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Subch onic Ciga e e Smoke Exposu e E ec s on Ca diomyocy es: A Li e a u e
Re iew
Muhammad Da a Ra smawan 1 and Mei y A diana 2, *
1 Medical S udy P og am, Facul y o Medicine, Uni e si as Ai langga, Su abaya, Indonesia.
2 Depa men o Ca diology and Vascula Medicine, D Soe omo Gene al Academic Hospi al, Facul y o Medicine,
Uni e si as Ai langga, Su abaya, Indonesia.
Wo ld Jou nal o Ad anced Resea ch and Re iews, 2025, 27(02), 1880-1885
Publica ion his o y: Recei ed on 09 July 2025; e ised on 16 Augus 2025; accep ed on 18 Augus 2025
A icle DOI: h ps://doi.o g/10.30574/wja .2025.27.2.2971
Abs ac
Subch onic exposu e o ciga e e smoke has been shown o induce pa hological changes in a ious o gan sys ems,
including he ca dio ascula sys em. This li e a u e e iew syn hesizes cu en e idence on he e ec s o subch onic
ciga e e smoke exposu e on mouse ca diomyocy es, wi h a ocus on oxida i e s ess, mi ochond ial dys unc ion,
gene ic egula ion, con ac ile unc ion, and in lamma ion. Expe imen al models ypically in ol e whole-body o nose-
only exposu e o se e al weeks, simula ing human subch onic exposu e pa e ns. Mechanis ic indings e eal
inc eased eac i e oxygen species (ROS) p oduc ion, impai ed mi ochond ial espi a ion, and dis up ion o an ioxidan
de ense sys ems, pa icula ly in ol ing supe oxide dismu ase (SOD) and adenine nucleo ide ansloca o (ANT). Gene
exp ession s udies demons a e al e ed egula ion o apop o ic, in lamma o y, and me abolic pa hways, accompanied
by epigene ic modi ica ions such as DNA me hyla ion and mic oRNA dys egula ion. Func ional assessmen s indica e
dec eased ca diomyocy e iabili y, educed con ac ile ac i i y, and inc eased cellula senescence. In lamma o y
esponses a e cha ac e ized by ele a ed cy okine p oduc ion, including TNF-α and IL-6, which may con ibu e o
myoca dial emodeling. While e idence s ongly sugges s a de imen al e ec o subch onic ciga e e smoke on mouse
ca diomyocy es, limi a ions emain due o he sca ci y o long- e m ollow-up s udies and di ec ansla ional models
in humans. Fu u e esea ch should ocus on a ge ed in e en ions o mi iga e oxida i e and in lamma o y damage in
ca diomyocy es exposed o obacco smoke.
Keywo ds: Ciga e e Smoke Exposu e; Subch onic; Ca diomyocy es; Oxida i e S ess; Mi ochond ial Dys unc ion
1. In oduc ion
Ciga e e smoking emains one o he leading p e en able causes o mo bidi y and mo ali y wo ldwide, con ibu ing
signi ican ly o ca dio ascula diseases, ch onic obs uc i e pulmona y disease, and a ious cance s (Messne e al.,
2014). While he dele e ious e ec s o long- e m smoking ha e been ex ensi ely documen ed, subch onic exposu e,
ypically de ined as con inuous o epea ed exposu e o e a pe iod anging om se e al weeks o a ew mon hs has
ga ne ed inc easing a en ion o i s ole in ini ia ing ea ly pa hophysiological changes, pa icula ly in ca diac issue
(Pa ma e al., 2023). Expe imen al models using mice ha e p o en aluable o unde s anding he mechanis ic
pa hways h ough which ciga e e smoke induces ca diac inju y, as hei ca dio ascula physiology and cellula
esponses sha e key simila i ies wi h humans (A diana e al., 2021).
