Chrono‐nutrition for hypertension

Despite the advancement in blood pressure (BP) lowering medications, uncontrolled hypertension persists, underscoring a stagnation of effective clinical strategies. Novel and effective lifestyle therapies are needed to prevent and manage hypertension to mitigate future progression to cardiovascular and chronic kidney diseases. Chrono‐nutrition, aligning the timing of eating with environmental cues and internal biological clocks, has emerged as a potential strategy to improve BP in high‐risk populations. The aim of this review is to provide an overview of the circadian physiology of BP with an emphasis on renal and vascular circadian biology. The potential of Chrono‐nutrition as a lifestyle intervention for hypertension is discussed and current evidence for the efficacy of time‐restricted eating is presented.

are particularly important as they provide the time cues for the regulation of our central and peripheral clocks.Indeed, the time of feeding/eating is a well-established zeitgeber and as such, Chrononutrition is emerging as a potential lifestyle intervention for disease prevention.Therefore, the purpose of this review is to discuss what is currently known about the potential of chrono-nutrition for the prevention and management of hypertension, with a focus on renal and vascular circadian physiology.

| RENAL AND VASCULAR CONTRIBUTORS TO BLOOD PRESSURE REGULATION
BP is physiologically regulated through complex integrative system modulation of cardiac output and total peripheral resistance.Two important systems that are implicated in BP control, the kidney and the vasculature, will be highlighted in this review.The kidney functions to regulate electrolyte and fluid retention that contribute to changes in BP.When blood volume or serum sodium concentrations are too high, renal function is altered to increase fluid and sodium excretion.Alternatively, fluid and sodium are retained when blood volume or sodium concentrations are low.Subsequent changes in plasma volume have a direct impact on BP.
In addition to renal regulation of electrolyte and fluid volume, the vasculature also plays an integral role in BP regulation by transiently modulating total peripheral resistance.Disease or negative lifestyle behaviours can provide chronic stressors that induce vascular dysfunction. 11Vascular endothelial dysfunction and arterial stiffness are hallmark characteristics of impaired vascular function that result in vessels being less adept at responding to changing physiological needs.Indeed, this vascular dysfunction contributes to the pathophysiology of hypertension over time. 12,13| OVERVIEW OF CIRCADIAN RHYTHMS

| Molecular control
The molecular clock is composed of two regulatory feedback loops (Figure 1). 14,15The positive arm involves two transcriptional activators, brain and muscle ARNT-like protein 1 (BMAL1) and circadian locomotor output cycles protein kaput (CLOCK) that initiate their cycle at circadian dawn. 15BMAL1 and CLOCK form heterodimers in the cytoplasm and enter the nucleus where they bind to the circadian cis enhancer box (E box) sequence of promoters of the Period (PER1, PER2, and PER3) and Cryptochrome circadian regulator (CRY1, 2) genes. 15Once transcribed, PER and CRY proteins accumulate over 12 h and dimerise to form a complex. 16The PER-CRY complex subsequently translocates back into the nucleus where they accumulate to repress their own transcription by inhibiting CLOCK-BMAL1. 15 addition to the positive and negative arms of circadian gene transcription, accessory feedback loops are involved in the regulation of transcription factors and circadian clock mRNA. 16To regulate BMAL1, CLOCK-BMAL1 binds to promoters of genes that encode the retinoic acid-related orphan nuclear receptors, REV-ERBα and RORα that repress and activate BMAL1, respectively. 17,18These two elements compete for the retinoic acid-related orphan F I G U R E 1 Positive and negative feedback loops regulating circadian gene expression.
receptor element in the BMAL1 promoter to stabilise the feedback loop and drive circadian behaviour. 18These feedback loops generate transcription cycles with phases of expression that depend on the combination of elements in the promoters and enhancers of specific target genes. 19[22]

| Central clock control
Circadian rhythms are the 24-h oscillations in biological functions, primarily controlled by the suprachiasmatic nucleus (SCN), the central clock regulator within the hypothalamus. 15Light cues entrain the circadian rhythm as the SCN receives direct photic input from intrinsically photoreceptive retinal ganglion cells. 23,24The SCN functions as a neural network of ~200,000 neurons that oscillate together 25 to control the expression of downstream genes 26 and synchronise circadian rhythms of peripheral tissues. 27

| Peripheral tissue clock control
8][29][30] The peripheral clocks are largely controlled by the central clock and are typically delayed 3-9 h from the SCN rhythms due to delays from transcription and protein translation. 31However, peripheral tissues have also been shown to operate independently from the SCN when removed from central clock control 27,32 and can also be entrained by local mechanisms. 33In this respect, non-photic extracellular systemic cues such as exercise and food intake can mediate peripheral circadian rhythms independent of the central clock. 26Thus in summary, peripheral oscillators are affected by the SCN's autonomic neural influences [34][35][36][37][38] in addition to regulation from external cues such as activity or food timing, independent of light/dark cues.

