ARTICLE IN PRESS

Journal of Cardiothoracic and Vascular Anesthesia 000 (2024) 17

Contents lists available at ScienceDirect

Journal of Cardiothoracic and Vascular Anesthesia

journal homepage: www.jcvaonline.com

Review Article
Dexmedetomidine and Perioperative Arrhythmias
Shengji Duan, MD*, Shuzhi Zhou, MDy
,1

*
Department of Anesthesiology, The Second People’s Hospital of Yibin, Sichuan, China
y
Department of Anesthesiology, Ya ’an People Hospital, Ya ’an, Sichuan, China

The highly selective a2-adrenoceptor agonist dexmedetomidine is a commonly used sedative drug for patients undergoing anesthesia and intensive
care treatment. Several studies have indicated that dexmedetomidine may have a potential role in preventing and treating perioperative tachyarrhyth-
mias. However, the specific effect and mechanism of action of dexmedetomidine in this context remain unclear. Dexmedetomidine is known to regu-
late the electrophysiologic function of the myocardium by inhibiting the function of the sinus node and atrioventricular node, as well as affecting
myocardial repolarization. This paper aims to provide a theoretical basis for the prevention and treatment of perioperative arrhythmias by summariz-
ing the effects of dexmedetomidine on myocardial electrophysiologic function and its impact on different types of arrhythmias.
Ó 2024 Published by Elsevier Inc.

Key Words: dexmedetomidine; arrhythmias; electrophysiology

DEXMEDETOMIDINE (DEX) IS A highly selective alpha-
2 adrenergic receptor (a2-AR) agonist that exhibits sedative,
analgesic, antisympathetic, and antianxiety effects. It is exten-
sively used for sedation and analgesia in anesthesiology and
intensive care unit (ICU) patients. With the increasing use of
DEX in clinical practice, research has revealed its beneficial
effects on various organs, including the heart, lungs, kidneys,
and brain, offering multiorgan protection. For its cardioprotec-
tive aspects, there is research evidence that DEX may affect
the development of perioperative arrhythmias, but the mecha-
nism of action is not yet clear. This article reviews the progress
of research related to DEX for the prevention and treatment of
cardiac arrhythmias.
Targets of Action
a2-AR Distribution and Subtypes
there are 4 a2-AR isoforms identified, namely a2A, a2B, and
a2C.1 a2-AR is a member of the inhibitory G protein-coupled
receptor family.2 The distribution of a2A-AR is mainly
observed in central regions, such as the locus coeruleus, parabra-
chial nucleus, pontine nucleus, parahippocampal gyrus, and
cerebral cortex. On the other hand, a2B-AR is primarily found
in peripheral tissues, such as the kidney, liver, lung, heart, and
vascular tissues. a2C-AR, although mainly distributed in central
nerves, including the striatum, olfactory bulb, hippocampus, and
cerebral cortex, exhibits low expression.3
The Effect of DEX on a2-AR
Dexmedetomidine acting on different subtypes of a2-AR in
different tissues can mediate different pharmacologic effects
(Table 1).

Adrenergic receptors belong to the G protein-coupled receptor Acting on a2A-AR

family and include a1-AR, a2-AR, and b-AR. In mammals,
This work was supported by the Sichuan Science and Technology Program
[2023YFS0143].
1
Address correspondence to Shuzhi Zhou, MD, Department of Anesthesiol-
ogy, Ya ’an People Hospital, No.9 Ankang Road, Yucheng District, Ya’an
City, Sichuan Province, China.
E-mail address: zszch@sina.com (S. Zhou).
Dexmedetomidine acts on a2A-AR in the blue spot nucleus,
inhibiting the activity of the locus coeruleus through the fol-
lowing 2 mechanisms: presynaptic inhibition and postsynaptic
inhibition. This action blocks the excitatory transmission of
the upstream norepinephrine pathway from the locus coeruleus
to the subcortex. As a result, DEX triggers and maintains a