Ca diomyocy es, he con ac ile cells o he myoca dium, a e c i ical o main aining ca diac ou pu and o e all
ca dio ascula unc ion. These cells a e highly me abolically ac i e, elying on obus mi ochond ial unc ion o sus ain
con inuous con ac ion. Subch onic ciga e e smoke exposu e has been shown o impai ca diomyocy e s uc u e and
Wo ld Jou nal o Ad anced Resea ch and Re iews, 2025, 27(02), 1880-1885
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unc ion h ough mul iple mechanisms, including oxida i e s ess, mi ochond ial dys unc ion, in lamma o y ac i a ion,
and apop o ic signaling. Reac i e oxygen species (ROS) gene a ed om ciga e e smoke cons i uen s such as nico ine,
ca bon monoxide, and polycyclic a oma ic hyd oca bons can damage lipids, p o eins, and nucleic acids, dis up ing
cellula homeos asis (Bu on e al., 2011).
In addi ion o oxida i e s ess, mi ochond ial inju y plays a pi o al ole in he pa hogenesis o smoke-induced
ca dio oxici y. S udies ha e epo ed dec eased mi ochond ial memb ane po en ial, impai ed espi a o y chain ac i i y,
and al e ed ATP p oduc ion in ca diomyocy es exposed o ciga e e smoke ex ac (CSE) (Bu on e al., 2011). These
mi ochond ial al e a ions o en coincide wi h he ac i a ion o apop o ic pa hways, including up egula ion o p o-
apop o ic p o eins such as Bax and down egula ion o an i-apop o ic p o eins like Bcl-2 (He e al., 2017). Mo eo e ,
sys emic in lamma ion igge ed by smoke exposu e can exace ba e myoca dial inju y h ough ele a ed ci cula ing
cy okines, including umo nec osis ac o -alpha (TNF-α) and in e leukin-6 (IL-6), con ibu ing o myoca dial
emodeling and e en ual con ac ile dys unc ion (Higashi e al., 2014).
Animal s udies using subch onic exposu e p o ocols, such as whole-body inhala ion o nose-only exposu e chambe s,
ha e shown ea ly his opa hological changes in he myoca dium, including in e s i ial ib osis, myo ib illa disa ay, and
inc eased collagen deposi ion (Husna e al., 2019). While hese al e a ions a e less se e e han hose seen in ch onic
exposu e models, hey ep esen ea ly indica o s o po en ial p og ession owa d hea ailu e i exposu e pe sis s. The
ansla ional ele ance o hese indings lies in he ac ha e en mode a e-du a ion smoking o secondhand smoke
exposu e may ini ia e pa hological p ocesses in he hea well be o e clinical symp oms appea (Husna e al., 2019).
This li e a u e e iew aims o p o ide a comp ehensi e syn hesis o cu en esea ch on he e ec s o subch onic
ciga e e smoke exposu e on mouse ca diomyocy es. Speci ically, i will add ess he expe imen al models used o
simula e subch onic exposu e, he molecula and cellula mechanisms in ol ed, unc ional consequences on
ca diomyocy e pe o mance, and he b oade implica ions o ca dio ascula heal h. By elucida ing hese pa hways,
his e iew seeks o b idge he gap be ween basic science indings in animal models and po en ial p e en i e o
he apeu ic s a egies o smoke-induced ca diac inju y in humans.
2. Re iew Con en
2.1. Ca dio ascula Disease
Ca dio ascula disease (CVD) is he leading cause o dea h wo ldwide. CVD encompasses a wide ange o diso de s,
including diseases o he hea muscle and he ascula sys em ha supplies he hea , b ain, and o he i al o gans
(Gaziano e al., 2006). Ca dio ascula diseases a e a g oup o diso de s a ec ing he hea and blood essels. They a e
a he e ogeneous se ies o condi ions, wi h a he oscle osis being he mos equen p ima y cause o hei de elopmen .
CVDs a e ch onic diseases ha de elop g adually o e a li e ime and o en emain asymp oma ic o a long pe iod.
