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Published: 2023.11.21
5780 1 2 105
Circadian Rhythms in Cardiovascular Function:
Implications for Cardiac Diseases and
Therapeutic Opportunities
EF 1,2 Jiayue Lin*
F 1 Haoming Kuang*
BF 3 Jiahao Jiang
A 4 Hui Zhou
B 2 Li Peng
AE 2 Xu Yan
EF 5 Jianjun Kuang
* Jiayue Lin and Haoming Kuang contributed equally to this paper
Corresponding Authors: Xu Yan, e-mail: yanxu0116@163.com, Jianjun Kuang, e-mail: 13755069374@163.com
Financial support: None declared
Conflict of interest: None declared
Circadian rhythms are internal 24-h intrinsic oscillations that are present in essentially all mammalian cells
and can influence numerous biological processes. Cardiac function is known to exhibit a circadian rhythm and
is strongly affected by the day/night cycle. Many cardiovascular variables, including heart rate, heart rate vari-
ability (HRV), electrocardiogram (ECG) waveforms, endothelial cell function, and blood pressure, demonstrate
robust circadian rhythms. Many experiential and clinical studies have highlighted that disruptions in circadi-
an rhythms can ultimately lead to maladaptive cardiac function. Factors that disrupt the circadian rhythm, in-
cluding shift work, global travel, and sleep disorders, may consequently enhance the risk of cardiovascular dis-
eases. Some cardiac diseases appear to occur at particular times of the day or night; therefore, targeting the
disease at particular times of day may improve the clinical outcome. The objective of this review is to unravel
the relationship between circadian rhythms and cardiovascular health. By understanding this intricate inter-
play, we aim to reveal the potential risks of circadian disruption and discuss the emerging therapeutic strate-
gies, specifically those targeting circadian rhythms. In this review, we explore the important role of circadian
rhythms in cardiovascular physiology and highlight the role they play in cardiac dysfunction such as ventricu-
lar hypertrophy, arrhythmia, diabetes, and myocardial infarction. Finally, we review potential translational treat-
ments aimed at circadian rhythms. These treatments offer an innovative approach to enhancing the existing
approaches for managing and treating heart-related conditions, while also opening new avenues for therapeu-
tic development.
Keywords: Arrhythmias, Cardiac • Chronobiology Disorders • Circadian Rhythm • Heart Rate
Full-text PDF: https://www.medscimonit.com/abstract/index/idArt/942215
Authors’ Contribution:
Study Design A
Data Collection B
Statistical Analysis C
Data Interpretation D
Manuscript Preparation E
Literature Search F
Funds Collection G
1 Postgraduate School, Hunan University of Chinese Medicine, Changsha, Hunan,
PR China
2 Department of Cardiovascular, The Affiliated Hospital of Hunan Academy of
Traditional Chinese Medicine, Changsha, Hunan, PR China
3 Department of Chinese Medicine, The First People’s Hospital of Kunshan, Suzhou,
Jiangsu, PR China
4 Department of Cardiovascular, Beibei Hospital of Chinese Medicine, Chongqing,
PR China
5 Department of Orthopedics and Traumatology, The Affiliated Hospital of Hunan
Academy of Traditional Chinese Medicine, Changsha, Hunan, PR China
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DOI: 10.12659/MSM.942215
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Background
Circadian rhythms are a natural phenomenon that consists
of approximately 24-h intrinsic oscillations that regulate the
sleep–wake cycle and various other biological processes [1].
In mammalians, circadian rhythms are affected by 2 sets of
circadian clocks: the central/primary clock and the periphery
clock. The central clock is located in the suprachiasmatic nu-
cleus (SCN) of the hypothalamus, whereas peripheral clocks
are present in tissues [2,3].
The central circadian clock system plays a pivotal role in the
generation of circadian rhythms in mammals [4]. In this way, it
regulates the biological clocks of peripheral organs (eg, heart,
liver, lung, and brain) through the nervous system and endocrine
hormones, thereby fine-tuning the biological clock to changes
in the external environment [5]. Stimulation of SCN with ex-
ternal stimuli such as light signals triggers the production of
biological rhythms which align internal body changes with the
external environment [6]. The peripheral biological clocks exist
in cells, tissues, and organs, where they function by directly
modulating the expression of target genes. In so doing, they
maintain homeostasis of the local internal environment [7].
Circadian processes can be viewed as an integrated system
composed of genes that alter various aspects of organ, tissue,
and cell function, including in the myocardium. Various studies
have identified the presence of peripheral clocks in cardiovas-
cular cells [8,9]. Numerous cardiovascular variables, including
heart rate, cardiac contractility, stroke volume, ECG waveforms
(RR, PR, QRS, and QT intervals), endothelial function, and blood
pressure, exhibit robust circadian rhythms [10-14]. In humans,
the circadian clock system is an evolved process synchronized
with the alternating light-to-dark changes of the external envi-
ronment – a phenomenon termed entrainment. Consequently,
humans are awake during the daytime and sleep at night.
Numerous biological processes and phenotypes, including
blood hormone levels [15], body temperature [16], sleep [17],
and locomotor activity display a circadian pattern [18]. In the
cardiovascular system, circadian rhythms modulate cardiac
contraction and metabolic activities and maintain other func-
tions, such as heart rate and blood pressure, which are high-
er during the daytime and lower at night [15].
Circadian disruption broadly refers to multiple types of circa-
dian clock disturbances, including circadian misalignment [19]
and circadian desynchrony [20] or desynchronization [21].