https://doi.org/10.1053/j.jvca.2024.01.006
1053-0770/Ó 2024 Published by Elsevier Inc.
 ARTICLE IN PRESS
2 S. Duan and S. Zhou / Journal of Cardiothoracic and Vascular Anesthesia 00 (2024) 17
Table 1
The Actions of Dexmedetomidine on Different Receptors
Dexmedetomidine Action
a2A-AR Sedative, analgesic, anti-sympathetic, anti-anxiety,
anti-inflammatory
a2B-AR Vasoconstriction
a2C-AR Cognitive, emotional, and sensory processes
sedative hypnosis similar to the natural sleep state. This unique
property of DEX distinguishes it from other commonly used
intravenous anesthetics. Dexmedetomidine is used commonly
for sedating patients in the ICU and those undergoing awake
craniotomy due to its effective sedation, minimal impact on
respiratory function, protection of organ function, and ease of
patient arousal.4-9 Dexmedetomidine acts on the presynaptic
membrane of central and peripheral nerves, inhibiting the syn-
thesis and release of norepinephrine, thereby producing an
anti-sympathetic effect.10 Additionally, DEX acts on the pre-
synaptic a2A-AR of spinal cord dorsal horn neurons, resulting
in hyperpolarization of the cell membrane and blocking of sig-
nal transduction. As a result, DEX exhibits an analgesic effect.
However, the mechanism of its analgesic action is still unclear,
and it could produce analgesic effects via the supraspinal level
and peripheral nerves in addition to the spinal level.11
Acting on a2B-AR
The a2B-AR receptor is primarily associated with periph-
eral vasoconstriction, resulting in vasoconstriction and anti-
chilling effects. Dexmedetomidine also triggers a2B-AR-
mediated increases in blood pressure, followed by a2A-AR-
mediated antisympathetic effects, leading to a decrease in
blood pressure.12 The constrictive effect of DEX may be dose-
dependent. Zhou et al.13 discovered that DEX caused coronary
artery diastole in pigs at lower concentrations, whereas higher
concentrations caused coronary artery constriction.
Acting on a2C-AR
a2C-AR is mainly associated with modulation of cognitive,
emotional, and sensory processes. It is not clear whether the
improvement of cognitive dysfunction by DEX is related to it.
Pharmacokinetics
Dexmedetomidine can be administered intravascularly or
extravascularly (intramuscular or intranasal). It is important to
note that DEX is mainly bound to albumin in plasma. After
administration, DEX quickly and extensively spreads through-
out the body, with a distribution half-life of about 6 minutes
and a steady-state volume of distribution of approximately
1.3-2.5 L/kg.14,15 The liver primarily metabolizes DEX
through glucuronidation and hydroxylation, and the metabo-
lites are eliminated through the kidneys. The elimination half-
life of DEX is around 2-3 hours.16,17 It is worth mentioning
that impaired liver function significantly affects the pharmaco-
kinetics of DEX.
Effects of DEX on Cardiac Electrophysiologic Function
Action Potential Duration
Action potential duration (APD) refers to the time it takes
for an excitable cell to go from phase 0 depolarization to rest-
ing potential at the end of phase 3 repolarization. This duration
is a crucial measurement in electrophysiologic studies. Chen
et al.18 conducted a study to examine the impact of DEX on
ionic currents and membrane potentials in neurons. The results
indicated that DEX had the effect of prolonging the APD at
90% repolarization in differentiated NG108-15 cells. A recent
study revealed that DEX, in a dose-dependent manner, reduced
the occurrence of spontaneous ventricular-like action poten-
tials and increased the duration of the APD at 90% repolariza-
tion in ventricular-like cardiomyocytes derived from human-
induced pluripotent stem cells without innervation.19
QT Interval
The QT interval, which represents the timing of ventricular
depolarization and repolarization, and the Tp-e interval, which
reflects ventricular repolarization dispersion, are both common
electrocardiogram indicators of arrhythmia risk. To account
for the influence of heart rate, the corrected QT (QTc) interval
is commonly used for evaluation.20,21
A study showed that in patients undergoing elective general
anesthesia, the 3 different doses had no significant effect on
the Tp-e interval when administered with loading doses of 0.6,
0.8, and 1 mg/kg of DEX, indicating that DEX had no signifi-
cant effect on ventricular repolarization dispersion.22 All 3
doses of DEX can shorten the QTc interval significantly, yet
there is no concentration correlation, suggesting that adminis-
tration of the above 3 loading doses of DEX affects ventricular
repolarization and decreases electrocardiographic stability to
some extent. The results of Tan et al.23 showed that the QTc
interval was prolonged significantly in patients after adminis-
