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Circadian Rhythms: Attributes, Disruption, andImplementation in Cardiometabolic Health
  JOHTN
CARDIOVASCULAR PHYSIOLOGY
Circadian Rhythms: Attributes, Disruption, and
Implementation in Cardiometabolic Health
1Narsingh Verma, 2Shipra Bharadwaj
1Professor, 2Research Scientist
1Department of Physiology, King George Medical UniversityLucknow, Uttar Pradesh, India
2Department of Medicine, King George Medical UniversityLucknow, Uttar Pradesh, India
Correspondence Author: Narsingh Verma, Professor, Departmentof Physiology, King George Medical University, Lucknow, UttarPradesh, India
e-mail: narsinghverma@gmail.com
 
ABSTRACT
It is a well-known fact, proved by evidence, that all the organismsconsist of an internal biological clock, right from the singlecelledorganisms to humans. In the hierarchy of classification ofvertebrate, these rhythms have shown to play an important roleconcerning the physiological aspects of all organisms. Not onlyare these rhythms related to sleep, seasonal migration, reproduction,etc., in animals, but also, in humans, circadian rhythmscontrol various vegetative functions including regulation of temperature,cardiac activity, endocrine secretion, blood pressure(BP), oxygen utilization, metabolic rate, menstrual and ovariancycles, and other body functions. The change in the normalpattern of the circadian clock because of genetic, behavioral,and various environmental factors can produce cardiovascular,metabolic, and endocrinal disorders including hypertensionand diabetes. The concentration of glucose in plasma displayscircadian variation; in the morning hours, it is the highest. Sincethe level of insulin depends on the feeding behavior, the glucoseconcentration follows the daily rhythm of intake of food. On thecontrary, BP and other cardiovascular reflexes have characteristicand diurnal circadian rhythms. Circadian trends are exhibitedin many cardiovascular pathophysiological conditions likestroke, myocardial infarction, rhythm disorders, and bed deathsyndrome. There is enough evidence to show that disruption ofcircadian rhythms can act as a risk factor for the developmentof cardiovascular diseases. Recent research also suggests thatthe circadian clock and associated central as well as peripheralgenes are responsible for glucose and lipid metabolic rhythms.
Keywords: Cardiometabolic functions, Chronomics, Circadianrhytms, Midline estimating statistic of rhythm.
How to cite this article: Verma N, Bharadwaj S. CircadianRhythms: Attributes, Disruption, and Implementation CardiometabolicHealth. Hypertens J 2017;3(2):58-63.
Source of support: Nil
Conflict of interest: None
 
 

INTRODUCTION

Biological functions are precisely organized in time inthe form of circadian rhythms. These rhythms are an integral part of the vegetative systemic functions, displayingendogenous oscillations from seconds, minutes,and hours, days, weeks, and even months and years.These rhythms are present in almost every cell includingthose of plants, bacteria, animals; isolated cultures of thecells of animals, plants, bacteria, and even cultured cellspossess these rhythms. The suprachiasmatic nucleus(SCN) acts as a master circadian pacemaker. The SCNis synchronized by environmental light-dark cyclesvia photoreceptors and neural pathways. These diurnaloscillations are regulated by clock genes expressed in theSCN and other cells. The SCN acts as a central pacemakerand entrains the lower circadian clock by various neuroendocrinepathways.1 It also serves as a central clock,while the peripheral organs have a peripheral clock.2The light input from the retina is received by the SCNand then converted to neural or hormonal signals, whichgenerate biological rhythms.3 In humans, the core clockgenes are constituted by Bmal1 (brain and muscle arylhydrocarbonreceptor nuclear translocator-like 1), CLOCK(circadian locomotor output cycles kaput), Per (Period),and Cry (Cryptochrome). These genes generate a systemfor feedback and regulation.4 These clock genes, in turn,control target genes and also regulate circadian rhythmsof various biochemical and physiological processes.4 Thecoordination of all these systemic genes is necessary foroptimal physiologic functions and maintenance of mentaland physical health.5 The loss of normal synchronizationbetween and among central and peripheral oscillationsleads to various diseased conditions. Circadian disruptionat the systemic and molecular levels is linked to sleep disorders,cardiovascular and metabolic diseases, cancer, andpsychiatric disorders. In addition, some new data suggestthat disruption of circadian rhythms may result in pancreaticclock disruption, leading to diabetes and obesity.6-8