These disturbances can manifest across various biological
levels, from cellular and tissue scales to organismal and sys-
temic scales. Circadian misalignment is a mismatch between
an individual’s internal circadian clock and their external en-
vironment or social schedule. Circadian desynchrony or de-
synchronization both refer to a variance in the cycles of 2 or
more rhythms. Both concepts can be quantified by measur-
ing the phase angle differences and comparing the estimated
durations of the rhythms.
Cardiac disorders are multifactorial, and circadian disruption
has been shown to enhance their risk by 40-63% [22-24], par-
ticularly in diseases such as arrhythmia and acute myocardial
infarction [25]. This paper reviews basic studies investigating
the mechanisms of circadian clock disorders, as well as clini-
cal studies exploring the impact of circadian clock disorders on
the cardiovascular system. In this review, we provide a detailed
discussion of the significance and impact of circadian rhythms
on cardiovascular function. Moreover, we dissect the correla-
tions between circadian rhythms and cardiovascular diseases.
Lastly, a summary of potential translational therapies target-
ing circadian rhythms are reviewed to offer insights into the
use of current management and treatment strategies of car-
diac diseases and guide future development of new therapies.
Circadian Genes
The circadian clock in most mammalian cells is driven by an
autoregulatory transcriptional–translation feedback network.
This circadian clock is regulated by a set of molecules that form
self-sustained transcriptional feedback loops with a 24-h cy-
cle, ultimately giving rise to fluctuations in the proteome and
cellular activity [9]. The core circadian “clock gene” products
are shown in Table 1.
In mammals, the circadian clock machinery includes the
core circadian molecules BMAL1 and CLOCK (and its paralog,
NPAS2). Upon heterodimerization, the BMAL1: CLOCK com-
plex binds to enhancer-box (E-box) domains in the promoters
of various target genes. A key function of this complex is the
regulation of 2 cryptochrome genes (Cry1, Cry2) and 3 period
genes (Per1, Per2, and Per3) involved in the early phase of the
cycle. It has been reported that PER3 makes a modest contri-
bution to circadian regulation function, while PER1 and PER2
play an essential role in circadian rhythm [26]. Moreover, it
has been suggested that PER and CRY proteins create a neg-
ative feedback loop by forming a complex, which upon entry
into the nucleus, interacts with BMAL1 and CLOCK, inhibiting
the transcriptional activity of BMAL1: CLOCK complex, there-
by suppressing their own transcription. The expression levels
of CRY and PER proteins are determined by E3 ubiquitin ligase
complexes, and the duration of this feedback cycle is approx-
imately 24 h [27]. In addition, other feedback loops interact-
ing with the core CLOCK-BMAL1/PER-CRY loop participate in
the regulation of the clock genes. One such loop is the Rev-
erba (Nr1d1) and RORa that coordinates CLOCK-BMAL1 func-
tions. REV-ERBa and RORa individually bind to retinoic acid-
related orphan receptor response elements (RORE) to regulate
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Abbreviation Full name Common alternative names
b-HLH-PAS proteins
CLOCK Circadian locomotor output cycles kaput bHLHe8
NPAS2 Neuronal PAS domain protein 2 Mop4, bHLHe9
BMAL1 Brain and muscle ARNT-like 1 Arntl, bHLHe5, Mop3, Arnt3
BMAL2 Brain and muscle ARNT-like 2 Arnl2, bHLHe6, Mop9, Clif
DEC1 Differentiated embryonic chondrocyte-expressed gene 1 Bhlhe40, Sharp-2, Stra13
DEC2 Differentiated embryonic chondrocyte-expressed gene 2 Bhlhe41, Sharp-1
PERIOD proteins
PER1 Period 1 (period circadian protein homolog 1)
PER2 Period 2 (period circadian protein homolog 2)
PER3 Period 3 (period circadian protein homolog 3)
Cryptochromes
CRY1 Cryptochrome 1 (photolyase-like)
CRY2 Cryptochrome 2 (photolyase-like)
Orphan nuclear receptors
REV-ERBa Nuclear receptor subfamily 1, group D, member 1 Nrld1, Rev-erb-alpha
REV-ERBb Nuclear receptor subfamily 1, group D, member 2 Nrld2, Rev-erb-beta, RVR
RORa RAR-related orphan receptor alpha (ROR-alpha) Nrlf1, Rora, ROR1
RORb RAR-related orphan receptor beta (ROR-beta) Nrlf2, Rorb, RZR-beta
RORy RAR-related orphan receptor gamma (ROR-gamma) Nrlf3, Rorc, Thor, TOR
Casein kinases
CK1 Casein kinase 1 delta Csnk1d,CK1d
CK1 Casein kinase 1 epsilon Csnkle, CK1e, tau mutation
CK1 Casein kinase 1 alpha Csnk1a1
CK2 Casein kinase 2 alpha 1 Csnk2a1
Ubiquitin ligase (SCF complex) F box proteins
FBXL3 F-box and leucine-rich repeat protein 3 SCF F-box like 3
FBXL21 F-box and leucine-rich repeat protein 21 SCFFbx121, FBXL3B
b-TrCP1 Beta-transducin repeat containing protein Fbw 1a; FWD1
b-TrCP2 Beta-transducin repeat containing protein 2 Fbxw11; BTRCP
PAR bZIP transcription factors
DBP D site albumin promoter binding protein D-box binding protein
HLF Hepatic leukemia factor
TEF Thyrotroph embryonic factor
R4BP4 E4 promoter-binding protein 4 Nuclear factor IL3 (NFIL3)
Table 1. Core circadian “clock gene” products and other clock-relevant protein families.