Fu he mo e, CVD is a majo cause o mo bidi y and mo ali y among pa ien s wo ldwide (F ąk e al., 2022).
A he oscle osis is he leading cause o ca dio ascula - ela ed dea h globally. I is cha ac e ized by he hickening and
ha dening o a e ial walls, which accompanies aging and has a signi ican nega i e impac on he ca dio ascula sys em
and a ious o he diseases. Inc eased plasma choles e ol le els (>150 mg/dL) a e a majo cause o a he oscle osis
p og ession (F ąk e al., 2022).
Co ona y a e y disease (CAD) is a common hea condi ion cha ac e ized by na owing o blockage o he main blood
essels, namely he co ona y a e ies. CAD is mos o en caused by he o ma ion o plaques wi hin he in imal laye o
he essel wall. These plaques, composed o a y ma e ials, de elop wi hin he in ima along wi h se e e in lamma ion,
pa icula ly when he in lamma ion is ch onic. This p ocess impai s he supply o su icien blood, nu ien s, and oxygen
o he ca diomyocy es. Consequen ly, a he oscle o ic plaques may e ode o up u e, ini ially leading o h ombosis and
subsequen ly essel occlusion, esul ing in myoca dial in a c ion, s oke, limb ischemia, and dea h. O he con ibu ing
ac o s include endo helial dys unc ion, low-g ade in lamma ion, and lipid accumula ion (F ąk e al., 2022).
A e ial hype ension (AH) is one o he mos common ypes o CVD. A e ial hype ension o en causes ew o no
symp oms bu is a majo isk ac o o myoca dial in a c ion, s oke, kidney ailu e, and pe iphe al ascula disease.
Acco ding o he mos signi ican guidelines, AH is diagnosed when a pe son’s o ice o clinic sys olic blood p essu e is
≥140 mm Hg and/o dias olic blood p essu e is ≥90 mm Hg a e epea ed measu emen s. CVDs a e caused by mul iple
ac o s. Some a e non-modi iable, such as age, sex, and gene ic backg ound, while o he s a e modi iable and he e o e
can be educed (e.g., smoking, lack o physical ac i i y, poo ea ing habi s, inc eased blood p essu e, ype 2 diabe es,
dyslipidemia, and obesi y) (F ąk e al., 2022).
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2.2. Ca diac Hype ophy
Ca diac hype ophy is he hea ’s esponse o a ious ex insic ac o s and in insic s imuli ha inc ease biomechanical
s ess. While hype ophy can ul ima ely no malize wall ension, i is associa ed wi h un a o able ou comes, placing
a ec ed pa ien s a isk o sudden dea h o p og ession o o e hea ailu e (F ey and Olson, 2003). Pa hological
hype ophy is associa ed wi h inc eased ca diomyocy e dea h and ib o ic emodeling and is cha ac e ized by educed
sys olic and dias olic unc ion, which o en p og esses o hea ailu e. The main igge ing e en s o hype ophic
hea disease a e mechanical s ess and neu ohumo al s imula ion, bo h o which con ibu e o he modula ion o
a ious cellula esponses, including gene exp ession, sa come e p o ein syn hesis, and cellula me abolism, leading o
he de elopmen and p og ession o ca diac hype ophy (Shimizu and Minamino, 2016). Neu ohumo al ac o s, such
as ca echolamines o angio ensin II, up egula e calcineu in/NFAT and CaMKII/MEF-2 signaling o induce pa hological
ca diac hype ophy. IL-6/gp130/JAK/STAT signaling also p omo es pa hological hype ophy. Ni ic oxide signaling
and na iu e ic pep ide/cGMP/PKG pa hways a e an i-hype ophic, whe eas PDE5 and PDE9A p omo e pa hological
hype ophy by supp essing hese signaling pa hways (Shimizu and Minamino, 2016).