tration of a loading dose of DEX at 1 mg/kg, suggesting that
DEX prolongs the duration of ventricular repolarization and is
detrimental to cardiac electrophysiologic stability. However,
the QTc interval was shortened after administration of a load-
ing dose of DEX at 0.5 mg/kg. The 2 loading doses of DEX
had no significant effect on the Tp-e interval. It is suggested
that higher doses of DEX may be detrimental to cardiac elec-
trophysiologic stability, whereas lower doses are relatively
safe. However, there is some contradiction between the 2 stud-
ies regarding the effect of DEX on the QTc interval. There are
also experimental animal studies showing that DEX does not
significantly affect the QT interval.24 Although the effect of
DEX on the QTc interval is still controversial, clinicians can
conclude from the above study that a small dose of DEX may
have less effect on cardiac repolarization compared to a high
loading dose, and is more beneficial for maintaining cardiac
electrophysiologic homeostasis in the perioperative period.
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S. Duan and S. Zhou / Journal of Cardiothoracic and Vascular Anesthesia 00 (2024) 17
Ion Channels
Voltage-gated sodium channel 1.5 is the most important car-
diac sodium channel subtype, with important effects on myo-
cardial electrophysiologic activity.25 Dexmedetomidine
inhibits voltage-gated sodium channel 1.5 activity in a dose-
dependent manner to attenuate sodium currents, which can
produce cardiovascular adverse effects, such as bradycardia.26
However, at the same time, excessive activation of Na+ chan-
nels during myocardial ischemia also leads to electrophysio-
logic alterations and imbalance of intracellular Na+ and Ca2+
homeostasis. Increased intracellular Na+ during myocardial
ischemia will cause intracellular calcium overload by activat-
ing the reverse mode of the Na+/Ca2+ exchanger, which also
can trigger delayed postdepolarization and lead to repolariza-
tion diffusion.27 In this respect, the inhibitory effect of DEX
on sodium currents may contribute to the amelioration of myo-
cardial repolarization dissociation and arrhythmogenesis.
Yang et al.19 also showed that DEX inhibits sodium channels
in human-induced multipotent stem cell-derived cardiomyo-
cytes, which may be related to its antiarrhythmic effect.
The BKCa channel, a large conductance calcium-activated
potassium channel, is found primarily in vascular smooth mus-
cle cells. However, it also is distributed in cardiac myocytes and
plays a significant role in maintaining the membrane potential
of smooth muscle cells, regulating intracellular Ca2+ levels, and
reducing vascular tone.28,29 Lower concentrations of DEX have
been found to directly activate BKCa channels in porcine arte-
rial smooth muscle cells, leading to coronary artery dilation.13
Additionally, BKCa channels located on the mitochondrial
membrane of cardiomyocytes have been associated with cardio-
protective effects after ischemia-reperfusion injury.30 Previous
studies have demonstrated that DEX can attenuate ischemia-
reperfusion injury in rat hearts, and this protective mechanism is
believed to be linked to the activation of BKCa channels.31
BKCa channels have recently gained significant attention due to
their potential effects on arrhythmias.32,33 However, it remains
unclear whether the antiarrhythmic effects of DEX are related
to these channels.
The L-type calcium channel is a voltage-dependent calcium
channel that generates L-type calcium currents (ICa-L). Zhao et
al.34 investigated the impact of DEX on ICa-L using the whole-
cell membrane clamp technique. The findings demonstrated
that DEX dose-dependently inhibited ICa-L, leading to a reduc-
tion in calcium channel activity and an elongation of the recov-
ery time after channel inactivation. Consequently, this resulted
in a decrease in calcium influx. Furthermore, the inhibitory
effect of DEX on ICa-L was counteracted partially by yohim-
bine, suggesting a potential association between the inhibitory
effect of DEX on ICa-L and a2-AR. This mechanism may pro-
vide insights into the adverse effects of DEX on myocardial
contractility and cardiac electrical activity. In the study con-
ducted by Yang et al.,19 DEX significantly suppressed ICa-L
without affecting the activation and/or inactivation profile of
calcium channels in human-induced multipotent stem cell-
derived cardiomyocytes; a2-AR was not expressed on human-
induced multipotent stem cell-derived cardiomyocytes,
3
suggesting that its inhibitory effect was not related to a2-AR.
Further studies are required to understand the variations in the
results of the 2 experiments. However, it is evident that DEX
can dose-dependently inhibit ICa-L.
