Improved aerobic capacity in a randomized controlled trial of noncombustible nicotine and tobacco products

Imp o ed ae obic capaci y in a
andomized con olled ial o
noncombus ible nico ine and
obacco p oduc s
Lucia Spicuzza1,2,3, F ancesco Pennisi2,3, G azia Caci4, Fabio Cibella5, Da ide Campagna1,2,4,
Yusu A. Adebisi6, Claudio Sai a7, Jacob Geo ge8, Giulio Ge aci9 & Ricca do Polosa1,2,9,10
Smoking nega i ely impac s ae obic capaci y, p ima ily by educing VO2max, he gold s anda d
measu e o ca dio espi a o y i ness. While smoking cessa ion is known o imp o e ascula unc ion,
exe cise pe o mance, and oxygen up ake, i s speci ic impac on VO2max emains unde explo ed.
Speci ically, no esea ch has ye e alua ed VO2max changes ollowing a swi ch o elec onic ciga e es
(ECs) o hea ed obacco p oduc s (HTPs). This is a seconda y analysis o he CEASEFIRE ial, a
12-weeks andomized con olled swi ching ial compa ing he impac o ECs o HTPs on changes in
smoking beha iou . The ial o e s a unique oppo uni y o p ospec i ely examine he ela ionship
be ween smoking beha io and ae obic capaci y, and o examine— o he i s ime— he speci ic
impac o exclusi e EC o HTP use on VO2max. Changes in VO₂max we e analized ac oss h ee
smoking pheno ypes: con inuous smoke s, hose who educed smoking, and hose who abs ained
om smoking Addi ionally, VO2max was also e alua ed speci ically in pa icipan s who comple ely
abs ained om smoking obacco ciga e es, e alua ing ou comes in exclusi e EC and HTP use s.
Qui e s showed he g ea es imp o emen in VO2max a bo h week 4 (2.4 ± 1.7 mL kg−1 min−1) and
week 12 (2.7 ± 1.9 mL kg−1 min−1). Reduce s also exhibi ed signi ican VO2max inc eases (1.3 ± 1.9 mL
kg−1 min−1 a week 4: 1.9 ± 1.8 mL kg−1 min−1 a week 12), while Failu es (i.e. hose who con inued
smoking) showed no change. Exclusi e use o EC and HTP esul ed in s a is ically signi ican and
clinically ele an imp o emen s in VO2max. Compa ed o baseline, VO2max signi ican ly inc eased
a week 4 (EC: 38.4 ± 5.9 o 41.0 ± 6.1 mL kg−1 min−1; HTP: 39.2 ± 6.7 o 41.4 ± 6.4 mL kg−1 min−1, bo h
p < 0.0001) and week 12 (EC: 38.4 ± 5.9 o 41.4 ± 6.3; HTP: 39.2 ± 6.7 o 41.6 ± 6.5 mL kg−1 min−1, bo h
p < 0.0001). No signi ican di e ences be ween EC and HTP we e obse ed a ei he ime poin . Rapid
imp o emen s in VO2max can happen when heal hy smoke s swi ch o exclusi e use o ECs o HTPs.
These indings ein o ce he po en ial ca dio espi a o y bene i s o smoking cessa ion and ha m
educ ion s a egies.
Keywo ds e-ciga e es, Hea ed obacco p oduc s, Smoking cessa ion, Ae obic capaci y, VO2max
Ch onic exposu e o he ha m ul chemicals in obacco ciga e e smoke signi ican ly impai s physical i ness,
p ima ily by educing oxygen a ailabili y a he issue le el and diminishing bo h ae obic and anae obic exe cise
capaci y1,2.
Smoking is well-documen ed o dec ease endu ance pe o mance in heal hy indi iduals and nega i ely
impac s physical i ness es ou comes, wi h educed oxygen up ake capaci y playing a cen al ole3,4. Fu he mo e,
1Cen e o Excellence o he Accele a ion o HA m Reduc ion (CoEHAR), Uni e si y o Ca ania, Ca ania, I aly.
2Depa men o Clinical & Expe imen al Medicine, Uni e si y o Ca ania, Ca ania, I aly. 3Respi a o y Uni , Uni e si y
Teaching Hospi al “Policlinico”, Via San a So ia, 95123 Ca ania, I aly. 4UOC MCAU, Uni e si y Teaching Hospi al
“Policlinico-S.Ma co”, Uni e si y o Ca ania, Ca ania, I aly. 5Ins i u e o Biomedical Resea ch and Inno a ion,
Na ional Resea ch Council o I aly, Pale mo, I aly. 6College o Social Sciences, Uni e si y o Glasgow, Glasgow,
UK. 7ECLAT S l, Spin-o o he Uni e si y o Ca ania, Ca ania, I aly. 8Di ision o Molecula and Clinical Medicine,
Uni e si y o Dundee Medical School, Dundee, Sco land. 9Facul y o Medicine and Su ge y, “Ko e” Uni e si y o
Enna, Enna, I aly. 10Cen e o he P e en ion and T ea men o Tobacco Addic ion (CPCT), Uni e si y Teaching
Hospi al “Policlinico-S.Ma co”, Uni e si y o Ca ania, Ca ania, I aly. email: [email p o ec ed]
OPEN
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an in e se ela ionship has been obse ed be ween smoking his o y and maximal ae obic capaci y (VO2max)2,5,
he gold s anda d o assessing ca dio espi a o y i ness6.