2.3. ROS and Ca dio ascula Diseases
Reac i e oxygen species (ROS) a e highly eac i e molecules p oduced p ima ily by oxidase sys ems, and hey play a
pi o al ole in he ini ia ion and p og ession o ca dio ascula diseases (CVD). These molecules can cause p o ound
biological e ec s because o hei abili y o oxidize lipids, p o eins, and nucleic acids, he eby impai ing no mal cell
unc ion. One o he key mechanisms h ough which ROS exe hei dele e ious e ec s is by dis up ing mi ochond ial
unc ion and al e ing in acellula calcium (Ca²⁺) homeos asis. This imbalance in mi ochond ial dynamics and Ca²⁺
egula ion leads o cellula inju y, apop osis, and unc ional de e io a ion wi hin he ca dio ascula sys em (Fei e al.,
2022). Among he di e se ypes o ROS in ol ed in he induc ion o p og ession o CVD, he mos no able a e supe oxide
anion (O₂⁻), hyd ogen pe oxide (H₂O₂), pe oxyni i e (ONOO⁻), and hyd oxyl adical (HO•). O₂⁻ and H₂O₂ a e conside ed
enzyma ically p oduced ROS, and hey pa icipa e in bo h physiological signaling pa hways such as ascula one
egula ion and pa hological p ocesses, including ascula in lamma ion and ib osis. O₂⁻ can be spon aneously
dismu a ed in o H₂O₂ by he enzyma ic ac ion o supe oxide dismu ase (SOD), a c i ical an ioxidan de ense mechanism
in he body. In con as , ONOO⁻ and HO• a e gene ally no ega ded as ROS signaling molecules due o hei ex eme
eac i i y and sho hal -li e. HO•, o ins ance, is o med ia he ca aly ic con e sion o H₂O₂ o en h ough he Fen on
eac ion and is capable o ini ia ing chain eac ions ha damage cellula memb anes and DNA. Glu a hione, a majo
in acellula an ioxidan , se es as an impo an de ense sys em by neu alizing HO• and p e en ing u he oxida i e
inju y. ONOO⁻ is gene a ed h ough he eac ion be ween O₂⁻ and ni ic oxide (NO), and i is pa icula ly damaging
because i no only deple es NO bu also impai s endo helial ni ic oxide syn hase (eNOS) unc ion. This leads o a sel -
pe pe ua ing cycle o educed NO bioa ailabili y, inc eased ascula oxida i e s ess, and p og essi e endo helial
dys unc ion. The p ima y enzyma ic and non-enzyma ic sou ces o CVD- ela ed ROS include mi ochond ial elec on
anspo chain componen s, NADPH oxidases (NOX), xan hine oxidase (XO), lipoxygenases (LO), and myelope oxidases
(MPO). No ably, he e is a phenomenon known as **ROS sou ce c oss- alk**, in which di e en ROS sou ces can ac i a e
each o he , ampli ying oxida i e s ess. Fo example, H₂O₂ can s imula e NOX ac i i y and p omo e he con e sion o
xan hine dehyd ogenase in o i s ROS-p oducing o m, XO. Simila ly, ONOO⁻ can enhance O₂⁻ gene a ion, u he
in ensi ying oxida i e damage. In addi ion, mi ochond ia and NOX sys ems engage in bidi ec ional in e ac ions, c ea ing
a eed- o wa d **oxida i e cycling** loop ha exace ba es he o e all edox imbalance in ca dio ascula issues (G acia
e al., 2017).
2.4. Ciga e e Smoke
Ciga e e smoke is di ided in o wo phases: he a phase and he gas phase. The a o pa icula e phase is de ined as
he ma e ial apped when he mains eam smoke is passed h ough a Camb idge glass ibe il e ha e ains 99.9% o
all pa icula e ma e wi h a size >0.1 μm. The gas phase consis s o ma e ial ha passes h ough he il e . The
pa icula e ( a ) phase con ains 10¹⁷ ee adicals pe g am, while he gas phase con ains 10¹⁵ ee adicals pe pu .