| Blood Pressure
The normal circadian rhythm of BP starts with an initial rise in the morning, called the morning surge. 8Upon awakening, the morning surge is characterised by a sharp rise in BP that, if exacerbated, can elevate the risk of hypertensive episodes, myocardial infarction, and stroke in the morning hours. 8Following the morning surge, BP is maintained throughout daylight hours, peaks in the late afternoon, and decreases in the evening, followed by a trough in the middle of the night 8 (Figure 2).Typically, a 10%-20% reduction in BP at night occurs in healthy individuals.Individuals who do not experience at least a 10% reduction in nighttime BP are termed non-dippers. 8In addition to the dipper and non-dipper classifications of nighttime BP, supplementary BP dipping phenotypes have been established to further classify nighttime BP changes.The classification as an extreme dipper refers to a >20% reduction in BP at night and reverse dipper refers to a nighttime increase in BP compared to daytime values. 8Throughout the nighttime dip, BP is lowest and highest during deep and light sleep, respectively. 39e circadian rhythms of BP are predominantly influenced by light and dark cues and are controlled by both the SCN and peripheral clock regulators.In pre-clinical studies, global deletion of the circadian clock repressors, CRY1 and CRY2 , results in salt-sensitive hypertension, suggesting a need for circadian control for optimal BP regulation. 40In support of this, global PER2 knockout (KO) mice demonstrate a reduction in BP dipping. 41The circadian rhythm of BP is controlled through various physiological mechanisms under clock control.Autonomic nervous system (ANS) modulation of the circadian rhythm of BP is driven by day and night alterations in plasma dopamine, epinephrine, and norepinephrine concentrations. 42,43ecifically, norepinephrine has a 24-h variation controlled by an endogenous circadian clock. 44Plasma levels of norepinephrine and epinephrine are highest from morning to early afternoon when BP is near or at peak values, and plasma levels are lowest during nighttime sleep 42,45 (Figure 2).In addition, the ANS influences BP regulation through increased parasympathetic activity at night 46 (Figure 2).
Renal sodium handling contributes to BP regulation through modulation of fluid volume and electrolytes by the rhythmicity of the renin-angiotensin-aldosterone system (RAAS) and the endothelin system, both of which are discussed in more detail later in this review. 39In addition, inappropriate regulation of renal sodium transporters and channels by the circadian clock also results in abnormal sodium handling and BP 47,48 (Figure 3).In this respect, abnormal rhythm of renal sodium reabsorption is one of the factors leading to the loss of nocturnal dipping of BP characterised in 35% of patients with hypertension. 49,50Participants with non-dipping BP in this cohort excreted three times less sodium during the day compared to nighttime and had higher pressures during the day and night compared to individuals who had high daytime sodium excretion. 49renal hormones also play an important role in the circadian rhythm of BP.In healthy individuals, aldosterone and cortisol levels increase in the morning, thus contributing to the morning surge 51 (Figure 2).Cortisol is modulated by adrenocorticotropic hormone (ACTH), which is under SCN control and drives the circadian rhythm of cortisol in combination with the sympathetic nervous system (SNS). 524][55] ACTH and ACTH-dependent cortisol production contribute to variation in cardiac output and therefore BP without an influence on peripheral resistance. 56,579][60] The impact of the adrenal gland on circadian rhythms has been further explored in adrenal specific BMAL1 KO mice. 61These mice displayed BOHMKE ET AL. activity and BP rhythm periods that were shortened by 1 hour. 61rthermore, the peaks in BP and activity rhythms were delayed by two and 3 hours respectively. 61These mice also had altered eating behaviour with a reduction in nighttime food intake and an increase in daytime intake. 61These data confirm a regulatory role of adrenal BMAL1 in BP rhythms and eating behaviour.
In addition to hormonal control of BP, blood-volume alterations contribute to circadian rhythmicity. 62,63At night, there is an increase in peripheral blood flow associated with the decline in body core temperature. 62,64,65The nighttime redistribution of blood flow shifts fluid from central to extracellular compartments resulting in a reduction of plasma volume 66,67 and contributing to BP decline. 62ring early morning sleep stages, blood flow is redistributed to the core, promoting a rise in body core temperature that is part of morning arousal. 68