VO2max ep esen s he maximum a e o oxygen consump ion measu ed du ing inc emen al exe cise and
e lec s he e iciency o he espi a o y, ca dio ascula , musculoskele al, and me abolic sys ems in oxygen
anspo and u iliza ion. A highe VO2max indica es imp o ed ae obic capaci y, which is associa ed wi h be e
ca dio espi a o y i ness and educed ca dio ascula and all-cause mo ali y isk7,8.
Impo an ly, he nega i e e ec s o smoking on ca dio espi a o y pe o mance can be e e sed upon cessa ion.
S udies ha e shown ha smoking cessa ion leads o signi ican imp o emen s in ascula endo helial unc ion,
exe cise pe o mance and ca dio ascula esponses o physical ac i i y9–12. These bene i s can be obse ed
as ea ly as 12 weeks pos -cessa ion and pe sis o up o h ee yea s9–12. No ably, he apid imp o emen s in
VO2max obse ed pos cessa ion sugges ha his pa ame e may se e as a sensi i e bioma ke o physiological
eco e y, e lec ing ea ly changes in ca dio espi a o y heal h. This makes VO2max pa icula ly aluable in he
con ex o smoking cessa ion and swi ching ials in ol ing al e na i e nico ine and obacco p oduc s. Howe e ,
he physiological e ec s and heal h bene i s o smoking cessa ion—especially hose measu ed by VO2max—
emain unde explo ed, wi h only one s udy o da e ha ing igo ously assessed his ou come11. Mo eo e , no
esea ch has ye e alua ed VO2max changes ollowing a swi ch o elec onic ciga e es (ECs) o hea ed obacco
p oduc s (HTPs), ep esen ing a c i ical gap in he li e a u e.
ECs and HTPs, ba e y-powe ed de ices ha deli e nico ine wi hou combus ion, ha e gained popula i y
as al e na i es o con en ional ciga e es13,14. These p oduc s a e widely used by smoke s aiming o educe hei
exposu e o ha m ul chemical emissions om combus ion15–17. The key o hei educed ha m po en ial lies in
he elimina ion o combus ion18, which is he p ima y sou ce o oxican s in ciga e e smoke. Al hough HTPs
con ain obacco and may no o e he same le el o ha m educ ion as ECs, bo h p oduc s ha e been explo ed
o hei po en ial o lowe smoking- ela ed ha m19,20 and hei e ec i eness as smoking cessa ion aids emains
subjec o ongoing esea ch21,22.
We hypo hesize ha smoke s who ansi ion om combus ible obacco ciga e es o non-combus ible
nico ine/ obacco p oduc s (N–C NTPs) such as ECs and HTPs may expe ience measu able imp o emen s in
ca dio espi a o y pe o mance as a esul o elimina ing obacco smoke exposu e23. While p e ious esea ch has
documen ed he physiological e ec s and heal h imp o emen s associa ed wi h swi ching o hese p oduc s24–26
he speci ic impac on VO2max emains insu icien ly explo ed. Gi en ha VO2max is a well-es ablished
indica o o ae obic capaci y, any obse ed imp o emen s ollowing smoking cessa ion could p o ide aluable
insigh s in o he po en ial espi a o y and ca dio ascula bene i s o smoking subs i u ion.
This s udy examines changes in VO2max, measu ed using he sub-maximal Ches e S ep Tes , in ela ion
o smoking educ ion and smoking abs inence among pa icipan s in he CEASEFIRE ial27. CEASEFIRE is a
la ge p ospec i e andomized con olled ial designed o assess smoking educ ion and cessa ion a es among
adul smoke s ansi ioning om con en ional ciga e es o N–C NTPs (ECs and HTPs). VO2max was assessed
a baseline and moni o ed a mul iple ollow-up isi s.
The CEASEFIRE ial o e s a unique oppo uni y o p ospec i ely in es iga e he impac o smoking
educ ion o cessa ion on ae obic capaci y. This s udy p esen s a seconda y analysis o he ial da a, speci ically
examining changes in VO2max ac oss h ee g oups: con inuous smoke s, hose who educed smoking, and hose
who abs ained om smoking. Addi ionally, no esea ch has e e documen ed VO2max changes a e swi ching
o ECs o HTPs. The e o e, we conduc ed a sepa a e analysis o assess he di e en ial impac o exclusi e EC
use e sus exclusi e HTP use on VO2max, o e ing unique insigh s in o he e ec s o hese non-combus ible
nico ine and obacco p oduc s.
Me hods
The cu en s udy se es as a seconda y analysis o a la ge p ospec i e andomized con ol non-in e io i y ial
ha ocused on examining he qui and educ ion a es among adul smoke s who ansi ioned om con en ional
obacco ciga e es o non-combus ible nico ine/ obacco p oduc s (N–C NTP) namely HTPs and ECs. The
speci ics ega ding he popula ion sample, s udy design, E hics Re iew Boa d app o al, s udy egis a ion, and
CONSORT epo ing s anda ds we e p e iously de ailed28.
Resea ch was pe o med in acco dance wi h he ele an guidelines/ egula ions and acco ding o he
Decla a ion o Helsinki. In o med consen was ob ained om all pa icipan s and/o hei legal gua dians.
The de-iden i ied da ase s om he ial we e sou ced om he open science eposi o y main ained by he
Cen e o Excellence o he Accele a ion o Ha m Reduc ion (CoEHAR) a he Uni e si y o Ca ania, and
subsequen ly u ilized o his analysis: h ps://zenodo.o g/ eco ds/7941030
Since he s udy exclusi ely used publicly a ailable, de-iden i ied da a, i was exemp om ERB e iew. Only
comple e and eliable da a we e ex ac ed o ensu e analy ical in eg i y.
