Evolution of circadian rhythm

1. Evolution of Circadian Rhythms and
Increased Risk of CVDs in the Morning
PROF. GHIZAL FATIMA
ERA UNIVERSITY,
LUCKNOW, INDIA

2. The Evolution of CIRCADIAN RHYTHM OF INCREASED CVDs IN THE 2nd QUARTER
OF 24 HOURs.
Homo erectus used to go to
river banks or lakesides in the
forest in the early morning for
hunting when animals emerged
from the forest to drink water.
It was associated with marked
physical exertion and mental
stress with underlying
biochemical storm of increase
in catecholamines, and cortisol.
Singh et al, 2007,2012,2017

3. The Evolution of CIRCADIAN RHYTHM OF INCREASED CVDs IN THE 2nd
QUARTER OF 24 HOURs.
Homo erectus used to go to river banks or lakesides in the forest in the early morning for
hunting when animals emerged from the forest to drink water.
It was associated with marked physical exertion and mental stress with underlying biochemical
storm of increase in catecholamines, and cortisol with low acetylecholine.
Singh et al, 2007,2012,2017

4. SYMPATHETIC ACTIVITY:
It is possible that this habit of the ancient men causing increased
sympathetic activity in the morning (6.00-12.00 hours) became a
circadian rhythm which has an adverse effects in modern men.
BMR:
The increased sympathetic activity may be also associated with
rise in thyroid hormones which are known to cause increase in
basal metabolic rate resulting in to increased energy expenditure
in the morning compared to other times of the day.

5. It has been proposed that to preserve their progeny, Homo sapiens mated
early in the morning.
TESTOSTERONE:
This routine became the most important chronobiological adaptation of
humans. An increased release of testosterone occurred in the morning to
coordinate sexual activity with the aim to impregnate.
Throughout human history, there have been various attempts to establish
the existence of a male cycle. The circadian testosterone cycle has been
well studied and verified.
Testosterone is highest in the morning and lowest at bedtime, hence men’s
propensity for morning erections, which follows a 24-hour cycle. Circadian
Singh et al 2012

7. Women also make testosterone -
the main sex drive hormone -but
produce a fraction of the amount
and it rises by only a tiny bit
overnight.
It is also kept in balance by
oestrogen and progesterone.
Women has more testosterone in
the night after make up, when she
looks at mirror, she has more
desire for sex.
Men need only a normal amount of
testosterone to feel like having sex. The raised
levels in the morning means most men will
wake up two to three times a week with
erections.

8. Women are often driven
by their hormones,
particularly on a
monthly cycle.
But men go through a
hormone cycle every
single day.
His testosterone levels
peak in the morning, which is
why he is so primal and turned
on, and they drop off
throughout the day, leaving
him at his most nurturing at
night.

9. The earth rotates around its axis (and around the
sun); hence our physiology has adapted to
coordinate functions according to circadian (and
circannual) rhythms, resulting in to Circadian
Dysruption in the morning between 6.00 to
12.00 noon
A disturbance in sleep wake cycles, such as late
night sleep or late night eating, may cause
increased cardiometabolic risk in the modern
society.

10. Our planet revolves around its axis,
causing The light and dark cycles of
24-Hrs. resulting in day and night.

11. GRAVITATIONAL WAVES IN COSMOS 2015: tiny vibrations
suggestive of gravitational waves passing through our planet
have been recorded which may influence Biological Functions
including Circadian Rhythms? Singh RB, Chibisov et al 2015.

12. The Magnetic Force in the Cosmos
Influences Circadian Clock of SCN and
establish it as Imp. ENVIRONMENTAL
RISK FACTOR OF CVDs & other Chro.
Astrochronocardiology IS THE SCIENCE WHICH PREDICTS EARLIEST RISK
FACTORS AND TRIGGERS OF ATHEROTHROMBOSIS Or ACS
Chen L, Yang G. Recent advances in circadian rhythms in cardiovascular system. Front Pharmacol. 2015; 6: 71.Published
online 2015 Apr 1. doi: 10.3389/fphar.2015.00071
Halberg F, Variability in eosinophil counts more in the morning than evening?
Cornélissen G, Halberg F, Rostagno C, Otsuka K. A chronomic approach to cardiac arrhythmia and sudden cardiac death. The Autonomic
Nervous System 2007; 44: 251-4.
Singh RB, Pella D, Rastogi S, et al. Increased concentrations of lipoprotein(a),circadian rhythms,and metabolic reactants evoked by acute
myocardial infarction in relation to large breakfast. Biomed
Pharmacother 2004; 58: 116-22.
Singh RB, Pella D, Neki NS, et al. Mechanism of acute myocardial infarction(MAMI) study. Biomed Pharmacother 2004; 58: 111-5.
Halberg F. Chronobiology. Annu Rev Physiol 1969; 31: 675-725.Halberg F, Visscher MB. Regular diurnal physiological variation in eosinophil
levels in five stocks of mice. Proc Soc Exp Biol (NY)1950; 75: 846-7.
1.Singh RB, Niaz MA, Cornelissen G, et al. Circadian rhythmicity of circulating vitamin concentrations and oxidative stress.. Scripta Medica
(BRONO) 2001; 74: 93-6.
2.Singh et al What is the best time for exercise? World Heart J 2013
3.Singh et al, Association of active prayer and FVL intake were inversely associated with BPV. World Heart J 2011