| Renal function
The circadian rhythm of kidney function was initially investigated in humans under controlled conditions with the observation of rhythm in urine flow, pH, and electrolyte excretion peaking in the waking hours 69 (Figure 2).Renal excretion rhythms were later deemed to be independent of activity and food timing after examining the rhythm of potassium excretion in males in a constant supine position who were provided a controlled liquid diet. 70Further studies have implicated the circadian clock in renal function, demonstrating rhythmic fluctuations in glomerular filtration rate (GFR), 71 sodium excretion, 47 and renal blood flow over the 24 h day. 72Renal blood flow, GFR, urine volume, and urinary excretion of sodium, potassium, and chloride have circadian rhythmicity with peaks in the early afternoon and early evening that are independent of meal timing, activity level, sleep, and posture. 73,74Renal blood flow, vascular resistance, and GFR decline at night.Interestingly, the circadian rhythm of GFR operates independently of BP oscillations and SNS activity. 75nal excretory rhythms are driven by circadian changes in filtration and tubular reabsorption 75,76 (Figure 3).Sodium reabsorption is controlled by rhythmic sodium transporter expression along the nephron that contributes to oscillations observed in BP and urine output. 9The proximal tubule expresses an apical sodium hydrogen exchanger (NHE3) and sodium-glucose transporter 1 (SGLT1) that are both clock controlled. 9,77,78PER1 has been shown to regulate the expression of NHE3 and SGLT1 in the mouse renal cortex and human proximal tubule cells. 77In the loop of Henle, the clock regulates the expression of NKCC2 and oestrogen receptor beta (ERβ). 78,79ERβ expression increases with hypoosmolality to stimulate vasopressin F I G U R E 2 Circadian rhythms of BP.Rhythms are included for the nervous system and renal and vascular factors possibly influencing the circadian rhythm of BP.BP, blood pressure.release 80 , while NKCC2 functions to reabsorb sodium to aid increases in fluid volume. 81In the distal convoluted tubule, sodium reabsorption occurs primarily through the sodium chloride cotransporter (NCC). 9NCC and the kinase regulating its expression, have been shown to be controlled by the circadian clock; however, the timing of peak transcription and expression have not been investigated. 82,83A small percentage of highly regulated sodium reabsorption occurs at the distal convoluted tubule. 9Sodium entry is controlled by the apical epithelial sodium channel (ENaC), and the alpha subunit of ENaC and other regulators in the collecting duct have been linked to the clock. 47,48,84Gene transcription within the distal convoluted tubule and collecting ducts in mice have shown 24h circadian rhythmicity, 84 specifically the vasopressin V2 receptor and aquaporin RNA have exhibited maximal expression in the active period. 84[86][87][88] BP is controlled in part by RAAS hormone actions involved in the modulation of sodium and water reabsorption. 9In this regard, BP control is regulated by hormone secretion of angiotensin II, 89 aldosterone, 90 vasopressin, 91 angiotensin-converting enzyme, 92 and plasma renin activity, 89,90 which are all in phase with the plasma sodium circadian rhythm, with peaks in the active phase. 9The circadian rhythms of plasma renin and angiotensin II concentration exist in the absence of a sleep/wake cycle, as observed in sleep-deprived subjects. 93The peak of aldosterone occurs in the first half of the active phase parallelling increases in GFR and filtered sodium load. 40,94,95The variation of plasma aldosterone is regulated by the ACTH circadian rhythm, which peaks in the middle and latter portion of sleep; however, during awake hours, RAAS predominantly mediates aldosterone levels. 58Exerting regulatory control on the RAAS and BP is the vasodilator atrial natriuretic peptide (ANP). 96ANP functions to suppress plasma renin, angiotensin II, aldosterone, and catecholamine concentrations, increasing sodium excretion. 97ANP rhythmicity is independent of posture, with peak concentrations occurring between 2300 and 0400 h.98 In nocturnal hypertension, ANP circadian rhythmicity is either altered or removed. 99Urodilatin, a compound similar to ANP with four additional amino acids, is secreted only in the kidney and further contributes to natriuresis and diuresis. 100When high BP is sensed, urodilatin inhibits sodium and water reabsorption and has been shown to have a maximal expression during the day. 101AS hormone regulation is partly mediated through dopaminergic mechanisms from the SNS. 102Dopamine is synthesised from cells in the proximal tubule and acts to inhibit sodium and water reabsorption when extracellular fluid is increased. 102,103Dopamine has not been shown to display a circadian rhythm under constant darkness, demonstrating that its expression is likely mediated by light/dark cues 78 ; however, circadian expression in the kidney has not been investigated.Vitamin D has also been shown to contribute to RAAS regulation.Although Vitamin D synthesis varies by season, F I G U R E 3 Renal sodium transporters by the nephron segment and their respective circadian rhythms.In the circadian rhythm figures, the yellow and grey boxes correspond to active and inactive periods, respectively.quantity and distribution of skin melanin, and exposure, circulating levels are typically highest during midday and early afternoon. 104e peptide endothelin-1 (ET-1) and its receptors ET A and ET B have a vasoactive function within the kidney that contributes to renal regulation of BP. 105 The renal ET-1 system is important to kidney function and overactivation leads to the development of renal disease that can contribute to hypertension development and progression.[106][107][108][109] The endothelin-1 gene (End-1) is controlled by the molecular clock with peaks in rhythmic expression in the kidney occurring during the active period.In the kidney, ET-1 increases natriuresis through ET B mediated inhibition of the ENAC sodium transporter.110,111 In this respect, disruptions in the ET-1 system have been shown to alter sodium handling rhythms, 112 promoting prolonged sodium retention that could contribute to non-dipping BP.
Circulating ET-1 has two peaks, one at 0800 and the other at 2000, with a trough at 1600 h. 113In patients with CKD, increased plasma levels of ET-1 at night are associated with a loss of nighttime BP dipping that could be partly mediated by vascoconstriction. 114The role of the endothelin system in BP rhythmicity is further supported by clinical trials in CKD demonstrating that ET A receptor blockade restores BP rhythms. 114