S udy pa icipan s
Adul smoke s o ≥ 10 ciga e es pe day ( egula ly smoking o a leas he pas yea ) and wi h exhaled ca bon
monoxide (eCO) le els o ≥ 7 ppm, no planning o qui soon (wi hin he nex 30 days om sc eening), bu open
o swi ching o HTPs o ECs we e ec ui ed om hospi al and uni e si y s a , ia social media, and h ough
wo d o mou h. They con i med no qui in en ion by answe ing “No” o hese wo ques ions: “Do you plan o
qui smoking wi hin he nex 30 days?” and “Do you wish o pa icipa e in a smoking cessa ion p og am?”. They
also me speci ic exclusion c i e ia including: (1) his o y o men al disease, (2) his o y o alcoholism o d ug
abuse, (3) p esence o clinical diseases ha , in he opinion o he in es iga o , would jeopa dize he sa e y o he
pa icipan o impac he alidi y o he s udy esul s, (4) use o any N–C NTPs wi hin he las 3 mon hs, and
(5) use o nico ine eplacemen he apy o o he smoking cessa ion he apies wi hin he las 3 mon hs. Subjec s
we e in o med ha he pu pose o he s udy was o quan i y he impac o educ ions in ciga e e consump ion
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on ca dio- espi a o y pe o mance. The s udy was app o ed by he local E hical Re iew Boa d (Comi a o
E ico, Azienda Ospedalie o Uni e si a ia “Policlinico-V. Emanuele,” Uni e si à di Ca ania, I aly; app o al no.
215/2017/PO). All pa icipan s p o ided w i en in o med consen p io o pa icipa ion in he s udy. The s udy
was egis e ed a ClinicalT ial.go ( ial egis a ion ID: NCT03569748).
T ial design and s udy isi s
Eligible subjec s we e en olled in o a 12-week, andomized, wo pa allel a m, con olled ial consis ing o se en
s udy isi s (one sc eening isi and six s udy isi s) a smoking cessa ion clinics o he Uni e si y o Ca ania
(Cen o pe la P e enzione e Cu a del Tabagismo – CPCT) designed o compa e cessa ion and educ ion a es
be ween HTPs and ECs s udy a ms. The ial also measu ed maximal ae obic capaci y by Ches e s ep es a
baseline, week-4, and week-12.
A he baseline isi , subjec s we e andomized o ei he he HTP (IQOS 2.4) g oup o he EC (Jus Fog Q16
S a e Ki ) g oup and we e ins uc ed o use he assigned p oduc o assis in abs aining om ciga e e smoking.
Pa icipan s we e asked o e u n o he CPCT o ollow-up isi s o ob ain egula supplies o obacco s icks ( o
IQOS 2.4 use s) and e-liquid e ills ( o Jus Fog Q16 use s). Du ing hese isi s, subjec s we e equi ed o epo
hei obacco ciga e e and EC/HTP consump ion, unde go measu emen s o eCO le els, and ha e hei blood
p essu e (BP) and hea a e (HR) assessed. Sel - epo ed use o obacco ciga e e and HTPs o ECs since he
p e ious isi was no ed in a s udy dia y and eco ded in he elec onic case epo o m a each isi ( om V2 o
V6). Addi ionally, EC/HTP consump ion was e i ied h ough checks o p oduc use (by coun ing he numbe
o used and unused obacco s icks and liquid e ill con aine s) and calcula ed as a e age consump ion on a pe
daily basis. Addi ionally, he Ches e s ep es was scheduled o be epea ed a weeks 4 and 12.
Exhaled ca bon monoxide measu emen s
Measu emen s o exhaled ca bon monoxide (eCO) le els, exp essed in pa s pe million (ppm), we e aken using
a hand-held CO me e (Mic o CO; Mic o Medical L d, UK). Subjec s we e ins uc ed o exhale slowly in o a
disposable mou hpiece connec ed o he CO me e , ollowing he manu ac u e ’s ecommenda ions. Expi a o y
maneu e s we e aken la e in he mo ning o ea ly in he a e noon wi h pa icipan s si ing com o ably.
Pa icipan s we e eques ed o e ain om smoking, aping, o using hea ed obacco p oduc s (HTPs) o a
leas 30 min p io o each measu emen . Smoking s a us was objec i ely con i med when eCO le els exceeded
10 ppm.
Ches e s ep es p ocedu e
The Ches e S ep Tes (CST) is a alida ed es assessing maximal ae obic capaci y (maximal oxygen consump ion,
VO2Max) by ha ing subjec s s ep on and o a gym s ep a g adually inc easing s epping a es e e y wo minu es
o inc ease hei hea ’s a e, which was used o calcula e hei VO2 max29,30. The es p o ides good es – e es
eliabili y and is an accep able me hod o es ima ing VO2max in he gene al heal hy adul popula ion31.
Be o e he commencing he es , pa icipan ’s blood p essu e (BP) and es ing hea a e (HR) we e measu ed.
Pa icipan s we e hen ins uc ed o s ep in ime wi h he bea o a me onome ini ially se a 15 bea s/minu e.
E e y 2-min, s epping a e was inc eased by 5 s eps/minu e ( om 15 o 35 bpm, a o al o 5 s ages). HR and
a ing o pe cei ed exe ion (RPE) we e eco ded a each s age. The es con inues un il he pa icipan eaches
a speci ic HR (80% HR max) o a mode a ely igo ous le el o exe ion (RPE below 14). Ae obic capaci y
(VO2Max) and i ness a ing a e de e mined using a Ches e S ep Tes calcula o a ailable a : h p s : / / w w w . b i a
n m a c . c o . u k / c h e s e . h m .
