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Chronic Supplementation of Melatonin restoresImpaired Circadian Rhythm in Patients withCoronary Artery Disease
  JOHTN
NOVEL CONCEPT
Chronic Supplementation of Melatonin restores
Impaired Circadian Rhythm in Patients with
Coronary Artery Disease
1Shipra Bhardwaj, 2Narsingh Verma, 3VS Narain, 4Vinod Kumar, 5Kshitij Bhardwaj, 6Saumya Mishra
1-6Research Scientist, 2-4Professor, 5Scientist
1Department of Radiation Oncology, Dr Ram Manohar LohiaInstitute of Medical Sciences, Lucknow, Uttar Pradesh, India
2,5Department of Physiology, King George Medical UniversityLucknow, Uttar Pradesh, India
3Department of Cardiology, King George Medical UniversityLucknow, Uttar Pradesh, India
4Department of Zoology, University of Delhi, New Delhi, India
6Department of Medicine, King George Medical UniversityLucknow, Uttar Pradesh, India
Corresponding Author: Narsingh Verma, Professor, Departmentof Physiology, King George Medical University, Lucknow, UttarPradesh, India
e-mail: narsinghverma@gmail.com
 
ABSTRACT
Blood pressure (BP) has a characteristic and reproducible circadianpattern with high values during the day and low values atnight. Previous studies have shown that in patients with coronaryartery disease (CAD), the nocturnal dip of BP is absent or blunted,which may be correlated to the reduced melatonin levels or alteredmelatonin-cortisol interplay. Our objective was to assess the effectof bedtime melatonin administration on circadian pattern of BP andheart rate (HR) in CAD patients. One hundred CAD patients wererecruited for the study. General health records were individuallymaintained. Each study participant was given a 5 mg pure melatoninsupplement each night at bedtime for a period of 1 year. A 24hour/7 day ambulatory blood pressure monitoring (ABPM) usingambulatory blood pressure monitor and serum melatonin levelestimations were done initially, after 6 months, and after 1 year ofmelatonin supplementation. The rhythmic parameters of systolicBP (SBP) and diastolic BP (DBP), HR, viz. midline-estimatingstatistic of rhythm (MESOR), double amplitude, acrophase, 3 hourfractionated hyperbaric index (HBI) were significantly reducedand serum melatonin concentration significantly increased after6 and 12 months of exogenous melatonin supplementation.Circadian hyperamplitude tension (CHAT) incidence decreasedas melatonin treatment progressed. The number of subject diagnosedwith CHAT was as follows: 37/100 at the beginning, 17/100after 6 months, and 6/100 after 12 months. These data suggestthat 5 mg/day melatonin treatment improved and restored thecircadian pattern of BP in CAD subjects.
Keywords: Ambulatory blood pressure monitoring, Circadianhyperamplitude tension, Coronary artery disease, Hyperbaricindex, Melatonin.
How to cite this article: Bhardwaj S, Verma N, Narain VS,Kumar V, Bhardwaj K, Mishra S. Chronic Supplementationof Melatonin restores impaired Circadian Rhythm in Patientswith Coronary Artery Disease. Hypertens J 2017;3(2):94-100.
Source of support: Nil
Conflict of interest: None
 
 