 
Circadian Rhythms of the Cardiovascular System

Various physiological vegetative functions like BP, heartrate, cardiac contractility, vascular reactivity, and varioushomeostatic factors follow a characteristic circadianpattern. There are many studies suggesting that the onsetof various cardiac disorders exhibits a circadian patternand the best examples can be acute coronary syndromeor atrial fibrillation, which is more common in morninghours. Some other published reports by our group suggest that several cardiac functions show 24-hour and 7-daycircaseptan and circadian variation, including rate of heartand arterial pressure (BP).9,10 The cardiovascular systemand BP have a definite and reproducible pattern exhibitedby daytime elevation and nocturnal decline.11,12 Variousparameters of the cardiovascular system, like BP and heartrate, keep on changing across the 24 hours, which is insynchrony with the rest-activity cycle.13,14 This diurnal BPvariation is modulated by internal factors, such as gender,race, tone of autonomic nervous system, vascular hormones,and other blood, plasma, and renal variables.15,16
 
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Circadian Rhythms: Attributes, Disruption, and Implementation

The various factors determining arterial pressureshow circadian variability like plasma and urinarymineralocorticoids, plasma cortisol and urinary markerslike sodium, angiotensin II, plasma and urinary epinephrine,norepinephrine, and prostaglandins. Chronobiologicalanalysis of BP for at least 7 days helps indiagnosing circadian hyper-amplitude-tension (CHAT),a condition in which excessive circadian BP amplitudesare seen even before the chronic established hypertension.17-19 This CHAT is considered as a very highand independent risk factor for stroke. Our group hasshown that the CHAT reversal is possible by changingthe timing of administration of few drugs when morethan one drug is being used. Based on rhythmic, fixeddiurnal variations of BP, people have been groupedas dipper and nondipper broadly. Dippers are thosesubjects who have a nighttime (sleep period) fall inBP with respect to their daytime (wake period) value.In contrast, nondippers are those in whom there is nosignificant fall in BP during nighttime. The reproduciblecharacteristic circadian pattern of data can beobtained by ambulatory BP monitoring (ABPM). Thechief determinant of circadian pattern of BP appearsto be the sympathetic reactivity. Serial measurementsof plasma catecholamine over 24 hours indicate thatboth norepinephrine and epinephrine have a patternof variability very similar to that of BP. The increasedsympathetic activity during arousal from sleep maybe an important factor in producing the sharp, rapid,early morning BP increases. Norepinephrine levels, inparticular, appear to demonstrate a slight overshoottoward the end of morning-arousal process, similar tothat seen with BP.20 Early studies using intra-arterialABPM devices established that 24-hour BP curves arereproducible when studied on consecutive days andseparate weeks apart. Studies have demonstrated thatvarious cardiac events like arrhythmias, sudden cardiacdeaths, episodes of stable angina, unstable angina, acutemyocardial infarction, and cerebrovascular events arepredominant in the morning hours. The cause of earlymorning predominance of these adverse events ismainly attributed to early morning rise in BP.21