13. Fat cell Liver Digestive tract Muscle,CV Pancreas
SCN : Brain-Renin-Angioten-Aldos.
System-Neuronal Oxidative StressLight/dark
cycle/Geomag.
Food
Circadian clock
Entrainment of Circadian Clock by Light and Dark Cycles,geomagnetic activity can
influence the metabolism in various organs shown below, Singh RB, J Fedacko,Takahashi Toru, WHJ
2015, 2016
Peripheral tissue
Endothelial injury
Athero-thrombosis

15. VARIATIONs IN Esinophil count and hormones and
genes were reported in 1950s and 1960

16. VARIATION IN ARTERIAL PRESSURE THROUGHOUT
THE DAY AND NIGHT.
Richardsion DW; Honour AJ; Fenton GW; Stott FH;
PICKERING GW.
Clinical Science. 26:445-60, 1964.
Further details of BPVariations Given by Franz Halberg

17. Time (h), Maximum catecholamines, 6.00-12.00
hours
140
120
100
80
60
40
20
0
Blood pressure (mm Hg)
Heart rate (beats/min)
Plasma Noradrenaline (pg/mL, glucocorticoids),Angio en.
II
Plasma Adrenaline (pg/mL), Cortisol
24.00 2-4AM 6-8AM 10-12 16.00 20.00 24.00 hours
Figure . Circadian rhythms of blood pressure, heart rate
and catecholamines. (Halberg et al 1949,
Effects of time on Circadian rhythms of BPs and HR and
Catecholamines. Highest: 8.00-12.00hrs

18. Time (h), Maximum catecholamines, 6.00-12.00
hours
140
120
100
80
60
40
20
0
Endothelial Dysfunction & Coronary constriction
Platelet aggregation, Thrombus formation
Plasma adrenaline, Noradrenaline (pg/mL), Cortisol
High Free radicals & pro-inflammatory cytokines,
endothelin 1, Metaloprotenases, rupture of plaque.
12AM 2-4AM 6-8AM 10-12.00 20 24.00 hours
Figure 1. Circadian r.hythms of harmful
biomarkers and catecholamines
16
Effects of time on Circadian rhythms of Cardiovascular Markers
and Catecholamines and cortisol. Highest: 8.00-12.00hrs

19. Triggers,Clocks and Rhythms
responsible for VVDs.
• Triggers:
• Emotion
• Exersion
• Large meals
• Sleep deprivation
• Exposure-cold,hot
• Smoking
• Upright posture
• Light
• Clocks
• Suprachiasmatic nucleus
• Pineal gland,mel2,1
• Social contact/pets
• Clock gene expression
• Biochem factors/Resis
• to therapy.

20. Circadian rhythm of CV Events in the 2nd quarter of 24 hours
1.Among 1000 high risk subjects, CV events were more common
in the 2nd quarter of 24 hrs, which showed decline with increased
intake of ALA.
Gal D,Pella D, Singh RB. The effect of an alpha-linolenic acid rich diet on the circadian rhythm of cardiac events. World Heart J 2008;1:49-56.
2.Among 200 patients with ACS, increased levels of Lp (a),
hyperglycemia, hyperinsulinemia, rise in TG, and increased CV
events occurred in the 2nd quarter of 24 hours.
Singh RB, Pella D,Rastogi S,Sharma JP,K Kartikey, Goyal VK et al. Increased concentrations of lipoprotein(a),circadian rhythms, and metabolic
reactants evoked by acute myocardial infarction in relation to large breakfast. Biomed Pharmacother 2004, 58(Supple):116-122.
3.SIMILAR FINDINGS WERE OBSERVED AMONG 500 PATIENTS WITH ACS,
Fedacko et al, World Heart J 2018 (In press)