Smoking pheno ypes
The s udy analyzed he ime-cou se o VO2max changes in ela ion o h ee di e en smoking pheno ypes:
qui e s s. educe s s. ailu es.
Smoking abs inence is de ined as comple e sel - epo ed abs inence om ciga e e smoking since he p e ious
s udy isi , which was biochemically e i ied by eCO le els o < 10 ppm. Smoke s in his ca ego y a e classi ied as
qui e s. Con inuous abs inence a e om week 2 o week 4 (CAR 2–4 Weeks) and om week 2 o week 12 (CAR
2–12 Weeks) we e used as a obus cha ac e iza ion o smoking abs inence. Among he qui e s, we employed a
u he subclassi ica ion o dis inguish be ween indi iduals who achie ed abs inence a e swi ching o ECs and
hose who qui a e swi ching o HTPs. This allowed o a mo e g anula compa ison o ou comes based on he
ype o s udy p oduc used.
Smoking educ ion is de ined as sel - epo ed ≥ 50% educ ion in he numbe o ciga e es smoked pe day
om baseline (eCO le els we e measu ed o e i y smoking s a us and con i m a educ ion compa ed wi h
baseline). Smoke s in his ca ego y a e classi ied as educe s. Con inuous educ ion a es om week 2 o week
4 (CRR 2–4 Weeks) and om week 2 o week 12 (CRR 2–12 Weeks) we e used as a obus cha ac e iza ion o
smoking educ ion.
Smoking ailu e is he smoking pheno ype ha excludes smoking abs inence o smoking educ ion. Smoke s
in his ca ego y a e classi ied as ailu es.
S a is ical analysis
In he p ima y analysis, a o al o 220 smoke s we e en olled, wi h 110 pa icipan s assigned o he EC S udy
a m and 110 o he HTP S udy a m. Fo he cu en seconda y analysis, subjec s’ VO2max measu emen s om
bo h s udy a ms we e pooled and e alua ed o changes om baseline a he 4-week and 12-week ime poin s,
s a i ied by smoking beha io pheno ype: Failu es (con inued smoke s), Reduce s, and Qui e s (comple e
abs aine s). In addi ion, his seconda y analysis also in es iga ed possible di e en ial impac o exclusi e EC use
and exclusi e HTP use on VO2max, p o iding no el insigh s in o he ca dio espi a o y e ec s o N–C NTPs.
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Ca ego ical a iables we e summa ized using coun s and pe cen ages, while con inuous a iables wi h
symme ical dis ibu ion we e p esen ed as mean and s anda d de ia ions (SD). Skewed con inuous da a we e
summa ized using median and in e qua ile anges (IQR). Compa isons we e conduc ed using he χ2 es o
ca ego ical a iables, and one-way Analysis o Va iance (ANOVA) and K uskal–Wallis es s o no mally and
no no mally dis ibu ed da a, espec i ely. A wo-way ANOVA was used o assess he e ec s o classi ica ion
and sex on VO2 max a baseline. A epea ed measu es ANOVA model was applied o examine po en ial e ec s
o classi ica ions and sex on VO2 max o e ime. To e alua e he associa ion be ween smoking pheno ypes
and changes in VO2 max om baseline o week 4 and week 12, while accoun ing o po en ial con ounde s,
a mul iple linea eg ession analysis was pe o med. The ou come a iable was ΔVO2 max (i.e., he absolu e
di e ence in VO2 max om baseline o weeks 4 and 12), wi h classi ica ion, age, sex and BMI changes om
baseline included as independen ac o s. These a iables we e selec ed based on exis ing e idence indica ing
hei po en ial in luence on ca dio espi a o y pe o mance.
The analyses we e pe o med using S a is ical Package o Social Sciences (SPSS Inc., Chicago, IL) o
Windows e sion 20.0 and p alues < 0.05 we e conside ed signi ican .
Resul s
Fo his seconda y analysis, da a om 187 subjec s we e a ailable. This accoun ed o missing da a om subjec s
who ei he could no pe o m he Ches e S ep Tes o did no quali y as con inuous smoking pheno ypes
(Qui e s, Reduce s, o Failu es, based on he p o ided de ini ions). Among he 187 e alua ed subjec s, 32
(17%) we e classi ied as Failu es, 88 (47%) as Reduce s, and 67 (36%) as Qui e s. A desc ip ion o he e alua ed
sample is p esen ed in Table 1. Table 2 illus a es he le el o ciga e e consump ion o each smoking pheno ype,
showing ha Reduce s had on a e age a g ea e han 75% educ ion in ciga e e consump ion om baseline.
A baseline, he equency dis ibu ion o sex among classes (i.e., Failu es, Reduce s, and Qui e s) was
signi ican ly di e en (p = 0.027, χ2 es ). Con e sely, no signi ican di e ence was ound o age among classes
and sex (Two-way ANOVA). Addi ionally, no signi ican di e ence was ound a baseline o ciga e es pe
day, pack-yea s, and he numbe o yea s o smoking among sex and classes (Two-way ANOVA). As expec ed,
VO2max was signi ican ly di e en be ween males and emales (p < 0.0001) a baseline, while no di e ence was
ound among classes (p = 0.147, Two-way ANOVA).