 
Chronocardiology and Circadian
Rhythm Disruptions


Circadian rhythms are disrupted during cardiovasculardisease or it could be vice versa. Various changes in circadianrhythms can influence or even construct variousdiseases. The onset of various cardiac emergencies likemyocardial events, sudden cardiac death, and cerebrovascularaccident increases between 06:00 and 12:00 hours.The reason behind it mainly may be due to increasedsympathetic activity after an individual gets out of bed,and also due to the interaction between catecholaminesand platelets, thus affecting atherosclerotic plaque pathophysiology.These circadian clocks exist within cardiacmyocytes and smooth cells of the vessels. These circadianvariations have been seen exhibited by various circulatoryreflexes, factors of platelet aggregation, coagulationfactors, and the concentration of fibrinogen and fibrin-lysingsystem.22 It is an established fact that the SCN receivesexternal cues or zeitgebers like SCN nucleus processesexternal signals like ambient light and inputs from thebrain for regulation of variety of physiological functionslike body temperature, sleep/wake cycles, and secretionof hormones, such as cortisol, melatonin, thyroxin, andvasopressin,23 which are regulated by SCN and possiblyby melatonin (MT) receptors MT1 & MT2, that have beenreported in human coronary arteries. Animal studiessuggest that depending upon the type of receptor beingactivated, melatonin can have an effect on vasculature.There is vasoconstriction with MT1 and vasodilatationwith MT2 receptor activation. Endogenous productionof melatonin is approximately 30 mg/day, but the peakscan go very high up to 100 pg/mL.24,25

Chronobiologic considerations, in turn, aim at chronologicalrisk assessment using values that may lie wellwithin the physiological range as a step toward prevention.In both physiological and pathological conditions,BP and heart rate follow the activity levels of the bodyand brain, especially during sleep and wakeful conditions.Nocturnal BP value and heart rate variations areaccording to sympathetic activity. The morning valuesof norepinephrine are mostly higher than night (sleep)values, but they may not be said to be highest values ofthe last 24 hours. This also suggests that, under someconditions, the morning incidences of myocardial infarctionand/or other high cardiac death rates may be dueto increased response of these organs to circulatingnorepinephrine levels.

The inherent variability of the rhythm in most of thehealthy individuals has less amplitude. This geneticallydesigned day-night difference is amplified by activityand stress profile; and, in majority of individuals, thistrough-to-peak difference amounts to the tune of 15 to 25 mm Hg. Various systemic diseases do have the influenceon expression and features of this circadian change.In primary and secondary hypertension, the midlineestimating statistic of rhythm (MESOR) values (24-hourtime adjusted mean) and amplitudes of the rhythm maybe altered; in few cases, the rhythm itself may be obliterated.In secondary hypertension, nighttime values ofBP may be increased and reverse dipping patterns maybe seen, whereas many disease conditions have nocturnalBP deregulation. The nondipping pattern of circadianBP variability is clinically important as there is increasein cardiovascular morbidity.25 Deregulated autonomicnervous system functions, syndrome Z (disturbed breathingdue to sleep disorder), and other qualitative andquantitative sleep defects are known causes of alteredcircadian BP profile, while certain secondary causes ofhypertension may enhance the rapidity of BP change. Wedo not know much about the pathophysiology of nocturnalrise in pressure, but the increasing age and ethnicityare important determinants.26

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Narsingh Verma, Shipra Bharadwaj

IMPLICATIONS OF CHRONOTHERAPEUTICS
FOR CARDIOVASCULAR DISEASES


A major objective of chronotherapy for cardiovasculardiseases would be to ensure the appropriate drugdelivery and the required concentrations according tocircadian patterns of the disease. At present, there arenot enough data to know whether altering the dosingtime of a conventional drug can have any benefits. Fewrecent studies have evaluated the effect of timing of drugon circadian BP patterns, with somewhat inconsistentresults.27-29