| Vascular function
Vascular function is regulated on a 24-h cycle.9][120][121] The circadian rhythms of endothelium-dependent and independent vascular function have also been examined by pharmacologic modulation with acetylcholine (ACh) and sodium nitroprusside (SNP), respectively.Microvascular EDD measured with a laser Doppler perfusion imager at the forearm during delivery of ACh by transdermal iontophoresis, mirror studies using FMD, with the greatest dilation at 1600 and the lowest at 0400 and 0800 h. 113ing a dose-response infusion of SNP, endothelium-independent dilation did not possess a circadian variation using the average of all four SNP doses; however, the highest dose of SNP had the same rhythm as EDD. 113Arterial stiffness is generally age-dependent and has been shown to progressively increase from morning to evening in patients with hypertension, with the highest measure at 2100 h. 121is is likely driven by BP rhythm as overall pulse wave velocity measures were not significant after adjusting for mean BP. 121 Potential differences in vascular function have been examined in individuals with appropriate nocturnal dipping compared with nondipping hypertension.Following intra-arterial infusion of ACh, the forearm blood flow response, measured by strain-gauge plethysmography, was impaired in non-dippers compared to dippers but not after administration of the endothelium-independent vasodilator isosorbide dinitrate, which suggests EDD dilation is impaired in non-dippers. 122Following intra-arterial infusion of N-Methylarginine, a nitric oxide synthase (NOS) inhibitor, the greater ACh-induced forearm blood flow response in dippers was abolished. 122Therefore, this evidence shows that vascular dysfunction is mediated by a reduction in nitric oxide bioavailability in individuals with nondipping hypertension. 122e circadian variation of NOS has been assessed in pre-clinical models.In this regard, with the use of phenylephrine, a potent alpha-1 agonist to initiate vessel constriction, a greater amplitude of contraction during the inactive period compared to the active period was observed. 123In this study, NOS inhibition by L-NG-Nitro arginine methyl ester resulted in greater phenylephrine-induced contraction that was not significantly different between the active and inactive periods.This suggests that there is greater NO bioavailability during the active period. 123This was supported by the measurement of endothelial NOS (eNOS) gene and protein expression in the mesenteric artery tissue with higher expression in the active period compared to the inactive period. 123The finding of increased eNOS expression in the active period has also been shown in the rat aorta. 124Dihydrofolate reductase, a molecule that recycles dihydrobiopterin to the eNOS cofactor tetrahydrobiopterin, has been shown to peak during the active period. 125,126In patients with myocardial infarction undergoing emergency percutaneous coronary intervention, asymmetric dimethylarginine, which competitively inhibits eNOS, peaks in the morning at 0600 and 1159 h.Asymmetric dimethylarginine reached an absolute peak between 0600 and 0759 h and preceded symptoms of myocardial infarction. 127 addition to NO, other antioxidants and free radicals have been shown to contribute to circadian variation in vascular function.The antioxidant melatonin has photic dependent circadian rhythm and can reduce free radicals and break down H 2 O 2 . 128Recently, in young healthy individuals, melatonin supplementation has been shown to improve nocturnal BP in the setting of a high sodium diet. 129scular sympathetic activity has been measured through the forearm blood flow response after alpha adrenergic sympathetic blockade and SNP at various times of day. 130The circadian variation in alpha-adrenergic activity mediated the phenomenon of higher vascular resistance and lower blood flow in the morning than at other times of the day. 130The time of day variation was not influenced by smooth muscle-mediated vasodilation which confirmed the contribution of alpha-adrenergic activity to be predominantly endothelial mediated. 130Increased sympathetic activity in the morning has also been shown with higher plasma catecholamine levels in the morning. 42,131ere are many factors that modulate the circadian rhythms of renal and vascular function that contribute or respond to changes in BP.Animal models have provided a wealth of knowledge regarding the timing of peaks in the expression within the circadian rhythm literature.Additional work is needed to have a greater understanding of circadian influences on BP in humans.Further translational research is needed to establish chronotherapy related treatment targets for hypertension.In this respect, pharmacological intervention for circadian disorders is rare; however, several molecules have been identified as potential therapeutic agents that warrant development and investigation for hypertension in pre-clinical trials. 132More importantly, robust clinical trials are warranted to comprehensively understand the influence of lifestyle factors on circadian BP rhythms, including but not limited to chrono-nutrition, exercise intervention and light therapy.

