Circadian Blood Pressure Rhythm in Cardiovascular and Renal Health and Disease

Circadian rhythm refers to an endogenous biorhythm with a 24 h cycle driven by an intrinsic and periodic molecular clock that adjusts behavior and physiological activities to external environmental changes [1,2]. In mammals, the master pacemaker located in the suprachiasmatic nucleus (SCN) of the hypothalamus elaborately controls the peripheral clocks in other tissues to ensure the synchronization of all existing clocks [3,4]. As is shown in Figure 1, the molecular circadian clock in mammals is driven by interactional transcription-translation auto-regulatory feedback loop with a subset of core clock genes including Bmal1 (brain and muscle aryl-hydrocarbon receptor nuclear translocator-like 1), Clock (circadian locomotor output cycles kaput), Per1/2/3 (period1/2/3) and Cry1/2 (cryptochrome1/2). BMAL1 and CLOCK proteins collectively form a heterodimer to bind on E-box elements in promoter regions of clock-controlled genes (CCGs) including several important genes related to cardiovascular and renal function [5,6]. When the accumulation of PER and CRY proteins is fully superfluous in the cytoplasm, both of them translocate to the nucleus where shut down the transcription of heterodimeric activator [7]. In addition, nuclear receptors ROR (RAR-related orphan receptor) activates and REV-ERB (nuclear receptor subfamily 1, group D) suppresses RORE (ROR element) to directly control Bmal1 and Clock transcription [8]. Moreover, another nuclear receptor PPARγ integrated in this loop is also a target gene of BMAL1 by directly binding to PPRE (PPAR response element) in its promoter [9]. Particularly, all of dynamic but coordinated PPAR isoforms displayed diurnal expression at different time point in mouse tissues [10]. It is estimated that almost 10–15% of the gene transcripts in the heart and kidney are under circadian transcriptional control [11].

Emerging evidence indicates that most cardiovascular and renal functional fluctuations are evolutionarily controlled by circadian clocks. BP, which is crucial to cardiovascular and renal health, displays obvious circadian rhythm with nocturnal dip and morning surge in both human and rodents [12]. The circadian pattern of BP can be affected by many factors.

For instance, melatonin, secreted from the pineal gland at night, may significantly reduce nocturnal BP and improve sleep in patients with essential hypertension [13]. Rhythmicity of atrial natriuretic peptide (ANP) appeared to be in antiphase with BP rhythm, which has been proven to serve as an important regulatory factor of the 24 h BP pattern and affect the cardiovascular system [14]. Circadian rhythms of plasma renin activity (PRA), angiotensin converting enzyme (ACE) activity, concentration of AngII, aldosterone and thyroid hormone contribute to the maintaining 24 h BP rhythm as well [15,16,17,18,19]. In addition to hormones, blood vessel components, such as smooth muscle cells and endothelial cells, and many vasoactive substances can change the diurnal variations of BP. Typically, nitric oxide (NO) secreted from endothelial cells modulates vascular tone and thus BP. NO production is increased in the morning, followed by a morning surge in BP. Yet, whether the diurnal variation of NO is directly related to BP rhythmicity is in debate. Disruption of the diurnal oscillation of NO production has been closely connected with BP alterations in cardiovascular disease [20]. Furthermore, endothelial NO synthase (eNOS) is one of the three NO synthase enzymes, which produce NO in blood vessels and regulate vascular function. In animal studies, the phosphorylated-eNOS (p-eNOS) in the blood vessels of young mice exhibited a circadian rhythm. The core clock genes can also regulate the coupling of eNOS and contribute to the maintenance of rhythmicity of endothelial function and BP [21]. Similarly, although 3.5-day rhythm and 8-hourly change have been reported in the human circulation [22], the secretion of endothelin 1 (ET-1) in plasma and excretion in urine has been also pronouncedly confirmed to be circadian rhythmic and closely related with BP homeostasis [23,24,25]. ET-1 receptor antagonists had been proved to be efficient for the treatment of essential hypertension, however, significant fluid retention and edema side effects were also reported [26]. Besides the above, there are many other endogenous factors contribute to the 24 h BP oscillations through humoral, endocrine, neural or other coordinated regulation signals. Furthermore, some diseases can alter the 24 h BP rhythm. For instance, patients with obstructive sleep apnea (OSA) are more likely to have non-dipper BP, which will increase the incidence of cardiovascular events [27].