A study with angiotensin-converting enzyme inhibitorshas shown that evening dosing of drug was able toreduce nocturnal pressure more effectively than morningdoses.27 The daytime BP in both groups did not have anysignificant difference. The increase in dipping may bedangerous in the elderly and high cardiovascular-riskindividuals. In contrast to these studies with atenolol,30nifedipine GITS or amlodipine, showed no differentialeffects on BP. All these studies are not significant becauseof small sample sizes. The first therapy following chronomedicineconcepts has been developed recently. Thismode of therapy matches the circadian pattern of BPand myocardial ischemia. The calcium channel blockerdrug, verapamil, has been employed in this deliverysystem that has a delay in release for approximately 4 to5 hours after dosing and then has an extended releasefor approximately 18 hours. When taken at bedtime, thedelivery system of this therapy provides optimal drugconcentrations in the morning hours, the most dangerousperiod for all these events to occur. Now with the effects on this system, the effect of drug is higher at the time ofrequirement. This delivery system has the maximumeffect during the daytime and minimum effects duringthe nighttime when the requirement of the effect of drugis decreased because BP goes down during nighttime.This mode of drug delivery is novel, but we must notforget that all long-acting drugs do have almost the sameeffects. The effect of night dosing of drugs is very muchformulation-dependent. For example, antihypertensivemedications with conventional delivery systems canincrease nighttime ischemic episodes when given topatients of "extreme dipping." Alternatively, doxazosin,which has a slow rate of absorption, does not excessivelydecrease night BPs when administered at bedtime, butthe control of early morning peak is satisfactory. Recentstudies have much evidence to suggest that antihypertensiveand anti-anginal therapies can be developed, whichcan follow the circadian patterns. The implications ofthis type of therapy may be important since cardiovascularevents occur more frequently in the early morninghours.31 However, more outcome data are required toimplement all such formulations.

 
Accessing Circadian Variability of BP and
Heart Rate: Ambulatory BP Measurements


Ambulatory BP and heart rate measurements haveevolved as one of the crucial tools in assessing circadianvariability of the cardiovascular system. In our previousstudies on coronary artery disease and shift workers byemploying the 7-day/24-hour ambulatory monitoring ofBP and heart rate, it has been proven that timed analysisof ambulatory BP and heart rate using nondipping anddipping patterns, MESOR, double amplitude, acrophase,and hourly fractionated hyperbaric indices are importantearly predictive parameters of any cardiovascularmorbidity and mortality. Implementing chronobiologicalanalysis in routine clinical treatments can be helpful indiagnosis of BP variations, dipping status, excluding ofwhite coat hypertension, taking decisions on treatmentfor elderly patients, identifying nocturnal changes in BP,resistant hypertension, determining the efficacy of drugtreatment over 24 hours, and diagnosing and treatinghypertension in pregnancy and hypotension.

CHRONOMICS OF ALTERED METABOLIC STATE

In mammals and humans, feeding provides nutrients likeglucose, amino acids, and lipids, which are essential formetabolism and act as fuel for the metabolic pathways.During the resting period, the stored energy and substratesare utilized to maintain metabolic homeostasis.32Glucose concentrations in blood are maintained withinphysiological limits by signaling mechanisms responsible for secretion of insulin and glucagon. Plasma glucoseconcentrations do follow a characteristic circadianvariation, with the highest levels in the morning andday (active) time. It is also influenced by food patterns ofthe individuals. On the contrary, autonomous circadianrhythms have been observed in pancreatic islet cells.Clock mutants, as well as Bmal1 mutants, show decreasedsecretion of insulin due to defective size and function ofislet cells, leading to impaired glucose tolerance. Thesedisturbed clock mechanisms in the endocrine beta-cellswill produce an impaired insulin release, which willultimately produce hyperglycemia.33 Recently, it has beenfound that mutations in clock genes of alpha cells mayalter the glucagon secretion, which can compensate fordecrease action of insulin.

 
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Circadian Rhythms: Attributes, Disruption, and Implementation

The researchers show that beta-cells have their owndedicated clock, which regulates the outcome of theproteins and genes responsible for secretion of insulin.Any disturbance in these clock genes can produce diabetes.34,35 These circadian and metabolic systems areinterconnected at the genetic level.

CIRCADIAN DISRUPTION AND
METABOLIC DISEASES


There is plenty of evidence that suggests that circadiandisruption is one the major cause of metabolic diseases.The disruption of these circadian patterns may influencethe pathophysiological mechanisms involved in diabetes,inflammation, fibrinolysis, fluid balance, and cardiovasculardiseases including hypertension. The direct linkagebetween circadian mechanism dysfunction and metabolicabnormalities is demonstrated by phenotypes ofcircadian-clock gene mutants, knockouts, or disruptions.