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BMAL1 transcription. RORs active the Bmal1 gene expression
while REV-ERBa represses Bmal1 expression (Figure 1). This
loop affects the transcription of Bmal1 (and partially CLOCK)
triggering the antiphase oscillation of BMAL1. This machinery
is present in both central and peripheral clocks and controls
biological processes via clock-controlled genes. Other feedback
loops are those of the PAR-bZip family, TEF, HLF, and DBP; the
bHLH proteins, DEC2 (Bhlhb3, Bhlhb2) and DEC1, and the bZip
protein, E4BP4 (Nfil3), all of which are transcriptional targets
of CLOCK-BMAL1 [27]. In summary, at the start of this feed-
back loop, specific transcription factors stimulate the tran-
scription of genes, which serve as the inhibitory components
of the mechanism. Throughout a diurnal cycle, the concentra-
tion of these inhibitory components increases until they can
infiltrate the nucleus and impede the functions of the initiat-
ing transcription factors. After their degradation, the initiating
transcriptional factors are reactivated, thereby re-initiating the
cycle. This intricate mechanism engenders a consistent oscil-
latory pattern of gene expression that is approximately con-
gruent with a 24-h circadian rhythm.
In addition to the feedback loops, circadian rhythms are gov-
erned by a range of alternative processes. For instance, cir-
cadian rhythms are modulated by polyadenylation, histone
modification, methylation, and non-coding RNAs. The preci-
sion and robustness of circadian rhythms rely heavily on the
indispensability of translational and epigenetic processes [28].
By modulating the expression of different components of the
circadian clock process, the clock can regulate a plethora of
cellular processes, such as signal transduction, transcription,
translation, metabolism, and ion homeostasis. Consequently,
it is estimated that circadian clocks regulate a 3-16% of the
transcriptome [29].
Circadian Clock-Related Cardiac Function
Normal cardiac function is tightly intertwined with circadian
rhythm, which regulates aspects of cardiac activity, such as
blood pressure, heart rate, electrocardiography (ECG) wave-
form, and cardiovascular health. Circadian clocks are ubiq-
uitous and are present in various cardiovascular cell types,
REV-ERB
rev-erb
EBOX
EBOX per
EBOXcry
ccg
EBOX
EBOXD-box
dbp/tef/hlf/e4bp4
DBP
HLF
TEF
E4BP4
RORE Bmal1
BMAL1
RORE CLOCK
CLOCK
PER
CSNK1
E/D
CRY
PER
CSNK1
E/D
CRY
EBOX Rorα
RORs
Cytoplasm
Nucleus
Promote Repression
Repression
Nuclear
translocation
Clock controlled genes
CLOCK
OUTPUTS
Figure 1. The molecular mechanism of the circadian clock in mammals. Constituting the core circadian clock is an autoregulatory
transcriptional feedback loop involving the activators CLOCK and BMAL1 and their target genes Per1, Per2, Cry1, and Cry2,
whose gene products form a negative-feedback repressor complex.
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including cardiomyocytes, vascular smooth muscle cells, fibro-
blasts, endothelial cells, and immune cells [6,30,31]. Oishi et al
first reported day-dependent rhythmic cardiac expression of
circadian gene Bmal1 and Per2 mRNA in the mouse myocar-
dium [32]. A study conducted using isolated adult rat cardio-
myocytes in culture found robust rhythmic expression of circa-
dian clock genes with periodicities of 20-24 h following serum
shock [33]. A study using human embryonic stem-cell-derived
cardiomyocytes found rhythmic expression of clock genes dur-
ing cardiac differentiation [34]. Moreover, the mRNA level of
Bmal1 has been shown to peak at the beginning of the light
phase in the rat myocardium, whereas in humans this peak
occurs at the onset of night. This difference coincides with be-
havioral changes, such as the wake/sleep cycle difference ob-
served between nocturnal rodents and diurnal humans [35].
These observations suggest that the heart not only responds
to external circadian signals but also possesses its own intrin-
sic rhythmic regulatory mechanisms.
The cardiac metabolism has been proposed to have a tempo-
ral partitioning: the peak of oxidative metabolism occurs in
the initial half of the active phase, potentially supplying ade-
nosine triphosphate to meet the heightened energy require-
ments of increased contractility. During the latter half of the
active period, the synthesis of glycogen and triglyceride peak
in the heart to prepare for sleep. During the initial phase of
rest, emphasis shifts to protein turnover, ensuring the cell or
organ functions properly upon waking up [36]. Loss of circa-
dian genes can affect cardiac metabolism; in cardiac-specific
Bmal1 or Clock gene knockout mice, the rates of synthesis of
triglyceride and glycogen, glucose oxidation, and cellular con-
stituent turnover are all altered and dysregulate the day/night
rhythm in cardiomyocytes [37-40]. Imbalances in these met-
abolic pathways can lead to obesity and diabetes, which are
major risk factors for cardiovascular diseases.
Circadian genes also regulate the cardiac electrophysiology.
Many key ion channel subunits function, including Nav1.5,
Ca
v
1.2, K
v
4.2, KChIP2, K
v
1.5, ERG, TASK-1, Cx40, and Cx43, vary
with the circadian rhythms in the atria and ventricles [41], and
IKr, ICaL, and Ito have also been demonstrated to match the
circadian rhythm pattern [42-45]. Furthermore, the sinus node
was found to be a circadian clock that controls intrinsic pace-
maker activity of the heart via regulation of HCN4 and the cor-
responding funny current (If), and loss of Bmal1 in the heart
abolished the heart rate day–night difference [46].