 
INTRODUCTION

Most physiological parameters exhibit circadian rhythmsreflecting an innate temporal program provided bybiological clocks. Chronobiological studies include but arenot limited to comparative anatomy, physiology, genetics,molecular biology, and behavior of organisms withinbiological rhythms mechanics. Systemic BP has a characteristicand reproducible daily pattern, as regulated by thecircadian timing system.1,2 In most people, BP drops by10 to 20% during night are called dippers; those in whomsuch reductions are not present appear to be at increasedrisk for cardiovascular events and these peoples are callednondippers. In addition, it was reported that in peoplewhose 24-hour BP exceeded 135/85 mm Hg, were nearlytwice as likely to have a cardiovascular event as those with24-hour mean BPs < 135/85 mm Hg, irrespective of thelevel of the office BP.3 The regular cycle of BP is importantespecially because an inverted daily pattern with higher BPvalues during the night and lower during the day is associatedwith an increased target organ damage (in cardiac,cerebral, vascular, and renal tissues) and worsened cardiovascularoutcome. Patients with CAD, a major complicationof chronic hypertension, show a blunted day-night rhythmin vasodilatation and suppressed or attenuated night-timemelatonin levels,4 and thus the normal dipping patternof BP is absent or disturbed.4,5,8,9 Melatonin is a circadianclock-regulated hormone produced largely from the pinealgland. Mounting evidence reveals that the rhythmicity ofmelatonin has a crucial role in a variety of cardiovascularpathophysiological processes including anti-inflammatory,antioxidant, and antihypertensive and, possibly, antilipidemicfunctions.6,7 Normally, melatonin levels are lowduring the day and high at night.6 A possible link betweenmelatonin and circulation is suggested by the following:(i) The rhythms in melatonin and cardiovascular activityhave inverse phase relationship. The nocturnal rise in melatonincoincides with the declined cardiovascular activity.8,9(ii) In experimental animals, melatonin is shown to preventischemia and/or reperfusion-induced cardiac arrhythmias,influence BP control,10,11 regulate blood flow to the brain,12and modify peripheral artery responsiveness to norepinephrerine.13 A melatonin supplement at night increasesendogenous melatonin levels and hence, helps to protectfrom cardiovascular diseases.14 Zonobani A et al (1978) further suggested that melatonin by its action on the suprachiasmaticnucleus (SCN), the circadian clock influencesthe autonomic output to the cardiovascular system15 andin turn improves the circadianly regulated autonomicregulation of BP in hypertensive patients. Hence, it canbe reasoned that low melatonin levels are linked withthe impairment of the cardiovascular functioning. Inhumans, melatonin production not only diminishes withage, but also lowers in many age-related diseases, includingcardiovascular disease.16,17 Coronary artery diseasepatients show a markedly decreased nighttime melatoninsynthesis,17 which may be assumed reason for absence ofnocturnal dip in BP and high chances of myocardial infarction.5 In addition, light/dark variations in the productionof endogenous inflammatory markers in patients withCAD to some extent may be related to day/night fluctuationsin circulating melatonin levels.6 Melatonin secretedfrom pineal gland and controlled by SCN plays a vitalrole in maintaining normal circadian pattern18 and alsoin autonomic regulation of cardiovascular system.19 Thereis a growing body of evidence suggesting that a blunteddecrease in nighttime BP is associated with a greater riskof target organ damage. It has been suggested that impairmentof the sympathetic nervous system may contributeto the attenuation of the nocturnal BP dip.20 However,the mechanisms underlying this abnormal nighttime BPdipping pattern are not fully understood.16 There is someevidence suggesting that a nondipping BP pattern may berelated to advanced age,21 sodium sensitivity,22 postmenopausalstatus,20 sleep apnea, and poor sleep quality.21 Somestudies state that melatonin supplementation at certaintimes during the night may function to increase endogenousmelatonin level, potentially protecting against themelatonin downregulation associated with cardiovasculardiseases.44,47 Because melatonin via SCN influences theautonomic output to the cardiovascular system,15 restorationof proper functioning of the SCN in patients withhypertension could improve the autonomic regulationof BP. In this study, we used a 7 day timed analysis ofthe records of BP through ABPM to diagnose day-to-dayvariability,23 which is termed as CHAT, a condition inwhich excessive circadian BP amplitude precedes chronicestablished hypertension.24 We therefore, investigated in a1 year study the effect of bedtime melatonin supplementationon the circadian pattern of BP in patients with CADand established the clinical implications of it on 24 hours/7days rhythmic pattern of BP in CAD patients.

 
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Chronic Supplementation of Melatonin restores Impaired Circadian Rhythm

MATERIALS AND METHODS

Registration of Volunteer Patients of CAD

One hundred patients of CAD diagnosed by invasive ornoninvasive techniques at King George Medical University,Lucknow, India, were registered for the present study. The protocol of this study was approved by the Committeeof medical Ethics, Research cell CSMMU (3118/R.Cell-08),Lucknow, in compliance with the declaration of Helsinkiprinciples of medical ethics. All the subjects were explainedabout the purpose and protocols of the study beforeobtaining written informed consent from each of themin English and Hindi languages. Statistical significancebetween initial, 6-month and 1-year experimental valueswas compared for analysis. No separate control group wasrecruited to avoid any medical/pathophysiological changesduring statistical comparisons.