In conclusion, DEX can inhibit sodium, potassium, and cal-
cium channels, leading to myocardial inhibition and protec-
tion. Nevertheless, the mechanisms involved in these effects
are still unclear and controversial in certain aspects, highlight-
ing the need for further investigation.
DEX and Connexins
The gap junction is a specialized channel that connects neigh-
boring cells, enabling the exchange of ions, signaling molecules,
and other molecular information. In the heart, various subtypes
of connexins are expressed, with Connexin 43 (Cx43) being the
predominant subtype in ventricular cardiomyocytes. Connexin
43 plays a crucial role in cardiac electrical signaling and rhyth-
mic contraction.35 Dexmedetomidine has been found to cause
bradycardia by regulating the expression of sinus node gap junc-
tion protein 45 along with Cx40.36 During acute myocardial
infarction, Cx43 undergoes increased dephosphorylation, which
in turn affects the electrical coupling between cardiac myocytes,
resulting in conduction abnormalities and various types of
arrhythmias.37 In a rat model of ischemic cardiomyopathy, the
use of DEX in rats after myocardial infarction had the following
effects: upregulation of Cx43, inhibition of the inflammatory
response, attenuation of myocardial fibrosis, reduction in the
occurrence of spontaneous ventricular arrhythmias, and decrease
in arrhythmia scores in programmed electrical stimulation-
induced ventricular arrhythmias.38 Behmenburg et al.31 discov-
ered that DEX pretreatment reduced infarct size and improved
cardiac function in a rat model of acute myocardial infarction.
Furthermore, they found that DEX’s protection against ische-
mia-reperfusion injury was associated with the activation of
Cx43 and BKCa channels.
Effects of DEX on Arrhythmias
Sinus Bradycardia and Conduction Block
Sinus bradycardia is a frequently observed adverse effect of
DEX. A study conducted on critically ill adult patients receiv-
ing mechanical ventilation in the ICU revealed that 5.1% of
patients who were sedated with DEX experienced bradycardia,
and 0.7% even experienced cardiac arrest.39 In a study con-
ducted by Erickson et al.,40 it was found that the incidence of
bradycardia was significantly higher in mechanically venti-
lated children receiving DEX sedation compared to the control
group. DEX is used commonly as an adjunct to sedation in
endotracheal anesthesia. Previous studies have demonstrated
that its use often leads to bradycardia, particularly in older
patients.41 In addition to intravenous administration, DEX also
can be administered intranasally. It is used commonly in clini-
cal settings to sedate pediatric patients before admission to the
operating room, reducing crying and anxiety in children. How-
ever, it should be noted that this mode of administration may
 ARTICLE IN PRESS
4 S. Duan and S. Zhou / Journal of Cardiothoracic and Vascular Anesthesia 00 (2024) 17
still lead to bradycardia. Studies have shown that the incidence
of bradycardia was significantly higher in children receiving
intranasal DEX compared to controls. Furthermore, the study
also found that the incidence of bradycardia was higher in
male children compared to female children.42
Dexmedetomidine has an inhibitory effect on atrioventricu-
lar (AV) node function and may cause conduction block to
develop during use. Ergul et al.43 demonstrated that adminis-
tering a loading dose of DEX (1 mg/kg intravenously over 10
minutes) resulted in the inhibition of AV nodal conduction
function in children. This was accompanied by the prolonga-
tion of the Wenckebach cycle length, ventriculoatrial block
cycle length, and AV nodal effective refractory periods. The
effects of DEX on AV nodal (AVN) function in adults are sim-
ilar. Electrophysiologic examination of healthy adult volun-
teers showed that administering DEX intravenously at a dose
of 1 mg/kg over 10 minutes resulted in decreases in the AVN
Wenckebach point and AVN 2:1 block point, a prolongation
of the AV nodal refractory period, and an inhibition of the AV
node that was dependent on the concentration.44
Atrial Fibrillation
Postoperative atrial fibrillation (AF) is a prevalent cardiac
surgery complication that can lead to stroke and increased
mortality. There is ongoing debate regarding the impact of
DEX on postoperative AF. According to a meta-analysis con-
ducted by Ling et al.,45 DEX demonstrated antiarrhythmic
effects and decreased the occurrence of ventricular arrhyth-
mias in comparison to other sedative medications administered
after cardiac surgery. However, the analysis did not find any
significant effect of DEX on the incidence of postoperative
AF. The analysis conducted by Zhu et al.46 also revealed that
DEX did not show a reduction in the incidence of AF after car-