Rega ding he e ec o indi idual smoking his o y on baseline VO2max, s ong nega i e co ela ions we e
ound be ween VO2max and bo h he na u al log o yea s o smoking (R2 = 0.469, p < 0.0001) and he na u al log
o pack-yea s (R2 = 0.389, p < 0.0001). In a mul iple linea model, bo h co ela ions disappea ed when co ec ed
o sex and age, which we e he only independen a iables co ela ed o VO2max a baseline. Howe e , o limi
he ob ious e ec o age on indi idual smoking his o y by e alua ing a na owe age window, in a subse wi h
age ange be ween 19 and 30 yea s, we ound ha in a mul iple eg ession model o VO2max a baseline, sex
Failu es Reduce s Qui e s
Baseline 22.1 ± 8.3 23.2 ± 12.1 21.4 ± 9.3
Week 1 17.7 ± 8.0 4.1 ± 2.0 0
Week 2 17.0 ± 7.9 4.8 ± 2.7 0
Week 4 16.4 ± 7.8 4.7 ± 2.6 0
Week 8 16.9 ± 7.0 5.0 ± 3.1 0
Week 12 17.8 ± 7.1 5.7 ± 3.3 0
Table 2. Ciga e e consump ion (ciga e es/day) da a a di e en ime poin s and o each smoking pheno ype
(mean ± SD).
Failu es
(n = 32) Reduce s
(n = 88) Qui e s
(n = 67) P alue
Sex, F/M, No 8/24 39/49 36/31 0.027
Age (yea s) 47.2 ± 17.2 39.4 ± 16.5 39.8 ± 15.1 0.113
Body mass index (Kg/m2)24.5 ± 4.2 24.4 ± 4.6 23.8 ± 4.0 0.617
Ciga e es/day (No.) 22 ± 8 23 ± 12 21 ± 9 0.769
Yea s o smoking 28.8 ± 14.8 21.3 ± 16.1 22.6 ± 14.8 0.073
Pack/yea s 34.2 ± 21.2 28.6 ± 29.4 25.8 ± 22.1 0.171
eCO (ppm) 28.8 ± 13.9 24.4 ± 11.9 27.5 ± 14.3 0.203
VO2max
(ml min−1kg−1)38.6 ± 5.7 38.6 ± 7.5 38.9 ± 6.3 0.704
Table 1. Demog aphic da a, smoking his o y and maximal oxygen consump ion (VO2max) a baseline o
each smoking pheno ype. Values a e exp essed as equencies o mean ± s anda d de ia ion. eCO Exhaled
b ea h ca bon monoxide; ppm Pa pe million.
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(B = − 4.834 [95% CI − 6.218/ − 3.451], e e ence: Males, p < 0.0001) and he na u al log o pack-yea s (B = − 1.269
[95% CI − 2.469/ − 0.069], p = 0.038) showed a signi ican co ela ion, bu no age (p = 0.820).
The co ela ion be ween VO2max and he na u al log o eCO a baseline was signi ican (R2 = 0.055,
p = 0.0013). Addi ionally, he co ela ion be ween changes in VO2max (ΔVO2max) a week 12 and a week 4
was also signi ican (R2 = 0.77, p < 0.0001).
Table 3 and Fig.1 p esen he means and s anda d de ia ions (SDs) o VO2max a baseline, week 4, and week
12, sepa a ely o each con inuous smoking pheno ypes. A Repea ed Measu es ANOVA model, using ime as
he wi hin-subjec ac o and classi ica ion and sex as be ween-subjec ac o s, showed ha ime (p < 0.0001),
pheno ype classi ica ion (p = 0.004), and sex (p < 0.0001) all had signi ican e ec s on VO2max changes o e
ime. In he model, no signi ican e ec was p oduced by he p oduc used (EC o HTP, p = 0.144).
In Fig.2 and Table 3, he means and SDs o changes in VO2max (ΔVO2max) a week 4 and week 12 om
baseline a e shown sepa a ely o each con inuous smoking pheno ypes. A one-way ANOVA model indica ed
ha , among Qui e s, ΔVO2max was signi ican ly g ea e a bo h week 4 (2.4 ± 1.7 mL kg−1 min−1) and week
12 (2.7 ± 1.9 mL kg−1 min−1, p < 0.0001 o bo h). S a is ically signi ican imp o emen s in ΔVO2max we e also
obse ed among Reduce s a bo h week 4 and week 12, wi h inc eases o 1.3 ± 1.9 and 1.9 ± 1.8 mL kg−1 min−1,
espec i ely (p < 0.0001 o bo h). In subjec s who con inued o smoke a he same a e as baseline, he es ima ed
VO2max emained unchanged.
In Fig.3 he means and SDs ele an o he compa isons o he changes in ΔVO2 max a week 4 and week 12
a e shown o Qui e s using EC o HTP. Bo h exclusi e EC and HTP use caused a s a is ically signi ican and
clinically ele an amelio a ion in VO2max. Compa ed o baseline, VO2max alues we e signi ican ly g ea e
a bo h week 4 ( om 38.4 ± 5.9 mL kg−1 min−1 o 41.0 ± 6.1 mL kg−1 min−1; p < 0.0001, Repea ed Measu es
ANOVA) and week 12 ( om 38.4 ± 5.9 mL kg−1 min−1 o 41.4 ± 6.3 mL kg−1 min−1; p < 0.0001) o exclusi e
EC use. Likewise, VO2max alues we e signi ican ly g ea e han baseline a bo h week 4 ( om 39.2 ± 6.7 mL
kg−1 min−1 o 41.4 ± 6.4mL kg−1 min−1; p < 0.0001) and week 12 ( om 39.2 ± 6.7 o 41.6 ± 6.5 mL kg−1 min−1;
p < 0.0001) o exclusi e HTP use. No signi ican di e ences be ween EC and HTP usage we e ound by means
o one-way ANOVA a bo h ime poin s.