In terms of cardiac function, blood pressure follows a cir-
cadian pattern, typically rising during the daytime and de-
creasing at night. This interaction is mediated by the circadi-
an clock and hormone fluctuation. Similar to blood pressure,
circadian rhythms have a significant influence on heart rate
and ECG waveform. The initial heartbeat is initiated by highly
specialized cells known as the pacemaker cells that form the
sinoatrial node (SAN). This pacemaker generates electrical sig-
nals that can be detected on the skin by ECG. Typically, ECG
constitutes a sequence of upward and downward spikes (la-
belled P, Q, R, S, and T) that reflect the repolarization (voltage
becoming more negative) and depolarization (voltage becom-
ing more positive) of the action potential in the atria and ven-
tricles. Humans have evolved a physiological diurnal rhythm
to adapt to the 24-h day–night changes. Among the main fea-
tures of this rhythm is the diurnal variation in the heart rate,
with the lowest rate during sleep time and the highest rate
during waking hours. The first evidence for the existence of
this phenomenon came from continuous electrocardiography
monitoring of patients over 24-h day/night cycles by Millar-
Craig in 1978 [47]. The circadian rhythm can be affected by
various aspects, such as light, feeding, homeostasis, and phys-
ical activities. When these factors are modified, there may be
a mismatch between the central clock and peripheral clock,
which can induce circadian misalignment (Figure 2).
Light
The endogenous diurnal rhythm of the SCN is synchronized to
the diurnal cycle most effectively by light. Herein, light is the
most potent external cue for SCN, which can affect neuronal
Physical
activity
Mental
stress
Feeding time
reschedule
Light
cycle
Circadian gene
modication
Cardiac function
SCN lesion
Figure 2. Environmental and behavioral cues to trigger circadian
disruption in animals. Circadian disruption can be
triggered by environmental cues, mainly light/dark
cycle manipulations, behavioral cues such as feeding
time rescheduling, physical activities, and mental
stress, suprachiasmatic nuclei lesions, and gene
modification.
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firing frequency, alter circadian gene expression [48], and af-
fect other peripheral clock functions (eg, in the heart). Because
light influences daily routine, cardiovascular risk also shows a
day–night difference. Most cardiovascular incidents occur in
the morning from 6 a.m. to noon), and there is another peak
from 6 p.m. to midnight, which indicates a bimodal pattern of
risk [49]. The “morning shift” in cardiac sympatho-vagal bal-
ance is probably involved in the risk of cardiovascular disease
at that time. Therefore, light-caused circadian clock disruption
may be a risk factor in cardiovascular disease, contributing to
increased HR and HRV during high-risk periods. Because the
endogenous circadian rhythm is best synchronized to the di-
urnal change by light [50], it is reasonable to infer that expo-
sure to light regulates cardiovascular function [51]. Thus, un-
derstanding the interaction between light exposure, circadian
rhythms, and cardiovascular health may suggest potential av-
enues for formulating preventive and therapeutic strategies.
Physical Activity
Physical activity is also an important factor in circadian rhythm
orchestration and cardiovascular function. It is well known that
the circadian rhythm of blood pressure is regulated by physi-
cal activity. Cardiovascular events have demonstrated a posi-
tive correlation with physical activity during the early morning
hours in individuals with hypertension. However, the surge in
cardiovascular incidents during this morning peak cannot be
exclusively attributed to daily variations in external factors such
as activity [52]. Rather, it is more likely to be associated with
the interplay of activity-induced circadian alterations in blood
pressure, vascular tone, catecholamines, platelet aggregation,
elevation in plasminogen activator inhibitor-1, heart rate (HR),
and fluctuations in the beat-to-beat interval. Conversely, the
cardiometabolic requirements exhibit significant fluctuations
throughout the day and night, aligning with physical activity
patterns. A study indicated that physical and mental activities
can incite ischemic episodes during the morning hours in indi-
viduals with stable coronary artery disease [53]. Additionally,
an activity-independent circadian influence maintains a height-
ened level of ischemic incidents during the awake period.
Consequently, the temporal fluctuations in cardiovascular in-
dicators stem from a combination of external activity and in-
trinsic circadian influences [54].
Feeding
Mammals exhibit daily anticipatory activity to cycles of
food availability. Early studies have demonstrated an SCN-
independent food-entrainable oscillator (FEO), which is sep-
arate from the light-entrained oscillator (LEO) located in the
SCN. The FEO is characterized by increased locomotor activity
in the hours preceding food delivery. This anticipatory behav-
ior is also referred to as food anticipatory activity (FAA) [55].
It has previously been well-documented that the circadian
rhythm is generated by circadian genes at the molecular lev-
el, and this may be the molecular basis of generation of food-
entrained rhythms. Numerous studies in GM mice have re-
vealed the role of clock gene and FAA [56-59]. It was reported
that Clock-mutant mice still have FAA, which demonstrated
that the Clock gene is not necessary for expression of FEO, but
suggests that FEO is mediated by a molecular mechanism dis-
tinct from that of the SCN [56]. Dudley et al found that NPAS2
knockout mice also exhibit similar results regarding FEO [57].
Studies have also reported that food entrainment decreases in
BMAL1-deficient mice [58] and Cry1/Cry2-deficient and Per2-
mutant (but not Per1-deficient) mice [59]. Together, these stud-
ies provide strong evidence for a functional food-entrainable
oscillator. In addition to this, the occurrence of FAA in animals
with complete SCN lesions reflects the presence of an SCN-
independent oscillator acting as a pacemaker that regulates
locomotor activity rhythms. The FEO misalignment may lead
to some metabolic changes; for example, Clock-mutant mice
showed an altered feeding rhythm, hyperphagia, and obesi-
ty, and a metabolic syndrome of hyperleptinemia, hyperlipid-
emia, hepatic steatosis, hyperglycemia, and hypoinsulinemia.