diac surgery when compared to other control drugs.
Additionally, it was found that DEX potentially may increase
the occurrence of AF in patients with a history of AF. However,
it is important to note that both meta-analyses on this topic suf-
fered from limitations, including insufficient quality of evidence.
Contrary to previous studies, recent research conducted by Peng
et al.47 has found that perioperative administration of DEX
could potentially lower the risk of AF after cardiac surgery. The
results indicated that DEX was particularly effective in prevent-
ing postoperative AF in low-risk patients. However, it is impor-
tant to note that high-risk patients who may have multiple AF-
related risk factors may not experience the same benefits from a
single intervention with DEX. The findings of Jing et al.48
revealed that DEX had a significant effect in reducing postoper-
ative AF, particularly in young female patients who underwent
coronary artery bypass grafting.
Further studies are required to investigate whether DEX
reduces the occurrence of AF after cardiac surgery. The opti-
mal timing and dosage for administering DEX remain incon-
clusive. Certain studies have indicated that administering DEX
during postoperative ICU treatment, as opposed to preopera-
tively, resulted in a lower incidence of AF.49,50 However, Jing
et al.48 proposed that preoperative or intraoperative adminis-
tration of DEX pretreatment might be more effective.
Ventricular Arrhythmias
Ventricular arrhythmias, such as ventricular tachycardia (VT)
and ventricular fibrillation, are serious conditions with high mor-
tality and complication rates. The results of a prospective cohort
study conducted by Chrysostomou et al.51 demonstrated that the
initiation of DEX at the induction of anesthesia, along with its
continuous intraoperative and postoperative administration,
reduced the occurrence of postoperative ventricular and supra-
ventricular tachyarrhythmias in children undergoing cardiotho-
racic surgery. Tobias et al.52 provided a summary of the
cardiovascular effects of DEX and supported its perioperative
use in pediatric patients with congenital heart disease to prevent
and treat postoperative ventricular and supraventricular tachyar-
rhythmias. In a randomized controlled trial conducted by Ren et
al.,53 it was found that DEX sedation in adult patients resulted
in reduced postoperative plasma norepinephrine and cortisol lev-
els. Additionally, it decreased the incidence of ventricular
arrhythmias and improved postoperative myocardial injury in
patients undergoing non-extracorporeal coronary artery grafting.
In a randomized controlled trial conducted by Soltani et al.,54
the effect of using DEX early, specifically during anesthesia
induction and intraoperatively, on postoperative arrhythmias in
patients undergoing coronary artery grafting without extracorpo-
real circulation was investigated. The study found that the early
use of DEX improved hemodynamic indices and reduced the
occurrence of common postoperative arrhythmias, such as pre-
mature ventricular beats and VT. Additionally, 2 recent meta-
analyses also supported the perioperative use of DEX in reduc-
ing the incidence of VT after cardiac surgery. However, these
analyses did not find a significant effect on the incidence of ven-
tricular fibrillation.55,56
The literature also has reported the role of DEX in the pre-
vention and treatment of specific types of ventricular arrhyth-
mias. Acquired long QT syndrome is a syndrome in which a
prolonged QT interval can be accompanied by Torsades de
Pointes. This condition is often caused by drugs, cardiac disease,
and metabolic abnormalities. In a rabbit model of acquired long
QT interval, a2-AR agonists, such as DEX, were found to
inhibit the occurrence of early postdepolarization and reduce the
incidence of VT.57 Ellermann et al.24 conducted animal experi-
ments that also confirmed the inhibitory effect of DEX on VT
in a rabbit model of erythromycin-induced acquired long QT
interval. The authors suggested that this effect may be attributed
to DEX’s ability to improve myocardial repolarization disper-
sion. Catecholamine-sensitive polymorphic VT (CPVT) is a rare
inherited arrhythmogenic disorder that often leads to sudden
death. It is typically not associated with structural heart disease.
Catecholamine-sensitive polymorphic VT is characterized by
the occurrence of bidirectional or polymorphic VT after exercise
or emotional stress, which can result in syncope and sudden car-
diac death.58 There have been case reports suggesting that DEX
can inhibit the occurrence of ventricular arrhythmias in patients
with CPVT. For instance, Shionoya et al.59 successfully
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S. Duan and S. Zhou / Journal of Cardiothoracic and Vascular Anesthesia 00 (2024) 17