 
Treatment

All study participants took 5 mg melatonin as supplement,orally before sleep for a period of 1 year. Thesupplement was pure melatonin procured from MarcLaboratories, Himachal Pradesh, India. All study participantswere allowed to continue their ongoing treatment.

Monitoring of Health Records

The health records of each subject were maintainedduring the entire period of treatment with generalobservations, like the presence or absence of headache,insomnia, hyperactivity, irritability, nausea, sleepinglimbs, dizziness, constipation, shaky hands, stomachcramp, drowsiness, sweating, hunger, weakness, andsore eyes. The participants were instructed to reportimmediately in case they developed symptom(s) of anyof these diseases, and advised to discontinue the oralintake of melatonin.

Ambulatory Blood Pressure Monitoring

A 24 hour/7 day ABPM of the subjects was done with anautomated ABPM device, A&D TM-2430 (A&D Company,Japan). The ABPM of each subject was done three timesbefore and after 6 and 12 months of the oral melatoninsupplement. Participants were told to carry out all theirroutine works during recording periods. The machinewas programmed to record BP and HR taken every30 minutes during the day and after 1 hour intervalduring the night. Measurements from the ABPM devicewere transferred and stored in the computer for furtheranalysis. For each individual, the data were summarizedin a sphygmochron (a computer comparison of patients'profile with the specified reference limit). The results wereanalyzed using Halberg Cosinor analysis. Each BP and HRprofile was analyzed by a sphygmochron, utilizing botha parametric and nonparametric approach. Ambulatoryblood pressure monitoring records were sent to HalbergChronobiology Center, University of Minnesota, and Minneapolis,USA, for further interpretation. The followingestimates were obtained: (i) MESOR, a time structure or chronome-adjusted mean;25 (ii) double amplitude orpredictable change, which is the total change within aday or the circadian amplitude of reproducible variabilitywithin a day,9 (iii) acrophase, which is a measure of timingof overall high values recurring in each cycle; (iv) CHAT.The average 7-day values of the MESOR, double amplitude,acrophase, and 3-hour fractionated HBI for SBP, DBP,and HR were determined for each subject at all the threerecordings, i.e., initial, after 6 and 12 months. The CHATwas diagnosed in subjects who were having larger-thanusualchange in BP, and overswinging BP pattern in thedouble amplitude which precedes an overall elevationin BP and is an indication or predictor of a great risk ofessential hypertension and CAD.

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Table 1: Clinical characteristics and observation of CAD subjects enrolled for the study
Chronic Supplementation of Melatonin restoresImpaired Circadian Rhythm in Patients withCoronary Artery Disease
Values represent the mean ± SE of 100 subjects; SE: Standard error

Serum Melatonin Estimation

Blood samples of CAD subjects were collected between8:00 and 10:00 am for the estimation of serum melatoninlevels by enzyme-linked immunosorbent assay kit procuredfrom IBL International, Germany.

Statistics

Statistical significance between initial, 6 months and1 year experimental values of ABPM were calculatedby Halberg Cosinor analysis and Student's t-test,9,25-27whereas melatonin hormone analysis was calculated byStudent's t-test only.

RESULTS

Clinical Observations

Twenty of the 120 patients dropped out of the study.There were 69 males and 31 female subjects (mean age60.44 years). Mean SBP/DBP of the subjects recorded bymercury sphygmomanometer was 140 ± 11.20/87.63 ±3.66. Mean HR was 87.63 ± 3.66 bpm (Table 1).

Ambulatory Blood Pressure Monitoring

Midline-estimating Statistic of Rhythm

There was significant difference between the baselineMESOR of SBP, DBP, and HR after 6 months and 1 yearof the supplementation of melatonin in CAD subjects. In CAD patients, baseline SBP/DBP was 142.07 ± 1.18/92.40± 2.77, which was significantly reduced to 133.03 ± 4.36after 1 year of melatonin supplementation. Melatoninsignificantly reduced SBP. A 3% decrease was noted after6 months and 6.3% decrease was noted after 1 year ofmelatonin supplementation. The decrease of 3.3% after6 months and 8.2% after 1 year was observed in DBP.There was a 5.58% decrease after 6 months and 9.63%decrease after 1 year in MESOR HR, which was highlysignificant (Table 2 and Graph 1).
 