Radicals associa ed wi h he a phase a e long-li ed (hou s o mon hs), whe eas adicals associa ed wi h he gas phase
ha e a sho e li espan (A diana e al., 2021). Ciga e e smoke inhaled om obacco in o he smoke ’s mou h is called
mains eam smoke. Sides eam smoke is he smoke emi ed om he bu ning end o he ciga e e. Mains eam smoke
consis s o 8% a and 92% gas componen s. En i onmen al obacco smoke is p oduced om a combina ion o
sides eam smoke (85%) and a smalle po ion o exhaled mains eam smoke (15%) om he smoke . Sides eam
smoke con ains ela i ely highe concen a ions o oxic gaseous componen s compa ed o mains eam smoke. Among
all he known elemen s, nico ine which ound in he a phase is he addic i e subs ance in ciga e e smoke (Amb ose
and Ba ua, 2004). The numbe o ac i e smoke s in Indonesia con inues o ise. Acco ding o he 2023 Indonesian Heal h
Su ey (SKI), conduc ed by he Minis y o Heal h (Kemenkes), he e a e a ound 70 million ac i e smoke s, wi h 7.4%
o hem aged be ween 10 and 18 yea s. The highes numbe o smoke s is ound among child en and adolescen s.
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Acco ding o he Global You h Tobacco Su ey (GYTS) 2019, smoking p e alence among school-aged child en (13–15
yea s old) inc eased om 18.3% (2016) o 19.2% (2019). Meanwhile, he 15–19 age g oup has he highes smoking
a e (56.5%), ollowed by hose aged 10–14 yea s (18.4%) (Kemenkes, 2024).
2.5. Smoking and Ca dio ascula Diseases
An imbalance be ween he oxida i e and an ioxidan sys ems is one o he cen al mechanisms unde lying many ch onic
diseases, pa icula ly hose ela ed o he ca dio ascula sys em. This imbalance is mos o en associa ed wi h he
excessi e p oduc ion o eac i e oxygen species (ROS), which leads o a s a e o oxida i e s ess. Oxida i e s ess occu s
when ROS gene a ion exceeds he body’s in insic an ioxidan de ense capaci y, esul ing in damage o lipids, p o eins,
and DNA (G acia e al., 2017). O e ime, his damage can comp omise cell iabili y, impai issue epai mechanisms,
and p omo e ch onic in lamma ion, all o which a e c i ical con ibu o s o ca dio ascula pa hology. Ciga e e smoke
is widely ecognized as bo h a di ec sou ce o ROS and an indi ec igge o oxida i e s ess wi hin cells. The smoke
con ains housands o chemicals, including ee adicals, oxidan s, and p o-oxidan compounds, which ei he di ec ly
gene a e ROS o s imula e endogenous ROS p oduc ion. This pe sis en oxida i e bu den is a well-es ablished causa i e
ac o o mul iple smoking- ela ed diseases. The oxida i e s ess induced by smoking ini ia es a cascade o pa hological
p ocesses, such as lipid pe oxida ion, endo helial inju y, mi ochond ial dys unc ion, and ch onic in lamma ion, which
collec i ely accele a e disease p og ession. The Wo ld Heal h O ganiza ion (WHO) epo s ha ac i e smoking emains
one o he leading p e en able causes o dea h wo ldwide, la gely due o he oxic e ec s o obacco smoke componen s
on a ious o gan sys ems. Epidemiological da a consis en ly iden i y smoking as a majo isk ac o o ca dio ascula
diseases (CVD), espi a o y diso de s, and se e al o ms o cance (Seo e al., 2023).