For exogenous aspect, growing studies have revealed that the sleep patterns may have significant effects on BP day-night profile [28]. For instance, people with sleep disturbance or circadian misalignment by shift work and social jet lag often suffer from hypertension [29], BP phase delay [30], abnormal rhythm of melatonin secretion [31] or increased high-sensitivity C-reactive protein [32]. Furthermore, although our own studies have illustrated that the diurnal rhythms of BP are subject to more direct control by the clock than behavior, at least under basal conditions [33,34]. The most recent study, however, found that the timing of food intake can entrain the diurnal BP rhythm independent to Bmal1 and the light-dark cycles [35]. In addition, the rhythm of BP can be affected by temperature, noise and many other environmental factors [36,37,38].

As mentioned above, the circadian rhythm of BP is driven by a complicated molecular clock network. Growing evidence from rodents has found that the circadian rhythms of BP can be distinctly altered by genetic manipulation of the core clock genes (Table 1).

BP rhythm is one of the most common circadian rhythms in the cardiovascular system [65]. Disruption of the BP rhythm has been considered to be a major contribution to many adverse cardiovascular events. It has been found that every 5% drop in the decline in nocturnal BP may increase the risk of cardiovascular death by about 20% [66].

Myocardial infarction (MI) is an acute heart disease, which can be complicated by arrhythmia, shock or heart failure, and is life-threatening. There is an inseparable connection between the rhythm of BP and MI. Abnormal BP circadian patterns or chronic hypertension may lead to changes in cardiac hemodynamics, and increase the incidence of MI [67]. Several Clinical studies have proved that the incidence of MI is rhythmic and significantly increased incidence rate was usually observed between 06:00 am and 12:00 pm which is somehow consistent to the BP morning surge. As for systolic BP, lower (<100 mm Hg) in post-MI period increase the risk of cardiovascular events, while patients with elevated systolic BP (>140 mm Hg) have a higher risk of stroke and combined cardiovascular events [68]. Compared with resting systolic BP, systolic BP after exercise can provide higher predictive value for acute MI [69]. In terms of diastolic BP, acute myocardial infarction (AMI) patients with lower diastolic BP (<70 mmHg) have increased postoperative risks, including all-cause death, cardiovascular death and cardiovascular hospitalization. Moreover, wide pulse pressure was also considered as a predictor of MI [70]. Furthermore, several core clock genes are considered as important components in regulating the rhythmic pathogenesis of MI. There is an association between MI and Clock and Arntl (also known as Bmal1) gene polymorphisms [71], and the genetic variants of Arntl, Clock and Per2 genes are proved to be related to circadian phenotype (i.e., chronotype or daytime sleepiness) in patients with MI [72].

Under the condition of heart failure with preserved ejection fraction, the increased variability of systolic and diastolic BP is related to the increase of adverse events [73]. Concurrently, abnormal systolic BP and diastolic BP can cause the variation of heart indicators. As the systolic BP increases, the left ventricular wall thickness and left ventricular mass index also increase with the higher diastolic BP; while the functional index of left ventricular diastolic function is inversely proportional to the increase of diastolic BP, but irrelevant with systolic BP [74]. Overall, there is a U-shaped relationship between systolic BP and heart failure, that is, lower or higher systolic BP will lead to higher risk of death and heart failure hospitalization [75]. The same phenomenon exists in diastolic BP [76]. Therefore, when diagnosing MI and related cardiovascular events, it is necessary to comprehensively consider the phenotype and rhythms of BP.

Given the significant correlation between acute cardiovascular events and BP rhythms, it is necessary to improve the therapeutic strategies according to the characteristics of circadian rhythm changes. In addition to optimizing the drug administration time, it has been reported that the time of cardiovascular surgery may have influences on the tissue repair and outcome of cardiovascular diseases as well. For example, although the most recent studies demonstrated that the time-of-day variation of aortic valve replacement surgery had no significant impact on clinical outcomes and had no clinically relevant biorhythm for myocardial ischemia-reperfusion tolerance [77,78,79]. Montaigne et al. did have reported that the incidence of major adverse cardiac events in the afternoon surgery group was significantly lower than that in the morning group [80]. More interestingly, in patients undergoing non-cardiac surgery, Lavallaz et al. found that the incidence of AMI during follow-up is instead increased in the afternoon surgeries [81]. Nevertheless, a better understanding of the relationship between circadian clock and cardiovascular disease may help to develop more targeted and personalized treatment strategies for patients.