The alternation of glucose homeostasis is associated with se-
vere comorbidities of cardiovascular disease [60].
Effects of Circadian Disruption on
Cardiovascular Function
Many studies have found a link between disruption of the
circadian rhythm and the onset of cardiovascular diseases.
Circadian disruption may be triggered by environmental manip-
ulation of the central clock, rescheduling of behavioral cues, or
genetic modification of circadian genes. This disrupts the mo-
lecular circadian clock machinery in peripheral tissues, causing
irregular circadian rhythm patterns of clock genes and their
downstream targets and circadian disruption-induced disor-
ders. Multiple studies have shown a positive correlation be-
tween the risk of developing cardiac disease and duration of
exposure and circadian disruption severity. Numerous cardio-
vascular processes are highly regulated by circadian rhythms.
Circadian disruptions can alter the function of the myocardi-
um, leading to cardiac dysfunction, onset of arrhythmias, and
acute myocardial infarction.
The impact of circadian disruption on 24-h heart rate appears to
be dependent on the duration of exposure. Short-term circadi-
an disruption studies, whether using a 8-day circadian misalign-
ment protocol on 14 healthy adults [22], an acute circadian dis-
ruption protocol consisting of 2 normal 24-h days followed by 7
recurring 28-h days on 10 adults [61], or 2 normal 24-h days (16
h awake, 8 h sleep), followed by twelve 20-h days (13 h 20 min
awake, 6 h 40 min sleep) on 12 healthy adults [62], consistently
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found no significant change in heart rate rhythms. However, the
effects become apparent during long-term disruptions. A 2-week
study involving 26 healthy adults exposed to restricted sleep re-
vealed a pronounced increase in daytime heart rate, particularly
for those sleeping during the day [63]. Furthermore, in a year-
long study with 71 participants, shift workers experienced a 2.08
beats per minute reduction in average 24-h heart rate compared
to the previous year, with a distinct difference emerging between
continuous daytime and shift workers [64]. In addition, circadian
disruption also affects cardiac function. For instance, short-term
circadian disruption causes atrial dysfunction, while prolonged
disruption leads to ventricular dysfunction [7].
Daytime sleep is the common way for nightshift workers to re-
store their sleep, but this cannot provide the same cardiovas-
cular restorative effect as night-time sleep. Chung et al found
night shift work is associated with higher sympathetic activ-
ity during night-time sleep than regular working. In addition,
nightshift work induces higher cardiac sympathetic regula-
tion [65]. Similar findings were obtained by Viola et al, who re-
ported that individuals with longer allele of the circadian clock
gene Per3 polymorphism have higher sympathetic cardiac dom-
inance during sleep compared to individuals with the short-
er allele [66]. There are various studies focusing on circadian
disruption-induced human health conditions. It is obvious that
circadian disruption affects cardiac function and metabolism
of shift workers. A study by Herrero et al revealed that chron-
ic circadian disruption triggers significant changes in neuro-
peptides secretion, lipid metabolism, inflammatory reactions,
and regulation of endoplasmic reticulum stress (ER stress) gene
profile in metabolically relevant tissues such as the hypothal-
amus, liver, white adipose tissue (WAT), and brown adipose
tissue (BAT) [67]. These findings point to the possibility that
abnormal alterations of circadian rhythm have widespread ef-
fects, including compromised metabolism at the transcription
level. It has been recognized that people who cannot adapt to
shift work may have a significantly increased RR interval com
-
pared with those who can adapt to night shift work, and the
latter group of people have a sympathetic dominance due to
circadian misalignment [68]. Additionally, a systematic review
examined the relationship of night shift work with cardiovas-
cular risk factors based on studies published in a 10-year pe-
riod [69], showing that the effect of night shift work on vari-
ous body indexes varied with age and gender. However, they
found that night shift work had a prominent effect on BMI and
lipid and glucose metabolism. This provides strong evidence
that occupational factors are related to cardiovascular disease.
Chronic circadian desynchronization can significantly decrease
survival in people with cardiomyopathic heart disease, which
may be related to reports of increased cardiovascular morbid-
ity and mortality in people engaged in long-term shift work.
Most shift workers have misalignment between endogenous
circadian rhythms and their atypical sleep–wake schedule.
Most night shift workers unable to parallel their circadian pace-
maker with phase shifts immediately, as indexed by loss the
rhythm in entrainment of the core body temperature, mela-
tonin, and cortisol levels to a night schedule [70,71]. Chronic
circadian misalignment leads to sleep and performance prob-
lems and contributes to the association between night work
and adverse health outcomes, which increases risk of cardio-
vascular diseases [72], metabolic syndrome [73], diabetes [74],
and autoimmune hypothyroidism [75] when compared to the
general population. Brown et al tested the heart rate variabil-
ity in emergency physicians and found the sympathetic tone
was heightened during shift work [76], suggesting that dis-
ruption of circadian rhythm deregulates sympathetic nervous
activation, thereby affecting heart rhythm.
Cardiac Hypertrophy
Various genetically engineered mice with circadian gene modi-
fications show signs of cardiac hypertrophy and ventricular dys-
function. Cardiomyocyte-specific CLOCK-mutant (CCM) mice,
which express a dominant negative CLOCK-mutant protein lack-
ing the transactivation domain, subjected to circadian disrup-
tion exhibited lower heart rates, attenuated diurnal variations,
lower cardiac efficiency, and a higher mortality rate relative to
control animals [77]. Mice displayed altered fractional short-
ening (FS), left ventricular ejection fraction, septal wall thick-
ness, increased biventricular mass, and increased biventricu-
lar weight-to-body weight ratio compared to controls [78,79].