Speci ically, wi hin he ca dio ascula domain, smoking signi ican ly inc eases he isk o co ona y hea disease (CHD)
by des abilizing a he oscle o ic plaques. This plaque des abiliza ion heigh ens he likelihood o plaque up u e, which
can apidly lead o h ombus o ma ion a he lesion si e. Such h ombi a e he p ima y cause o acu e co ona y
synd ome (ACS), encompassing uns able angina, myoca dial in a c ion, and sudden ca diac dea h. Beyond plaque-
ela ed mechanisms, ciga e e smoking also p omo es co ona y a e y spasms, which may occu wi h o wi hou
signi ican p e-exis ing na owing o he co ona y a e ies. These spasms can acu ely educe blood low o he
myoca dium, causing ischemia e en in he absence o se e e a he oscle osis. Nico ine, a p ima y psychoac i e
componen o obacco, exe s po en ca dio ascula e ec s by s imula ing sympa he ic ne e ac i i y, esul ing in
asocons ic ion, ele a ed blood p essu e, and inc eased hea a e. Ano he c i ical ac o is he ele a ed ca bon
monoxide (CO) le els obse ed in smoke s. CO binds o hemoglobin wi h an a ini y mo e han 200 imes g ea e han
oxygen, he eby educing he oxygen-ca ying capaci y o blood. This leads o a s a e o ch onic issue hypoxia,
pa icula ly a ec ing high-demand o gans like he hea . In he se ing o p e-exis ing hea disease, his ch onic
ischemia can signi ican ly wo sen hea ailu e symp oms and p ognosis. Fu he mo e, obacco smoke exposu e is
associa ed wi h sys emic in lamma ion, as e idenced by inc eased ci cula ing in lamma o y cy okines. I also causes
endo helial dys unc ion, impai ing he abili y o blood essels o dila e app op ia ely, and con ibu es o enal
impai men , which indi ec ly inc eases ca dio ascula isk. Toge he , hese ac o s oxida i e s ess, in lamma ion,
ascula dys unc ion, and end-o gan hypoxia explain he disp opo iona ely high p e alence o hea ailu e among
ac i e smoke s (Kondo e al., 2019).
3. Conclusion
In conclusion, subch onic exposu e o ciga e e smoke exe s p o ound de imen al e ec s on mouse ca diomyocy es
h ough a complex in e play o oxida i e s ess, in lamma ion, endo helial dys unc ion, and mi ochond ial impai men .
The high le els o eac i e oxygen species (ROS) gene a ed bo h di ec ly om ciga e e smoke and indi ec ly ia
endogenous enzyma ic sys ems dis up calcium homeos asis, impai mi ochond ial bioene ge ics, and igge cell dea h
pa hways. These p ocesses collec i ely comp omise ca diac con ac ili y, p omo e myoca dial emodeling, and
p edispose o he de elopmen and p og ession o ca dio ascula diseases. Expe imen al e idence om mu ine models
highligh s he c i ical ole o ROS-media ed oxida i e damage and he syne gis ic in e ac ion be ween di e en ROS
sou ces, u he ampli ying myoca dial inju y. Mo eo e , he sys emic e ec s o ciga e e smoke including inc eased
sympa he ic ac i i y, hypoxia due o ca bon monoxide, and heigh ened in lamma o y cy okine p oduc ion exace ba e
ca dio ascula dys unc ion. Gi en hese mul i ace ed mechanisms, educing o elimina ing obacco smoke exposu e
emains a i al p e en i e s a egy o p ese ing ca diac unc ion, and u he esea ch in o a ge ed an ioxidan o
an i-in lamma o y in e en ions could o e p omising a enues o mi iga ing smoke-induced ca diac inju y.
Wo ld Jou nal o Ad anced Resea ch and Re iews, 2025, 27(02), 1880-1885
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Compliance wi h e hical s anda ds
Acknowledgmen s
The au ho s would like o hank all he supe iso s, enabling he success ul implemen a ion o his s udy.
Disclosu e o con lic o in e es
The au ho s epo ha he e a e no compe ing in e es s o decla e.
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