Double Amplitude (Predictable Change)

The circadian amplitude of reproducible variability alsodecreased significantly after 6 months and 1 year of thesupplementation of melatonin in CAD subjects. There was 10% decrease in SBP, 20% in DBP, and 10% decreasein HR after supplementation (Table 3 and Graph 2).

Table 2: MESOR of 24 hours/7 days ABPM in CAD subjects initiallyand after 6 months and 1 year of melatonin supplementation
Chronic Supplementation of Melatonin restoresImpaired Circadian Rhythm in Patients withCoronary Artery Disease
*Significant at the level of p < 0.05; Δ Significant at the level ofp < 0.01

Chronic Supplementation of Melatonin restoresImpaired Circadian Rhythm in Patients withCoronary Artery Disease
Graph 1: Percent decrease in MESOR of SBP, DBP, and HR after6 months and 1 year of melatonin supplementation in CAD subjects


 
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Chronic Supplementation of Melatonin restores Impaired Circadian Rhythm

Table 3: Double amplitude (predictable change) of 24 hours/7 daysABPM in CAD subjects initially and after 6 months and 1 year ofmelatonin supplementation
Chronic Supplementation of Melatonin restoresImpaired Circadian Rhythm in Patients withCoronary Artery Disease
*Significant at the level of p < 0.05; Δ Significant at the level ofp < 0.01

Circadian Hyperamplitude Tension

Circadian hyperamplitude tension (CHAT) was diagonsedin 37/100 subjects. After 6 months and 1 year of melatoninsupplementation, CHAT was demonstrated in 17 and6 cases respectively (p = 0.05; Graph 3).

Acrophase

There were no statistically significant changes in acrophaseof initial, 6, and 12 months ABPM of CAD subjects.However, the circadian pattern of timing of overall highvalues recorded at baseline (SBP/DBP 14:51 ± 0.23/15:20 ±0.92) recurring in each cycle shifted toward normal (SBP/DBP 16:33 ± 1.14/13:41 ± 0.22) after 12 months of supplementationof melatonin. There was no significance differencebetween the initial and 12 months supplementationvalues of acrophase of HR (Table 4).

Serum Melatonin

Significant increase in serum melatonin levels was notedafter 6 and 12 months of melatonin supplementation. Graph 4A shows the total increase in serum melatoninlevel and Graph 4B shows the effect of serum melatoninlevels on the SBP, DBP, and HR.

Chronic Supplementation of Melatonin restoresImpaired Circadian Rhythm in Patients withCoronary Artery Disease
Graph 2: Percent decrease in double amplitude (predictablechange) of SBP, DBP, and HR after 6 months and 1 year of melatoninsupplementation in CAD subjects
 
Table 4: Acrophase of 24 hours/7 days ABPM in CAD subjectsinitially and after 6 and 12 months of melatonin supplementation
Chronic Supplementation of Melatonin restoresImpaired Circadian Rhythm in Patients withCoronary Artery Disease
Values represent the mean ± standard error of 100 subjects ateach time interval

