner time intake of these nutrients and energy are related to high blood pressure. As cholesterol synthesis in the body is high in the evening, cholesterol intake and synthesized cholesterol may cooperatively promote arteriosclerosis progression. The intake of saturated fatty acids and energy at dinner time cannot be consumed as an energy source because of sleep. Excess circulation of triglycerides and fatty acids may accelerate the progression of arteriosclerosis (53).

High energy intake and lipid intake at dinner are reported to lead to obesity, which is known to be strongly associated with blood pressure (16). In the present study, we found a positive relationship between BMI and blood pressure. However, the correlation of energy/lipid at dinner time was still observed when eliminating the obesity factor in the present experiment. It has been reported that early time-restricted feeding, with dinner before 3 pm, led to lower blood pressure without inducing weight loss (54). This study, along with our present data, strongly suggests that taking energy/lipid-rich dinner at an earlier clock time may prevent higher blood pressure. As it is well-known that hypertension is related with seriousness of diabetes and dyslipidemia, we should investigate the relationships between intake of Na, K lipid, and saturated fatty acids and these diseases in future. In the current experiment, we have not asked if participants had these diseases or not.

There are some limitations to our study. First, the dietary data were collected through self-reports by the subjects, and this self-reporting may have resulted in self-efficacy. Previous studies have discussed that self-monitoring results in behavioral changes (34). The second is blood pressure measurement. Blood pressure was reported by the participants themselves, and this may cause some inaccuracy in the data. We also could not measure the blood pressure at the same time. For more precise data, blood pressure needs to be measured at a standardized time, such as in the morning 1 h after awakening and in the evening before going to sleep according to the Japanese Society of Hypertension have presented in the guidelines for home blood pressure measurement (55). Third, only systolic blood pressure has been reported because many Japanese are unconcerned about their diastolic blood pressure. As both systolic and diastolic blood pressure are used for hypertension diagnosis, in future research, both systolic and diastolic blood pressure should be investigated. Fourth, we could not check the intake timing of snack, however similarity to lunch Na/K ratio suggests many participants may take snack at afternoon. Fifth, the characteristics of the participants being highly health-conscious may have affected the results. Lastly, we could only investigate saturated fatty acids this time, but by looking at the amount of DHA and EPA that work in suppressing arteriosclerosis, we would have been able to have a better understanding.

We analyzed the relationship between the intake timing of nutrients and blood pressure. In both males and females, a positive association between meals and blood pressure was observed in the Na/K ratio (lunch), energy (dinner), lipid (dinner), and saturated fatty acids (dinner). Moreover, a meal-specific negative association with blood pressure was seen in protein (breakfast), potassium (lunch), and dietary fiber (lunch). Our study provides possibilities to prevent hypertension by changing the timing of various nutrient intakes, especially sodium together with potassium and lipids. However, an intervention study to investigate the effect of the timing of each nutrient on blood pressure needs to be conducted in the future.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

This experiment was approved by the Ethics Review Committee on Research with Human Subjects at Waseda University (No. 2020-046) and followed the guidelines laid down in the Declaration of Helsinki. The patients/participants provided their written informed consent to participate in this study.

MI, HS, YT, TS, SM, MK, AT, NA, MM, and SS designed the research and analyzed the data. MI and SS wrote the manuscript. All authors contributed to the article and approved the submitted version.

This research was funded by the Japan Society for the Promotion of Science (JSPS) KAKENHI (Kiban A) and the JST-Mirai Program (Grant Number: JMPJM120D5) by SS.

MM is a corporate officer in Asken Inc. AT and NA are employees of Asken Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.