The cardiomyocyte cross-sectional area was also enhanced, in-
dicating cellular hypertrophy in CCM hearts. SERCA2a, MHC-
a
,
and MHC-
b
were significantly elevated by circadian disruption
in both CCM and control mice, and hypertrophy is known to be
time-of-day dependent. Upon administration of isoproterenol,
a pro-hypertrophic agonist, during the awake-to-sleep phase
transition (ZT 0) or during the sleep-to-awake phase transition
(ZT 12) for 7 consecutive days, biventricular weight-to-body
weight ratio was found to be highest at ZT 0 in CCM mice rela-
tive to controls. While isoproterenol-induced cardiac hypertro-
phy exhibited time-of-day variation in control mice, this oscilla-
tion was abolished in CCM mice. Consistently, ANF, a marker of
hypertrophy, was significantly elevated in isoproterenol-treated
CCM hearts at ZT 0 and ZT 12 in the absence of a diurnal varia-
tion [79]. Moreover, genetic deletion of BMAL1 predisposed the
heart to hypertrophic growth. Cardiac-specific BMAL1 knockout
(BMAL1
cko
) mice exhibited significantly enlarged hearts, with a
15% increase in left ventricular weight from 4 weeks of age.
Progressive eccentric hypertrophy-induced ventricular dilation
was observed in 32-week-old BMAL1
cko
mice. The fractional
shortening also significantly decreased (24.3%) and enlarged
(17.12%) the left ventricular internal diameter in 36-week-old
BMAL1cko mice relative to control littermates [80]. Moreover,
reduced BMAL1 expression in the heart was correlated with a
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marked reduction in amplitude of the circadian rhythms of cir-
cadian genes and their downstream targets [81]. MHC-
a
and
MHC-
b
mRNA levels were significantly reduced [80], while the
expression of the collagen isoforms Col3a1 and Col4a1 and
the cardiac dysfunction markers ANF and MHC-
b
were elevat-
ed. Additionally, Serca2a expression [81] and DBP diurnal vari-
ations were suppressed, while expression of the hypertrophic
marker MCIP1 was elevated [79]. Together, these observations
suggest that reduced BMAL1 expression enhances collagen ex-
pression in the myocardium, impairing myocardial contractility
and causing subsequent cardiac dysfunction.
Circadian disruption exhibits complex effects on cardiac hyper-
trophy in a transverse aortic constriction (TAC) animal model. A
study of 7-week-old rats did not find any differences in the cir-
cadian expression of the clock genes Bmal1, Clock, Per1-3, and
CRY1-2, in rats subjected to TAC relative to age-matched con-
trols. However, rhythmic expression of the clock-controlled tran-
scription factors, DBP, HLF, and TEF was blunted [82]. Indeed,
DBP/TEF/HLF triple knockout mice exhibit cardiac hypertrophy,
left ventricular dysfunction, increased morbidity, and shortened
life span [83]. Thus, DBP, HLF, and TEF might have major roles
in cardiac function and hypertrophy. Housing TAC mice in 20-h
light/dark cycles exacerbated pathophysiological signs, such as
enhanced LVEDD and LVESD, as well as decreased FS and con-
tractility. However, these TAC mice exhibit reduced hypertrophy
and myocyte size relative to TAC mice housed in 24-h light/dark
cycles [84]. Indicating that reduction of circadian disruption by
housing under a shorter light/dark cycle might minimize car-
diomyocyte hypertrophy, but not structural remodelling in TAC
mice. Interestingly, transferring TAC mice from 20-h to 24-h light/
dark conditions for 8 weeks rescued the pathological cardiac re-
modelling, resulting in reduced signs of vascular smooth muscle
layer hyperplasia, enhanced myocyte volume, normal Per2 and
Bmal1 expression relative to controls, and expression of hyper-
trophy markers, including ANF, BNP, ACE, and COLLAGEN [84].
Together, these findings showed that circadian disruption may
rescue the cardiac hypertrophy mediated by the clock output
targets DBP, HLF, and TEF. These studies revealed that such re-
versal of cardiac hypertrophy is mediated by the inhibition of
circadian clock genes, including Bmal1 and Per2. These findings
suggest that deregulation of circadian gene dynamics predis-
pose individuals to cardiac maladaptations, improving our un-
derstanding of the genes associated with human cardiac diseas-
es, especially in people exposed to irregular circadian patterns
or performing shift work. This review lays the foundation for
developing potential therapeutic interventions based on circa-
dian gene pathways to combat cardiac dysfunction.
Arrhythmia
In humans, circadian disruption can alter the function of both
the atria and ventricles, as short-term circadian disruption
causes atrial dysfunction, while prolonged disruption causes
ventricular dysfunction. A study involving 11 participants ob-
served a marked increase in atrial premature beats after work-
ing a 24-h shift [7]. Ventricular dysfunction induced by circadian
disruption correlates with the duration of exposure. Although
premature ventricular contractions were not observed after 1
night shift [7], a 24-h ECG monitoring study indicated that sig-
nificant exacerbation in ventricular dysfunction occurs with
increased duration of exposure to circadian disruption, which
correlates with cardiac disease. In a study of physicians with
58-106 months of night-shift experience, the number of ven-
tricular premature beats between midnight and 6 am on a 24-h
on-call shift was significantly elevated [85]. Following a 1-year
study, Van Amelsvort et al reported similar findings, demon-
strating that the frequency of premature ventricular complex-
es was significantly higher in 49 night shift workers relative to
22 daytime workers, and was significantly correlated with the
number of work nights [64]. Ventricular ectopic beats occurrence
also was correlated with frequency and duration of exposure
to night shifts [86]. Individuals routinely working night shifts
may face increased cardiac risks; therefore, people working pro-
longed night shift schedules may benefit from regular cardiac
monitoring, especially if they display or report any symptoms
of cardiac distress. This would allow for early detection and in-
tervention if arrhythmias or other cardiac issues are identified.