DISCUSSION

Baseline observation of our study shows that CAD patientshad disturbed circadian pattern of 24 hours/7 days ambulatoryBP, which were restored or improved after theytook melatonin as supplement. One year of melatonin assupplementation significantly reduced ABP and increasedserum melatonin level (Table 2 and Graph 1). A reductionof 3 mm Hg of systolic MESOR was observed after6 months, which was further decreased to about 9 mmHg after 12 months. Similarly, after 12 months, DBP wasreduced to 4 to 7 mm Hg and MESOR HR was reducedto 5 to 8 bpm. This is consistent with the previous reportsthat melatonin repeatedly given orally or intranasally canreduce BP with essential hypertension.28,29 However, noneof the subjects had complained of headache, palpitation,dyspnea, nausea, tremors, dizziness, sore eyes. Therewas initially high BP amplitude in 35% of our CAD subjects(Graph 3), which is the predictor of the CHAT andvascular disease risk associated with it.25,30 We found that after 6 and 12 months of the melatonin supplement,CHAT was reduced to 17 and 6% respectively, and nondippingpattern shifted toward dipping. Recent findingsof Rechcinski et al31 also suggest nocturnal decline in BPof CAD patients, but there was also a nonoptimal increasein the daytime BP. We have found that melatonin givenas supplement causes nocturnal decline in ambulatorydipping pattern without a nonoptimal increase in thedaytime BP. There was no significant difference betweenthe acrophases (time of excess) of BP and HR beforeand after the melatonin supplement. Circadian rhythmof acrophases (high values) lie at an interval of 12 to20 hours, and batyphases (lowest values) at an interval of2 to 6 hours.32 Similar pattern was observed in the acrophase(Table 4) of subjects after 12 months of oral melatonin,suggesting the synchronizing role of melatoninfor daily BP rhythms. Our results indicated a significantincrease in serum melatonin concentrations of CAD subjectsafter 6 and 12 months of melatonin supplementation.However, initial observation in same subjects indicatedlow levels of serum melatonin. Low levels of melatonin inCAD subjects have also been already reported.5,33 The risein serum levels of endogenous melatonin of CAD subjectsafter melatonin supplement may be due to the improvisationof SCN autonomic activity possessed by exogenousmelatonin supplementation. Previously Laakso et al34reported increase in endogenous melatonin level afteradministration of prolonged exogenous melatonin inyoung and old people. Melatonin may provide feedbackvia high-affinity melatonin receptors in the SCN,35,36 thusinfluencing the rhythm of its own production and othercircadian rhythms too.14,37 The mechanism of protectiveeffect of melatonin has been discussed by many authors.Being a lipophilic molecule, melatonin can effect intracellularMT1 and/MT2 receptors38 found in the cardiovascularsystem.39 The constrictive effect of melatonin canbe explained by receptor-mediated decrease in the cyclic adenosine monophosphate levels40,41 and phosphatidylinositol-4, 5-bisphosphate hydrolysis.38 During initialobservation of our study, hypertension was observed inmaximum number of CAD subjects; this may be associatedwith disturbed neurotransmission in SCN,42 whichis the regulatory center for melatonin secretion43 andautonomic tone.44,45 Our findings implicate that melatonininfluences central regulatory mechanisms involved inthe BP control, as indicated by reported restored baroreflexresponses,45 decreased sympathetic output,46 andassociated decreased HR or cardiac output with BP fallafter melatonin administration14,47 in other studies. Themechanisms participating in central effect of melatoninare yet not completely known; however, several pathwaysare suggested by many authors. It could be hypothesizedthat the modulation of SCN activity by melatonin36,38alters sympathetic tone and represents a protectivemechanism against excessive sympathetic excitation.Thus, our studies suggest a protective role of melatoninin synchronization of impaired circadian pattern of BPin subjects with CAD. Normal ABPM is itself a strongpredictor of enormous variability of BP and HR. Extent ofhour-to-hour and day-to-day variability, 24 hours/7 daysmonitoring has emerged as an important tool of studyingvariability in BP, which helps in prognosis of hypertensionand white coat hypertension. We recognize thatmelatonin is of special interest, being an endogenousmolecule that can be used in humans, and which isalso safe. In the future, more experiments are requiredto study the effect of melatonin on cardiovascularsystem and elucidate the potential interactions betweenmelatonin and the different classes of antihypertensivemedicine in BP regulation. Since cardiovascularregulation is a complex mechanism which may not besolely regulated by melatonin, we will like to concludethat melatonin offers a protective role in subjects withdissynchronous circadian pattern of cardiac functions and could minimize the risk of various clinical eventsassociated with BP rhythms.

Chronic Supplementation of Melatonin restoresImpaired Circadian Rhythm in Patients withCoronary Artery Disease
Graph 3: Percentage of number of subjects in whom CHATwas diagnosed during ABPM (n = 100)

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Chronic Supplementation of Melatonin restoresImpaired Circadian Rhythm in Patients withCoronary Artery Disease
Graphs 4A and B: (A) Total increase in serum melatonin level; and (B) effect of serum melatonin levels on the SBP, DBP, and HR
 

 
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Chronic Supplementation of Melatonin restores Impaired Circadian Rhythm

ACKNOWLEDGMENTS

Authors would like to thank Prof Franz Halberg, HalbergChronobiology center, University of Minnesota, for ABPMstatistics help. Last but not least, the authors are gratefulto all study subjects who participated so willingly andpatiently for the duration of a long 1 year.

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