Tables 4 and 5 p esen he mul iple linea eg ession models o ΔVO2max a week 4 and week 12, espec i ely.
A bo h weeks 4 and 12, VO2max signi ican ly inc eased in bo h Reduce s and Qui e s, wi h no signi ican
e ec s ound o age and sex. Being a Reduce o a Qui e esul ed in a signi ican ly g ea e imp o emen in
Fig. 1. Means ± SDs ele an o he alues o VO2 max a baseline, week 4 and week 12 sepa a ely o smoking
pheno ype classi ica ion. Time (p < 0.0001), smoking pheno ype classi ica ion (p = 0.01) and sex p < 0.0001
had a signi ican e ec on VO2 max (Repea ed Measu es ANOVA model, adop ing ime as wi hin ac o and
classi ica ion and sex as be ween ac o s).
Baseline VO2 max week 4 ΔVO2 max week 4 VO2 max week 12 ΔVO2 max week 12
Failu es (ml kg−1l min−1)37.6 ± 5.7 38.1 ± 6.2 0.4 ± 2.0 37.9 ± 5.9 0.3 ± 1.7
Reduce s (mll kg−1l min−1)38.6 ± 7.5 39.9 ± 7.6 1.3 ± 1.9 40.5 ± 7.3 1.9 ± 1.8
Qui e s (mll kg−1l min−1)38.9 ± 6.3 41.2 ± 6.3 2.4 ± 1.7 41.5 ± 6.2 2.7 ± 1.9
Table 3. Values o VO2 max (ml min−1kg−1) a baseline, week 4, and week 12 sepa a ely pe each con inuous
smoking pheno ypes along wi h absolu e changes in VO2 max om baseline a weeks 4 and 12 (means ± SD).
Time (p < 0.0001), smoking pheno ype classi ica ion (p = 0.004), and sex (p < 0.0001) all had a signi ican e ec
on VO2 max changes o e he ime (Repea ed measu es ANOVA). In he model, no signi ican e ec was
p oduced by he p oduc used (EC o HTP, p = 0.144). ΔVO2 max: Absolu e change in VO2 max wi h espec o
baseline.
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VO2max. The numbe o pack-yea s (as na u al log) was posi i ely co ela ed o ΔVO2max, while age was
nega i ely co ela ed. Changes in BMI om baseline ( his in o ma ion was only a ailable a week 12) we e
simila ly nega i ely co ela ed o ΔVO2max.
Discussion
Resea ch sugges s ha abs aining om smoking can imp o e exe cise pe o mance, hough he e idence om
longi udinal s udies is e y limi ed. This 12-week p ospec i e coho analysis shows signi ican and clinically
ele an imp o emen s in exe cise capaci y among smoke s who we e encou aged o qui hei ciga e e
consump ion by swi ching o HTPs o ECs. Imp o emen s we e also obse ed in indi iduals who educed
hei obacco ciga e e consump ion. The s udy speci ically shows— o he i s ime—consis en imp o emen
in VO2max, among qui e s exclusi ely using EC o HTP. No ably, he e was a signi ican inc ease in ae obic
capaci y (i.e. maximal oxygen consump ion, VO2max), obse able as ea ly as 4 weeks.
Fig. 3. Means ± SDs ele an o he changes in VO2 (ΔVO2) max a week 4 and week 12 sepa a ely o EC and
HTP use s, in Qui e s only. P alues we e compu ed by means o one-way ANOVA. MCID; he minimum
clinically impo an di e ence is de ined as an imp o emen in anae obic h eshold o a leas 2 ml O2/kg/min.
Fig. 2. Means ± SDs ele an o he changes in VO2 (ΔVO2) max a week 4 and week 12 sepa a ely o
pheno ype smoking classi ica ion. P alues we e compu ed by means o one-way ANOVA and Fishe ’s
p o ec ed Leas Signi ican Di e ence. MCID; he minimum clinically impo an di e ence is de ined as an
imp o emen in anae obic h eshold o a leas 2 ml O2/kg/min.
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The s udy used he s anda dized Ches e S ep Tes (CST) o es ima e maximal ae obic capaci y (i.e.,
VO2max). While he CST may no be as accu a e as di ec VO2max measu emen s ob ained h ough s anda d
ca diopulmona y exe cise es ing (which equi es gas analyze s and complex p ocedu es), i o e s a simple and
alid al e na i e ha could be easily inco po a ed in o ou ine clinical p ac ice29–31. Addi ionally, he CST, being
sub-maximal, is sa e han ca diopulmona y exe cise es ing and is also mo e apid, making i a use ul ool o
assessing la ge s udy samples wi h epea ed measu es a e in e en ions aimed a imp o ing he O2 anspo /
u iliza ion pa hway. Fo hese easons, CST was conside ed he ideal es o examine VO2max changes in he
con ex o a la ge p ospec i e swi ching ial o ECs and HTPs.