A 10-year study reported significantly prolonged QTc in 158
night shift workers relative to 75 daytime workers but did not
find differences in systolic or diastolic blood pressure [87].
Similar observations have been reported by Meloni et al, who
observed significant QTc prolongation in participants with ab-
normal repolarization phases. However, it did not correlate with
other ECG abnormalities, including conduction, heart rhythm
disorders, BMI, or age. Prolonged QTc interval may lengthen
action potential and is a putative pro-arrhythmogenic factor,
especially for long QT (LQT) syndrome. LQT 1, 2, and 3 are the
most common forms of LQT syndrome and result from cardiac
ion channel dysfunction. LQT 1 and 2 result in decreased out-
ward potassium currents, while LQT 3 enhances inward sodi-
um currents [88]. In LQT1 patients, only 3% of abnormal ECG
events occur during the night-time rest/sleep phase. However,
in LQT2 and 3, abnormal ECG events occurring at night have
been found to be 29% and 39%, respectively. Moreover, le-
thal events during rest/sleep without arousal occur in 49%
and 64% of LQT 2 and LQT3 cases, respectively [89]. A recent
clinical study of 26 LQT patients found that LQT1 patients ex-
hibit modest QTc shortening, LQT2 patients exhibit modest
lengthening at night versus daytime, and LQT3 patients ex-
hibit clear QTc lengthening at night. These changes are not ex-
plained by heart rate changes or by the use of beta-blockers
[90] and are thought to be associated with sodium and po-
tassium channels. Moreover, the voltage-gated Na+ channel,
Nav1.5, exhibits a circadian expression pattern in the heart,
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and circadian rhythm is dampened by BMAL1 ablation [91].
Similarly, the potassium channels Kv1.5, Kv4.2 and ERG1 ex-
hibit circadian variations in gene expression and electrophys-
iological current function [92,93]. Circadian disruption mod-
ifies key ion channel activities regulated by circadian genes,
inducing prolonged QTc intervals. This may explain the high-
er cardiac dysfunction, including sudden cardiac death, ob-
served in shift workers.
Ischemic Heart Disease
Circadian rhythms play an indispensable role in the manifes-
tation and progression of ischemic heart disease. Intriguingly,
some cardiac diseases preferentially occur at a particular time
of the day or night. In humans, attacks from ventricular ar-
rhythmias and sudden cardiac death are common in the morn-
ing (the start of the awake period) [41]. Moreover, single-nu-
cleotide polymorphisms in genes encoding for circadian clock
components have been linked to an increased risk of myocar-
dial infarction [94]. Durgan et al revealed that the heart’s tol-
erance to ischemia/reperfusion (I/R) damage varies based on
the time of day, with the most significant damage occurring at
the sleep-to-wake transition. This time-of-day dependence in
I/R tolerance is mediated by the cardiomyocyte circadian clock
[95]. Gaining insight into and potentially influencing this bio-
logical clock could present innovative approaches for address-
ing cardiac dysfunctions caused by ischemia. This is particu-
larly relevant given that the highest-risk time period coincides
with the typical occurrence of heart attacks in humans. A re-
cent study by Zhao et al found that shift workers had an in-
creased susceptibility to myocardial infarction reperfusion in-
jury [96]. Shift work was associated with increased infarct size
and increased risk of major adverse cardiac events. Consistent
with the clinical findings, shift work simulation in sheep and
mice worsened reperfusion injury in acute myocardial ischemia.
Mechanistically, it was identified that a novel nuclear receptor
subfamily 1 group D member 1/cardiotrophin-like cytokine fac-
tor 1 axis in the heart played a key role in regulating the path-
ological effects of shift work on the myocardium [96]. Using
a mouse model of short-term rhythm disruption, Faisal et al
found that disruption of diurnal rhythm after MI impaired heal-
ing and exacerbated maladaptive cardiac remodelling, dem-
onstrating that the short-term rhythm disruptions interfered
with an early inflammatory phase of LV remodelling, adversely
affecting the innate immune infiltration, and adversely affect-
ing scar formation [97]. Rhythm disruption can also dramat-
ically alter hepatic clock gene expression, bile acid metabo-
lism, and lipid homeostasis, contributing to dyslipidemia [98].
Diabetes
The relationship between circadian rhythms and diabetes is
intricately connected, and understanding this association is
pivotal for managing the disease effectively. Studies have dem-
onstrated the link between disruptions to circadian rhythms,
such as those experienced by shift workers or irregular sleep
patterns, can increase the risk of developing diabetes. Irregular
schedules can lead to impaired glucose tolerance, insulin re-
sistance, and obesity [99]. Circadian rhythms have a substan-
tial impact on glucose metabolism regulation. In humans, glu-
cose tolerance and insulin sensitivity follow a natural daily
cycle, peaking in the morning and reaching their lowest point
at night. This diurnal fluctuation can influence blood glucose
levels, as the level of insulin diminishes during night-time
hours, potentially resulting in elevated fasting blood glucose
levels among individuals with diabetes. Furthermore, eating
meals at consistent times that align with the natural circadi-
an rhythm may help stabilize blood glucose levels. Skipping
meals or eating irregularly can lead to glucose spikes and con-
tribute to diabetes mismanagement [74].