| SEX DIFFERENCES IN CIRCADIAN CONTROL OF BLOOD PRESSURE
Ambulatory BP was assessed in a cohort of 52,911 middle aged participants (45.6% male; 54.4% female) females and males. 133In this cohort, average 24-h, day, and nighttime, systolic blood pressure and diastolic blood pressure were higher in males compared to females. 133Females had a greater difference between day and night BP, whereas males were more likely to be non-dippers. 133The morning surge of BP was greater in males than in females. 133x differences in circadian gene expression have been observed in renal medulla cells in male and female C57BL/6 mice following a 0 potassium, high salt diet or control diet. 134Kidney medulla RNA samples were collected at 6 AM and 6 PM. 134BMAL1, CLOCK, CRY1, and PER1 were higher at 6 AM and 6 PM in females compared with males on a control diet. 134Sex differences in CLOCK and PER1 expression were lost on a 0% potassium, high salt diet. 134BMAL1 expression decreased in females at 6 AM and 6 PM, with no change in males after the dietary intervention. 134However, CRY1 expression increased in males at the two time points with no change in females. 134This suggests that gene expression differs between sexes in response to a 0% potassium, high sodium diet, which may result in differential regulation of BP and electrolyte excretion.
A study on male and female wild type and global PER1 knockout mice, assessed responses to a dietary treatment model of salt sensitive hypertension. 135Following the dietary intervention, kidneys were harvested during the middle of the inactive period and male PER1 KO had greater ET-1 expression in the renal cortex after high salt treatment compared to females. 135These data suggest that the circadian regulation of ET-1 may occur through a sex-dependent mechanism. 135ditional pre-clinical studies have assessed differences in kidney-mediated BP regulation between sexes.A study of collecting duct BMAL knockout mice resulted in a lower BP in male mice compared to their female counterparts. 136Following the consumption of a 6 day high salt diet, BP was increased in both male and female mice; however, the increase was lower in male mice. 136erefore, BMAL in the collecting duct plays appears to play a role in BP regulation in male mice but not in their female counterparts. 136erall, sexual dimorphisms of circadian rhythms are underexplored and further research is needed to understand sex differences in renal and vascular physiology and their influence on circadian rhythms of BP.