This s udy demons a es ha abs aining om smoking can imp o e VO2max. Speci ically, consis en
and clinically ele an imp o emen s we e obse ed among qui e s exclusi ely using EC o HTP. This adds
impo an new in o ma ion o he cu en unde s anding o how s opping smoking and comple e subs i u ing
obacco ciga e es wi h N–C NTPs can e e se he de imen al e ec s o ciga e e smoke exposu e on ae obic
capaci y in ela i ely young and appa en ly heal hy indi iduals. The imp o emen in VO2max in ou s udy
aligns wi h he indings ha he ae obic capaci y o cu en smoke s is signi ican ly lowe compa ed o non-
smoke s and o me smoke s32,33.
Ou s udy shows an imp o emen in VO2max o a leas 2.2 and 2.6 mL kg−1 min−1 om baseline among
HTP and EC use s, espec i ely. These changes a e is s a is ically signi ican as ea ly as week 4 and exceed he
minimum clinically impo an di e ence (MCID) o VO2max (de ined as an inc ease in anae obic h eshold
o a leas 2 mL O2 kg−1 min−1). The epo ed changes we e no signi ican ly di e en be ween EC and HTP.
This sugges s ha indi iduals who qui smoking by swi ching o ECs o HTPs can achie e an ea ly and
clinically meaning ul imp o emen in ae obic capaci y. An imp o emen beyond he MCID e lec s enhanced
ca dio espi a o y i ness, which may ansla e in o be e daily unc ioning and physical pe o mance.
An impo an addi ional inding o his p esen s udy is ha we ound s a is ically signi ican imp o emen s
in ΔVO2max among educe s, wi h inc eases o 1.3 and 1.9 mL kg−1 min−1 a week 4 and week 12, espec i ely.
In his coho o educe s, daily ciga e e consump ion was consis en ly educed by a leas 75% om baseline
h oughou he en i e s udy du a ion. By subs an ially educing ciga e e smoking wi h N-C NTPs (i.e. HTPs
o ECs) use and he eby cu ailing exposu e o se e al oxic chemicals, we obse ed an amelio a ion in ae obic
capaci y may ha e esul ed.
The apid and signi ican imp o emen s in VO2max ollowing smoking cessa ion a e swi ching o N-C
NTPs can be a ibu ed o se e al po en ial mechanisms, including a educ ion in ca bon monoxide (CO) le els.
Tobacco smoking inc eases CO in he bloods eam, which binds o hemoglobin wi h a much highe a ini y
han oxygen, leading o ele a ed ca boxyhemoglobin (COHb) le els and educed oxygen-ca ying capaci y. This
comp omises oxygen deli e y o muscle mi ochond ia, a ec ing VO2max by educing a ailable binding si es
on hemoglobin and slowing oxygen unloading a ac i e muscles34. Inhala ion o CO su icien o aise COHb o
app oxima ely 4.5% (equi alen o smoking h ee ciga e es) has been shown o dec ease VO2max by abou 7%35
Consis en ly, ou s udy ound a small bu signi ican co ela ion be ween exhaled CO and es ima ed VO2max.
The co ela ion emained modes because smoking in luences exe cise capaci y h ough mul iple mechanisms,
including imp o emen s in ascula endo helial unc ion, and educ ions in exposu e o ad anced glyca ion
B 95% CI p Value
Sex (Re . M) 0.302 − 0.201/0.805 0.238
Reduce s (Re . ailu es) 1.694 1.013/2.375 < 0.0001
Qui e s (Re . ailu es) 2.550 1.829/3.270 < 0.0001
ΔBMI a Wk 12 (kg/m2) − 0.981 − 1.291/ − 0.670 < 0.0001
Na u al log o Pack/Y s 0.650 0.248/1.051 0.002
Age (y s) − 0.035 − 0.064/0.006 0.019
BMI a baseline (kg/m2) 0.001 − 0.059/0.061 0.980
Table 5. Mul iple linea eg ession model o ΔVO2 max a week 12. B alues and ele an 95% con idence
in e al (95%CI) a e epo ed o each independen a iable. ΔBMI a Wk 12: absolu e change in BMI a week
12 wi h espec o baseline.
B 95% CI p Value
Sex (Re . M) 0.042 − 0.509/0.594 0.880
Reduce s (Re . ailu es) 0.835 0.087/1.583 0.029
Qui e s (Re . ailu es) 1.837 1.050/2.623 < 0.0001
Na u al log o pack (Y s) 0.628 0.186/1.069 0.006
Age (Y s) − 0.041 − 0.073/ − 0.009 0.012
BMI a baseline (kg/m2) 0.044 − 0.022/0.110 0.190
Table 4. Mul iple linea eg ession model o ΔVO2 max a week 4. B alues and ele an 95% con idence
in e al (95%CI) a e epo ed o each independen a iable.
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end p oduc s (AGEs) and ni osamines such as 4-(me hylni osamino)-1-(3-py idyl)-1-bu anone (NNK) and
i s me aboli e 4-(me hylni osamino)-1-(3-py idyl)-1-bu anol (NNAL)36,37. Fo example, yea s o smoking – a
key p edic o o educed physical i ness—was in e sely co ela ed wi h baseline VO2max in ou s udy.
The ma ked decline in CO and COHb le els ollowing ciga e e subs i u ion wi h combus ion- ee
al e na i es38,39 apidly es o es he oxygen-ca ying capaci y o he blood, imp o ing oxygen deli e y o
muscles du ing exe cise. This con ibu es o he ime-dependen imp o emen in ae obic capaci y, wi h g ea e
imp o emen obse ed a 12 weeks due o a highe p e alence o qui e s compa ed o 4 weeks. This aligns
wi h imp o ed exe cise ole ance seen in COPD pa ien s who swi ched o e-ciga e es26 and hea ed obacco
p oduc s40.