21. Circadian Rhythm of Cardiac Events &
other factors(6.00-12.00AM)
• Muller et al NEJM,1985 AMI, SCD, stroke
• Thompsn et al,Int J Cardiol 1985
• Peters etal, JACC,1993
• Willich et al, AJC 1992
• Singh et al, BMPharmaco,2004
• Platelet aggregation, inflammation,
• Oxidative Stress, and antioxidant deficiency
• is greater in the 2nd quarter of the day.
• Singh et al 2003,2005

22. Chronobiological RF of ACS ?
ACS (n=54) Contr.(n=95)
• Age (yr)49.5+ 4.2 52.1+ 5.2
• BMI(kg/m2)23.7+ 3.2 22.4+3.4
• BP (>140/90)25(46.3)* 25(29.4)
• Glu.Intol.12(22.2)* 10(11.8)
• DM 14(25.9) -
• Smoking 24(44.4) 28(32.9)
• HighTFA (>5g/day)27(50.0) -
• Large meals(>1000)27(50.0)* 25(29.4)
• LargeBreak Fast(>1000)22(40.7)** 10(11.8)**
• W-6/w-3 ratio 45.5 15.8
• Singh et al, Biomed and Pharmaco Ther 2005

23. Lab.data in patients of ACS-VVD,in
relation to Large BF,Singh et al 2004
• Large BF Smal BF
• Data Basal 4Wk Basal 4Wk
• Gluco 7.7 6.7* 6.6 5.5
• TG 1.8 1.7 1.8 1.6
• Insulin 47.5* 36.3* 43.2 27.6
• CoQ 0.2 0.3* 0.2 0.5
• Dconj 27.5 24.6 26.2 24.2
• IL-6 32.6* 23.5* 27.5 20.6
• TNF-a 42.5* 23.6* 38.2 19.6

26. The Physicians Health Study. 1990,
--------------------------------------
. Morning Increase in Platelet Aggregation was treated with
Aspirin or Placebo.
. Largest reduction in the incidence. of infarct was recorded in
morn.
.This indicated that platelet aggregation.is infact a trigger for
new ACS and SCD.

28. Framingham Study,
Am J Card, 2000, n=1919,popula.study
• Hyperglycemia and diabetes were associated.
With low HRV,Low fre. and High freq. Powers indicating their
relation to sympathetic and para sympathetic activity and
brain function.
• and LF/HF ratio were inversely related to glucose levels.
• SDNN and LF and HF powers were reduced in diabetics and in
glucose intolerance.
• Findings indicate that Metabolic Synd may be related to
brains SCN and pituitary and pineal functions.

29. A meta-analysis including 30 studies, Time of onset of AMI was available
in 66,635 patients.
In total 21035 (31.6%) infarction reported in the morning at: 6-12 AM
and remaining 15,200 in the rest 18 hours.
Thus the incidence of NF MI was 40%, RR 1.38(95%,CI 1.37-1.40) higher
in the morning than rest of the day.
27.7% infarctions were observed which accounted for 8.8% (95% CI 8.5-
9.0) of all infarctions, attributed to morning excess of AMI onset.
Cohen MC, et al, did Meta-analysis of the morning excess of AMI and SCD. Am J Cardiol. 1997; 79: 1512–
1516.
1.INCREASED PREVALENCE OF ACS AND SCD IN THE MORNING

30. SCD (Cohen et al, Contd)
All the 19 published on SCD were similar to MI and the results
were consistent across studies.
Of 19,390 patients in which time of death was known from 19
studies of SCD, there were: 5834 (31.1%) SCD reported in the
morning, and rest 4519 in the rest of 18 hours of the day.
The incidence rate of SCD was 29 %, RR 1.29,CI 1.26-1.32
Thus 22.5% of morning SCD which accounted for 6.8%, RR , CI
6.4-7.1 of all SCDs were attributable to morning excess.

31. CONCLUSIONS
The Evolution of the Circadian Rhythm Occurred as
an attempt to survive and preserve the progeny by
having mating in the morning before going to
jungle for hunting.
All the published studies on CVDs; ACS, & SCD
were similar and the results were consistent across
studies, showing that CV events are more common
during 2nd quarter of the 24 hour cycle of day and
Night.