| CHRONONUTRITION AND CIRCADIAN RHYTHMS OF BLOOD PRESSURE
Environmental factors have a strong influence on the circadian rhythms of BP; however, behavioural cues also control circadian clocks.In this regard, food is a powerful behavioural cue, and misalignment with internally regulated cues can cause circadian rhythm disruption; a prime example is shift work where individuals are active and eat during the night and early morning hours. 137,138ronic misalignment of cues and subsequent circadian disruption is now understood to be implicated in the pathogenesis of many chronic diseases.0][141][142][143] In addition, the World Health Organization has also now declared shift work as a carcinogen. 144ternatively, behavioural cues can also be leveraged as therapeutic interventions.In this regard, chrono-nutrition is emerging as a potential intervention to improve circadian physiology.As such, dietary patterns such as intermittent fasting and (TRE) have recently gained popularity.Comprehensive reviews have covered the topics of intermittent fasting, which typically involves a combination of alternating fed and fasting days. 145Alternatively, TRE entails consuming the daily calories within a certain time window.Importantly, compared with intermittent fasting, TRE typically does not incorporate caloric restriction.In this review, we will focus specifically on the timing of eating as it pertains to the alignment of feeding/eating cues with the central and peripheral circadian rhythms.In addition, we will discuss how manipulating the time of feeding/eating can alter and entrain the circadian rhythm of BP.
TRE is defined as an eating pattern in which the daily window for food consumption is restricted to a period of 3-10 h.Based on evidence from pre-clinical trials, windows <6 h do not allow for equivalent calorie consumption to an ad-lib feeding pattern; therefore, feeding windows between 6 and 10 h allow for this type of feeding pattern to be isocaloric as opposed to a calorie restriction intervention. 146TRE can be defined as early TRE, whereby the eating window is shifted to the earlier part of the day and is more aligned with the natural circadian rhythm; or late TRE, where the eating window is shifted later in the day.[149] With regard to the effects of TRE on BP and heart rate, clinical trials have reported contrasting results (Table 1, Figure 4). 153,154A potential explanation for these conflicting findings may lie in the observation that TRE appears to be effective at lowering BP in individuals who have elevated BP or hypertension at baseline. 148,149,157r example, trials that have shown no effect of TRE on BP have been conducted in young, healthy individuals 152,155 and non-obese healthy middle-aged and older adults. 153In contrast, trials that have demonstrated a BP-lowering benefit of TRE have been in overweight, obese, pre-diabetic and shift working populations. 148,149,157Importantly, these improvements in BP have been observed independently of weight loss. 147Moreover, the BP benefits of TRE appear to be more pronounced in early TRE interventions when the meal timing  window is more aligned with the natural circadian rhythm. 147,155deed, this is supported by studies that demonstrate that a highenergy 'big breakfast' and low-calorie dinner eating pattern positively affects the clock gene expression, thus promoting healthy circadian rhythms. 158e underlying mechanisms of the potential BP lowering effects of TRE are not yet fully understood.However, the effects could potentially be partly mediated by alterations in renal and vascular function.Meal timing can entrain both the central and peripheral clocks independently to influence the physiology of BP. [159][160][161] In preclinical trials, reverse feeding (feeding during the inactive period and fasting during the active period) has been shown to uncouple the peripheral circadian rhythm of the kidney from the SCN. 162In mice, the time of eating has been shown to alter BP independent of lightdark cues. 161This trend has also been observed in dogs, where the time of feeding drives BP and RAAS hormone activation with phase shifts of the rhythms to coincide with meal timing adjustments. 163,164 shifts to food timing have also been observed in rabbits with peak BP and heart rate coinciding with meal time shifts from the early afternoon to early morning.165 A pre-clinical study in mice that aimed to identify potential renal mechanisms contributing to feedingrelated alterations in BP circadian rhythm showed that reverse feeding inverted BP rhythms without an influence on urine output.161 This confirmed that the kidney clock was entrained to light-dark cues and not altered by feeding time.Thus, the authors speculated that an abnormal time of eating may place a metabolic load on the kidney during its inactive rhythm time.161 As discussed previously in this review, renal sodium excretion is lower at night, 9,166 therefore misaligning sodium intake with this rhythm could potentially result in greater sodium retention, ultimately increasing BP.161 Alternatively, sodium excretion is increased in the morning, 9,166 thus potentially presenting an opportune time to align sodium intake with the renal clock.
The role of TRE in modulating vascular function is not well understood and has only been assessed in healthy non-obese 153 and prediabetic adults. 147Clinical trials show that TRE is successful in reducing inflammation 152,167 and oxidative stress 147 , which are both contributors to vascular dysfunction.Therefore, TRE has the potential to induce changes in vascular function; however, additional studies are needed, and longer interventions may be necessary to observe improvements in vascular function measures.
The potential BP lowering effects of TRE may be particularly relevant to certain populations that are predisposed to chronic circadian disruption due to occupation, behaviour or disease.In this respect, a recent randomised controlled trial of TRE in shift-working firefighters showed that maintaining a consistent 10 h eating window over 12 weeks significantly reduced diastolic BP. 157 Importantly, this study also demonstrated that this type of intervention was feasible in this population.Timing of nutritional support may also be important for BP regulation in post-Intensive Care Unit (ICU) recovery.The circadian disruption is highly prevalent in this setting and continuous enteral feeding is the standard of care. 168The effects of intermittent or cyclical enteral feeding on BP in this patient population warrant further investigation.
While the premise of TRE is to shorten the daily eating window without altering caloric intake, several TRE clinical trials have indeed reported a reduction in calorie intake.This raises the question whether the observed benefits of TRE are a result of coincidental caloric restriction or circadian alignment.Recent pre-clinical work has set out to address this question by comparing five different calorie restriction groups that differed only in the pattern of food consumption. 169These studies showed that calorie restriction improved longevity and metabolic health; however, these benefits were magnified when restricting feeding to the active phase. 169milar studies are warranted to ascertain if these findings hold true for BP.