Chronic kidney disease has long been closely linked with sleep disturbance and hypertension and thus gradually become a worldwide health problem with a great economic burden [82,83]. In humans, accumulating clinical evidence indicated that blunted BP variation from 24 h BP recordings was associated with increased risk of end-organ damage and progressive loss of renal function [84,85]. Predictably, the consistency of circadian BP variation was ruined in chronic kidney disease stages 3–5 [86]. In addition, among patients with chronic kidney disease, circadian BP profile is closely related to the level of physical activity and the severity of target organ damage [87]. Moreover, clinical trials indicated that circadian BP profile is associated with mortality among elderly veterans with chronic kidney disease [88]. Meanwhile, the nocturnal dip in BP is nearly diminished in patients with glomerulopathy, resulting in enhanced urinary excretion rate of sodium and protein during the inactive phase [89].

To date, an explicit mechanism has not been expatiated between chronic kidney disease and disruption of circadian BP rhythm. In rodent models, studies have found that after treatment with adenine for 2 to 4 weeks to induce chronic kidney disease in mice or Sprague–Dawley rats, the animals will display significantly increased arterial BP and disrupted day-night variation [90]. In addition, the SCN of PER2::LUC mice with adenine-induced chronic kidney disease displayed dampened amplitude rhythms in their central circadian clock as measured by bioluminescence. Meanwhile, the kidney explants from chronic kidney disease mice expressed altered PER2::LUC rhythms with significantly longer period compared to control mice [91]. On the other hand, upon adenine treatment, Clock mutant mice showed significantly higher BP and worse renal function than control mice, implying the circadian BP disruption enhances the susceptibility to chronic kidney disease [91]. However, our own recent study found that postnatal Bmal1 deletion in mice protected against renal fibrosis via suppressing Gli2 transcription, which provides a prominent role of the core clock gene Bmal1 in tubulointerstitial fibrosis [92]. Nevertheless, more efforts need to be made from different point of view to further clarify the relationship between circadian BP disruption and chronic kidney diseases.

Altered day-night oscillation in BP has been associated with high morbidity and mortality of cardiovascular disease and increased progression of kidney damage. Of note, non-dipping hypertension is frequently observed in clinical outcomes of chronic kidney disease and associated with increased risk of cardiovascular event [93]. While an excessive circadian variation in BP is also associated with an increased risk of nephropathy [94,95]. Thus, the application of anti-hypertensive drugs, including angiotensin-converting enzyme inhibitors (ACEI), angiotensin II receptor blockers (ARB) and others, becomes fundamental to the prevention and treatment of many cardiovascular and renal diseases. The rational and effective administration time of these anti-hypertension medications has also been explored and reported in many clinical trials and animal studies.

Growing evidence indicates that the maintenance of BP circadian rhythm is highly associated with the cardiovascular and renal homeostasis, many anti-hypertension medications displayed clear circadian time-dependent efficiency and chronotherapeutic evaluation to the management of hypertension and the related cardiovascular and renal diseases had be taken into consideration for many studies. However, further research in this field still has to lay emphasis on accurate pharmacodynamics and pharmacokinetics of time-dependent administration by using novel compounds that modulate circadian timing system to superiorly prevent the onset and progression of hypertension and the related cardiovascular and chronic kidney diseases, which will provide a valuable and cost-benefit approach for BP control and potential merit of chronotherapy, as well as added systematic protection.

Moreover, the molecular link between the circadian BP regulation and cardiovascular and renal functions is still less known. RNA-seq analysis revealed that heart and kidney are two of the top five candidates along with the liver, lung and brown fat following obvious circadian regulation. However, the complexity of the cellular components and molecular network in the heart and kidney largely renders the mechanism exploration. Further study by tissue or cell specific depletion of the circadian genes in the heart and kidney may provide a better understanding of the relationship between BP rhythm and cardiovascular and renal function and pave a way for preventing the development of cardiovascular and renal diseases.

All authors have participated in the writing, review and editing of the manuscript. All authors have read and agreed to the published version of the manuscript.

This research was funded by National Key R&D Program of China (grant number: #2019YFA0802400) and National Natural Science Foundation of China (grant number: 32071157 and 31871190).

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The authors declare no conflict of interest.