Role of Diet and Lifestyle on Circadian
Rhythms Disruption


There are very interesting evidences that lifestyle andfeeding habits have a strong impact on proper synchronizationof circadian rhythms. The high-fat diet isinstrumental in expression of circadian clock genes. Inmost cases, dietary factors determine the various aspectsof chronomics of circadian clocks. However, more consistentdata are needed to establish this fact. In one study,6 weeks of high-fat diet was able to change gene expressionas well as desynchronized behavioral and endocrinerhythms including the pancreas and liver.36

EFFECT OF LIGHT POLLUTION

Light has a powerful influence on living organisms. Thelight stimulus reaches the retina and then the messagereaches the SCN nucleus. The neurotransmitter involvedis glutamate. The intensity and other variables of light exposure may change the rhythmicity of the internal circadianclock. During darkness, sleep occurs and sleep isattributed to cell repair and other physiological processeslike mental recovery. The neurotransmitter serotonin isresponsible for mood state and dips at night, while melatonininduces sleep and is responsible for stimulation fordeoxyribonucleic acid repair. Thus, these neuroendocrinerhythms, along with other physiological processes, areprogrammed to occur at specific moments of the circadiancycle. The disruptions in circadian rhythm can occur bothin very low or bright light; the duration and periodicity oflight is also important. Some other evidences indicate thatartificial light of both low and high intensity are involved;thus, even the light intensities used for households andworkplaces can have an impact on the biological clock andcircadian rhythms. The consequence of a shifted clockis manifested with insufficient sleep and rest, melatonindeficit, and hormonal insufficiency.

 
IMPLEMENTATION OF METABOLIC
CHRONOTHERAPEUTICS


There are specific circadian rhythms for glucose and cholesterolsynthesis, and it is influenced by both the sympatheticand parasympathetic inputs in glucose metabolism.Recently, we have observed enough evidence to suggestthat restricted feeding can change rhythmic patterns ofclock genes in the liver and thus, uncouple them from thecentral clock, which has not changed. About 350 circadiantranscripts have been identified in the liver, 10% of which,including the core gene Per2, maintain rhythmicity in theabsence of a functional hepatocyte clock responsible forbehavioral, hormonal, and autonomic rhythms, in theregulation of liver Clock gene expression. Cholesterolsynthesis takes place at higher paces during nighttime incomparison with daytime, and some of the individualsshow reversed patterns with inverted diurnal cholesterolsynthesis. Therefore, it is better to take statins (5-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors) inthe evening rather than in the morning. Free cholesterollevels are reported to be the lowest from 2 to 6 pm andpeak at 6 am. Advanced diagnostic technologies basedon circadian variations like ambulatory glucose monitorand ambulatory Glucose profile are of great advantage indetermining glucose levels and rate of change of glucose,which serve as alerts and alarms for actual or impendinghypo- and hyperglycemia.

CONCLUSION

Recently, there has been a sharp rise in prevalence ofcardiometabolic diseases. These diseases have a complicatedgenetic and environmental basal influence onpathophysiology. The disharmony between our intrinsic and extrinsic clock creates an imbalance between energyintake and utilization via metabolism, creating a pathwayfor several cardiometabolic disease. Current evidencesuggests that molecular central and peripheral clocks areimportant for regulation of metabolic and cardiovascularfunctions. Disrupting this process through mutations inthe core clock genes or by interfering with the environmentalzeitgebers that entrain the molecular clock maymodulate the functions of the cell and tissue, with lossof the synchrony that normally exists between the environmentand physiology. This leads to the developmentof cardiometabolic pathway abnormalities. Ultimately,a closer understanding of the roles of the central andperipheral molecular clocks in the pathogenesis of cardiometabolicdisease may help to develop novel therapeuticapproaches to combat obesity, type II diabetes, and associatedcardiovascular disease. Disruption of the circadianclock, because of shift-work or bad sleeping habits andlate night snacks can cause severe disturbances in theserhythms. There are a number of studies that describe therole of circadian clock genes and molecular regulatingfactors as discussed above mostly in animals; however,there is scarcity of similar data on humans, whichis needed in future research to achieve insights intosynchronization of environmental and internal clocks.
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