performed a dental extraction procedure on a patient with CPVT
by using total intravenous anesthesia with DEX, ensuring the
prevention of arrhythmias. A patient with CPVT during preg-
nancy was delivered successfully under epidural anesthesia and
DEX-assisted sedation without experiencing any arrhythmias.
The patient safely passed through the perinatal period.60
Junctional Ectopic Tachycardias
Junctional ectopic tachycardia (JET) is a highly concerning
arrhythmia that frequently manifests after pediatric cardiac
surgery. Despite numerous attempts, the available treatments
have shown limited effectiveness, emphasizing the importance
of prevention as the primary approach. According to a study,61
it has been observed that administering a loading dose of DEX
at 0.5 mg/kg before anesthesia induction and maintaining a
continuous infusion at a dose of 0.5 mg/kg/h for 48 hours after
surgery proved to be effective in reducing the incidence of
JET in children who underwent surgery for congenital heart
disease. The findings of a retrospective cohort study indicated
that the continuous use of DEX before and during surgery
decreases the occurrence of postoperative JET in children who
undergo ventricular septal defect repair compared to the rate
when DEX is administered only after surgery.62 In a prospec-
tive randomized controlled trial conducted by Rajput et al.,63 it
was found that continuous infusion of DEX during and after
surgery in children undergoing repair of tetralogy of Fallot
reduced the incidence of postoperative JET and potentially
shortened the duration of JET. Recent meta-analyses have
examined the impact of DEX on postoperative JET in pediatric
cardiac surgery. These studies suggested that administering
DEX during the perioperative period can stabilize patient
hemodynamics and reduce the occurrence of postoperative
JET.64,65 In summary, continuous intraoperative and postoper-
ative administration of DEX in children undergoing pediatric
cardiac surgery can effectively decrease the incidence of post-
operative JET.
Recommendations for Clinical Use
Cardiovascular Anesthesiology
The use of DEX during the induction stage of general anes-
thesia can decrease the response to tracheal intubation and
maintain hemodynamic stability. It also can be employed dur-
ing the maintenance stage of general anesthesia to lower the
dosage of sedative and analgesic drugs while providing organ
protection and antiarrhythmic effects.
ICU
Dexmedetomidine is used for the sedation of postoperative
ICU patients and offers several advantages. It improves sleep,
provides analgesia, has antiarrhythmic properties, and reduces
the duration of mechanical ventilation and ICU stay.
5
Additional Use
Additionally, it can be used for the prevention and treatment
of postoperative pediatric cardiac awakening agitation as well
as postoperative delirium in cardiac surgery.
However, there are certain precautions that need to be taken
into consideration. It only should be administered by a quali-
fied physician who closely monitors the patient’s vital signs. It
is important to be aware of any drug allergies and exercise cau-
tion or avoid using it in patients with bradycardia, conduction
block, cardiac insufficiency, or hemodynamic instability.
Conclusion
Dexmedetomidine has been proven to be beneficial in pre-
venting and treating tachyarrhythmias and JET. However, to
provide clinical recommendations, further high-quality clinical
trials are necessary to explore the effects of DEX. The impact
of DEX on postoperative AF remains a topic of debate. Addi-
tionally, it is important to note that DEX also can cause brady-
cardia and conduction block. The mechanism of DEX’s effect
on arrhythmia may be related to several factors. DEX can
inhibit sodium, potassium, and calcium channels in cardiac tis-
sue, which may affect the function of the sinus node and atrio-
ventricular node.
Additionally, DEX can prolong the action potential time
course and impact myocardial repolarization. The controversy
surrounding the effects of DEX on myocardial electrophysio-
logic function and its specific targets of action can be attrib-
uted partially to variations in the experimental subjects,
experimental conditions, technical methods used, and the dif-
ferent concentrations of DEX employed. Further studies are
required to examine the precise signaling pathways and molec-
ular mechanisms through which DEX influences cardiac func-
tion.
Declaration of competing interest
None.
CRediT authorship contribution statement
Shengji Duan: Investigation, Writing  original draft.
Shuzhi Zhou: Funding acquisition, Supervision, Writing 
review & editing.
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