The s udy had bo h s eng hs and limi a ions. The ini ial RCT p o ided a la ge, well-cha ac e ized coho
wi h s anda dized da a collec ion me hods, ensu ing ca e ul acking o physiological changes o e ime
and biochemical e i ica ion o smoking s a us. This app oach minimized biases commonly associa ed wi h
e ospec i e o c oss-sec ional s udies, enhancing he c edibili y o ou indings, pa icula ly in e ms o
da a quali y and consis ency. No ably, he use o biochemically e i ied con inuous abs inence a e (CAR) as
a measu e o abs inence is pa icula ly aluable in his ype o s udy, as con inuous abs inence is he key d i e
o heal h imp o emen s in a pe -p o ocol analysis. The high CAR in his da ase can be a ibu ed o s ong
accep abili y and e ec i eness o he smoking subs i u ion p oduc s used in he o iginal s udy27. This, combined
wi h pe sonalized counseling om psychologis s specialized in bo h smoking cessa ion and ha m educ ion,
played a c ucial ole in p e en ing elapse. While we ecognize he impo ance o e alua ing unaided cessa ion
in he b oade con ex o ha m educ ion, ou seconda y analysis speci ically ocused on he pa hophysiological
impac o smoking cessa ion/ educ ion, as e lec ed in measu able imp o emen s in ae obic capaci y. Bo h ECs
and HTPs we e e ec i e in p omo ing smoking cessa ion and imp o ing VO2max. Howe e , i is impo an o
emphasize ha he o iginal CEASEFIRE ial was speci ically designed o compa e ECs and HTPs, and he e o e
did no include a con ol g oup o isola e he indi idual e ec s o each p oduc . While he inclusion o an unaided
qui e con ol g oup would ce ainly enhance u u e esea ch, i s absence in his s udy does no comp omise he
alidi y o he cu en indings. Ano he limi a ion o his s udy is he limi ed gene alizabili y o he indings, as
he ela i ely young popula ion wi h no mal weigh and no p eexis ing diseases may no accu a ely ep esen
he b oade pa ien popula ion. Addi ionally, s udy pa icipan s we e om u ban Sicilian se ings, which may
limi he gene alizabili y due o unique li es yle ac o s such as die , exe cise, and gene ics. Fu he mo e, we
used only one exe cise modali y, namely CST, o assess imp o emen in ae obic capaci y, whe eas o he ypes
o exe cise es s may be mo e p ecise o his assessmen . Howe e , he Ches e S ep es has p e iously been
demons a ed as an app op ia e ool o ack changes o e he ime, which was he pu pose o ou s udy. I also
has a high es – e es eliabili y, which lends i sel o epea es ing manoeu es. We also could no con ol o
changes in exe cise habi s du ing he s udy, which is a known ac o in luencing imp o emen s in VO2max and/
o VO2peak41 bu his is unlikely o ha e been di e en be ween he andomised coho s o accoun o he
di e ences seen.
In conclusion, his pos -hoc analysis sugges s ea ly signi ican imp o emen s in exe cise capaci y among
heal hy smoke s who qui smoking by swi ching o ei he exclusi e ECs o HTPs use Gi en ha VO2max is he
key indica o o exe cise capaci y and a s ong p edic o o ca dio ascula mo bidi y and all-cause mo ali y7,8,
hese indings p o ide aluable insigh s in o he po en ial bene i s o swi ching om obacco ciga e es o
combus ion ee nico ine al e na i es. Howe e , as his is a pos -hoc analysis, causali y canno be es ablished,
and u he p ospec i e s udies a e needed o con i m he p esen indings.
Recognizing changes in VO2max as ea ly indica o s o heal h e ec will s eng hen hei alue ac oss
clinical, egula o y, and esea ch se ings. Clinicians can le e age his in o ma ion o ecommend smoking
cessa ion in e en ions, ha may lead o angible imp o emen s in physical pe o mance and o e all well-being.
Addi ionally, esea che s may conside including VO2max measu emen s as clinically meaning ul ou comes
in u u e s udies in ol ing e-ciga e es, hea ed obacco p oduc s, o al obacco/nico ine p oduc s, smoking
cessa ion medica ions, and o he medicinal p oduc s designed o imp o e physical pe o mance.
Da a a ailabili y
The de-iden i ied da ase s om he ial we e sou ced om he open science eposi o y main ained by he Cen e
o Excellence o he Accele a ion o Ha m Reduc ion (CoEHAR) a he Uni e si y o Ca ania, and subsequen ly
u ilized o his analysis: h ps://zenodo.o g/ eco ds/7941030.
Recei ed: 18 Oc obe 2024; Accep ed: 23 May 2025
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Au ho con ibu ions
Polosa Ricca do:designed esea ch Da ide Campagna: pe o med esea ch G azia Caci: collec ed da a, Fabio
Cibella, Claudio Sai a , Jacob Geo ge: analyzed da a and e ised hemanusc ip Lucia Spicuzza: w o e pape .
F ancesco Pennisi: MS second e ision and li e a u e e ision Giulio Ge aci MS second e ision and li e a u e
e ision Yusu Adebisi: Ms hi d e ision.
Funding
The au ho s ecei ed no unding o he seconda y analysis using he de-iden i ied da ase s sou ced o ee om
Scien i ic Repo s | (2025) 15:19104 9
| h ps://doi.o g/10.1038/s41598-025-03904-w
www.na u e.com/scien i ic epo s/