Circadian Rhythm Modulation for
Cardiovascular Disease Treatment
The essential role of circadian rhythms in biological processes
is fundamental in both health and disease. Recognizing and
understanding the importance of circadian rhythms has giv-
en rise to the idea that circadian clocks could potentially be
leveraged for treating and managing cardiovascular diseas-
es. Circadian rhythms display osculating patterns; therefore,
developing a treatment that can take advantage of circadian
governance may have great therapeutic value. Hence, a cru-
cial therapeutic approach involves mitigating these risks dur-
ing the periods of highest vulnerability in the circadian cycle
or reinstating the circadian phase and amplitude to their typ-
ical patterns.
A key consideration of therapeutically targeting the circadian
rhythm is timing. Although patient gender and comorbidities
are often considered during treatment, the timing of the treat-
ment is often overlooked. Many clinical studies investigating
cardiovascular disease treatment also fail to mention the tim-
ing of treatment administration [25]. For example, hypertension
exhibits a higher occurrence in the early morning. Hence, it is
noteworthy that most once-daily antihypertensive drugs are
prescribed for use at around 8 am. This timing leads to peak
drug plasma levels during the day, when adverse effects are
most common. A study by Hermida et al revealed that admin-
istration of an angiotensin-converting enzyme inhibitor at bed-
time resulted in lower nocturnal blood pressure compared to
morning administration [100], and also found that administra-
tion of 5 mg/day of ramipril at bedtime effectively reduced BP
for the entire 24-h period. In contrast, when the drug was tak-
en in the morning, its efficacy was reduced, lasting only for 16
h and did not effectively lower nocturnal blood pressure [100].
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Night-time BP has been determined to be a better predictor
of cardiovascular mortality compared to daytime or 24-h BP.
Therefore, controlling nocturnal BP is crucial. This is particu-
larly important because increased nocturnal BP and a non-dip-
ping pattern are linked to end-organ injury and cardiovascular
events, and this decrease improved cardiovascular outcomes
[100,101]. Furthermore, a recent study found that acutely tar-
geting the circadian driver REV-ERB using SR9009 (non-selec-
tive REV-ERBa/b dual agonist) at the time of perfusion over-
prolonged cardiac recovery and repair following myocardial
ischemia-reperfusion injury [102]. The single-dose treatment
resulted in an estimated 50% reduction in infarct size and de-
creased risk of heart failure development. Treatment resulted
in the downregulation of the cardiac NLRP3 inflammasome,
reducing the inflammatory response and allowing the healing
process to become dysregulated.
An alternate treatment approach could involve shifting the
phase of the circadian clock to a particular phase within phys-
iological rhythms or a specific time-of-day configuration that
would yield the most advantageous outcomes in a particu-
lar scenario. For instance, myocardial infarction typically oc-
curs in the morning, but manipulating the functional and mo-
lecular components of the heart to mimic an environment
similar to the afternoon or evening might hold great poten-
tial. Myocardial infarction patients typically present with in-
creased levels of thrombocytes in the morning, when the risk
of plaque rupture is significantly higher. However, Bonten et
al observed that administration of aspirin at bedtime signif-
icantly reduced platelet activity in the morning in compari-
son to the morning administration of aspirin [103]. The use
of time-specific therapy has also been implemented in stem-
cell-mediated repair. Stem cells derived from both cardiac and
non-cardiac patients (multipotent stem cells) have undergone
evaluation for their potential regenerative and paracrine ef-
fects in the clinical setting [104]. Stem cells have been shown
to have circadian clocks, but investigation into whether em-
ploying stem cells at a particular time of day enhances patient
outcomes remains unclear.
Another primary approach to minimize disruptions in the cir-
cadian rhythm involves reducing desynchronization and aver-
sion. This can be accomplished by exposing patients to regular
24-h signals, ensuring adequate light exposure, and maintaining
a dark environment during the night. When circadian disrup-
tion is evitable, such as during shift work, several strategies
have been developed to reduce the harmful effects, includ-
ing managing shift schedules, taking short naps during shifts,
and regular food intake, which together may limit the impact
of shift work [105].
Conclusions
Circadian clocks orchestrate various critical biological process-
es in virtually all cardiovascular cell types and a diverse spec-
trum of cardiovascular physiologies undergo circadian oscil-
lations, including blood pressure, ECG pattern, heart rate, and
metabolism. The development, progression, and outcome of
various cardiovascular diseases are closely linked to aberrant
circadian rhythms. Disruption of this circadian regulation has
been proven to lead to malfunction in cellular or organ pro-
cesses, ultimately triggering pathological conditions. A more
comprehensive understanding of the molecular mechanisms
that underlie cardiovascular diseases holds the potential to
yield novel treatment strategies or improve current strategies.
Therapeutically, there is increasing recognition of the potential
benefits of treatments for modulating the circadian rhythm in
cardiovascular disease. Timing of treatment, often overlooked
in clinical studies, can have profound effects on efficacy. For
instance, night-time administration of some drugs has been
shown to improve cardiovascular outcomes compared to
morning doses. This circadian–cardiovascular connection un-
derscores the need for clinicians and researchers to optimize
the timing of interventions and to develop strategies to mit-
igate circadian disruptions. Such an understanding could un-
lock novel therapeutic avenues and improve clinical outcomes
of patients with cardiovascular diseases.
Acknowledgements
The diagram in Figure 2 was created using BioRender.com.
Declaration of Figures’ Authenticity
All figures submitted have been created by the authors who
confirm that the images are original with no duplication and
have not been previously published in whole or in part.
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