| FUTURE PERSPECTIVES
Hypertension contributes to a significant economic and social burden on patients and the healthcare system.Despite recent advancements in our understanding of circadian rhythms, additional work is needed to understand more about the physiology of circadian rhythms in

1
Summary of TRE interventions that report blood pressure as a secondary outcome.
humans to leverage lifestyle interventions to reduce hypertension.In 2021, a National Heart, Lung and Blood Institute (NHLBI) Workshop was held on the circadian rhythm of BP and chronotherapy to stress the importance of better understanding chrono-therapy for F I G U R E 4 The risk of bias assessment for current randomised controlled clinical trials (parallel and crossover designs) that have investigated TRE and reported BP as a secondary outcome measure.There is a need for rigorous clinical trials to investigate the effects of TRE on BP and circadian BP rhythmicity.The risk of bias assessments made by two unblinded authors (Danielle Kirkman and Natalie Bohmke) according to the following criteria: Selection: Was the recruitment procedure completely described and adequate?Selection: Was the randomisation procedure adequate?Performance: Systematic difference in interventions other than that being evaluated?Detection: Were the outcome assessors blind to the intervention?Detection: Were the participants in the study blinded?Attrition: Were withdrawals and dropouts completely described?Attenuation: Was the analysis by intention-to treat?BP, blood pressure.treatment of hypertension, highlighting the role for chrononutrition. 10In addition to NHLBI efforts to highlight the need of research and therapies to leverage circadian rhythms, one of the National Institutes of Health strategic goals for nutrition research through 2030 is to determine the health benefits and mechanisms of time-based eating patterns.It is understood that dietary and lifestyle factors influence central and peripheral clocks that regulate BP; however, the mechanisms of chrono-nutrition in humans are not fully understood.Therefore, studies should be aimed at investigating how moderating lifestyle and dietary components around individual chronotypes may be beneficial towards developing personalised lifestyle therapies.Lifestyle factors should be leveraged to reduce hypertension prevalence and severity and additional work is needed to further understand the role of chrono-nutrition in hypertension treatment.
There are no known clinical trials that have investigated the effects of TRE on blood pressure as a primary outcome or blood pressure circadian rhythms.Abbreviations: ?, standard deviation unavailable from paper therefore effect size calculation not possible; eTRE, early time restricted eating; mTRE, midday time restricted eating; TRE, time restricted eating.