In e na ional Jou nal o
En i onmen al Resea ch
and Public Heal h
Sys ema ic Re iew
Exe cise In ensi y in Pa ien s wi h Ca dio ascula Diseases:
Sys ema ic Re iew wi h Me a-Analysis
Ca a ina Gonçal es 1,2 , A mando Raimundo 1,2 , Ana Ab eu 3and Jo ge B a o 1,2,*


Ci a ion: Gonçal es, C.; Raimundo,
A.; Ab eu, A.; B a o, J. Exe cise
In ensi y in Pa ien s wi h
Ca dio ascula Diseases: Sys ema ic
Re iew wi h Me a-Analysis. In . J.
En i on. Res. Public Heal h 2021,18,
3574. h ps://doi.o g/10.3390/
ije ph18073574
Academic Edi o : Paul B. Tchounwou
Recei ed: 23 Feb ua y 2021
Accep ed: 25 Ma ch 2021
Published: 30 Ma ch 2021
Publishe ’s No e: MDPI s ays neu al
wi h ega d o ju isdic ional claims in
published maps and ins i u ional a il-
ia ions.
Copy igh : © 2021 by he au ho s.
Licensee MDPI, Basel, Swi ze land.
This a icle is an open access a icle
dis ibu ed unde he e ms and
condi ions o he C ea i e Commons
A ibu ion (CC BY) license (h ps://
c ea i ecommons.o g/licenses/by/
4.0/).
1Depa amen o de Despo o e Saúde, Escola de Saúde e Desen ol imen o Humano, Uni e sidade de É o a,
La go dos Colegiais, 7000 É o a, Po ugal; [email p o ec ed] (C.G.); [email p o ec ed] (A.R.)
2Comp ehensi e Heal h Resea ch Cen e (CHRC), Uni e sidade de É o a, La go dos Colegiais,
7000 É o a, Po ugal
3Se ico de Ca diologia, Hospi al Uni e si á io de San a Ma ia/Cen o Hospi ala Uni e si á io Lisboa
No e (CHULN), Cen o Académico de Medicina de Lisboa (CAML), Cen o Ca dio ascula da Uni e sidade
de Lisboa (CCUL), Faculdade de Medicina, Uni e sidade de Lisboa, 1649-028 Lisboa, Po ugal;
[email p o ec ed]
*Co espondence: jo [email p o ec ed]
Abs ac :
Exe cise-induced imp o emen s in he VO
2
peak o ca diac ehabili a ion pa icipan s
a e well documen ed. Howe e , op imal exe cise in ensi y emains doub ul. This s udy aimed
o iden i y he op imal exe cise in ensi y and p og am leng h o imp o e VO
2
peak in pa ien s
wi h ca dio ascula diseases (CVDs) ollowing ca diac ehabili a ion. Randomized con olled ials
(RCTs) included a con ol g oup and a leas one exe cise g oup. RCTs assessed ca dio espi a-
o y i ness (CRF) changes esul ing om exe cise in e en ions and epo ed exe cise in ensi y,
isk a io, and con idence in e als (CIs). The p ima y ou come was CRF (VO
2
peak o VO
2
a
anae obic h eshold). Two hund ed and wen y-one s udies we e ound om he ini ial sea ch
(CENTRAL, MEDLINE, CINAHL and SPORTDiscus). Following inclusion c i e ia, 16 RCTs we e
conside ed. Me a- eg ession analyses e ealed ha VO
2
peak signi ican ly inc eased in all in ensi y
ca ego ies. Mode a e-in ensi y in e en ions we e associa ed wi h a mode a e inc ease in ela i e
VO
2
peak (SMD = 0.71 mL-kg
−1
-min
−1
; 95% CI = [0.27–1.15]; p= 0.001) wi h mode a e he e ogenei y
(I
2
= 45%). Mode a e- o- igo ous-in ensi y and igo ous-in ensi y in e en ions we e associa ed
wi h a la ge inc ease in ela i e VO
2
peak (SMD = 1.84 mL-kg
−1
-min
−1
; 95% CI = [1.18–2.50],
p< 0.001 and SMD = 1.80 mL-kg
−1
-min
−1
; 95% CI = [0.82–2.78] p= 0.001, espec i ely), and we e also
highly he e ogeneous wi h I
2
alues o 91% and 95% (p< 0.001), espec i ely. Mode a e- o- igo ous
and igo ous-in ensi y in e en ions, conduc ed o 6–12 weeks, we e mo e e ec i e a imp o ing
CVD pa ien s’ CRF.
Keywo ds:
ca diac ehabili a ion; ca dio espi a o y i ness; exe cise he apy; hea diseases;
high-in ensi y in e mi en exe cise
1. In oduc ion
Ca dio ascula diseases (CVDs) a e he leading cause o mo ali y in oday’s socie y,
being esponsible o up o one- hi d o all dea hs wo ldwide and 50% o all dea hs in
Eu ope, and his scena io is expec ed o wo sen in he coming yea s [1].
The concep o ca diac ehabili a ion (CR) has been de ined as he e o owa ds
ca dio ascula isk ac o educ ion, designed o lessen he chance o a subsequen ca diac
e en , and o slow and pe haps s op he p og ession o he disease p ocess. In he con ex
o CR p og ams, exe cise aining has been ecognized as one o he main componen s,
combined wi h educa ion, con ol, pha macological adhe ence and li es yle changes o
ca dio ascula isk ac o s [
2
]. Physical exe cise inclusion in CR p og ams esul ed in
se e al bene icial e ec s on ca dio ascula unc ional capaci y, quali y o li e, isk ac o
modi ica ion, psychological p o ile, hospi al eadmissions, and mo ali y [
3
,
4
]. Such ben-
e i s can be jus i ied by a 20% educ ion in mo ali y om all causes and in he le els o
In . J. En i on. Res. Public Heal h 2021,18, 3574. h ps://doi.o g/10.3390/ije ph18073574 h ps://www.mdpi.com/jou nal/ije ph
In . J. En i on. Res. Public Heal h 2021,18, 3574 2 o 19
ca dio espi a o y i ness (CRF) o each me abolic equi alen imp o emen (MET) in CRF
o pa ien s wi h CVD [5].
Exe cise p og ams o pa ien s wi h CVD adi ionally in ol e mos ly low- o mode a e-
in ensi y con inuous ae obic exe cise aining, wi h he consensus ha one o he bene i s o
ae obic exe cise is he inc ease in peak oxygen up ake (VO
2
peak) [
6
–
8
]. Con inuous ae obic
exe cise aining implica es highe du a ions unde mode a e-in ensi y and non a iable
ae obic ac i i y (60–80% o VO
2
peak) [
9
–
12
], compa ed o high-in ensi y p o ocols, which
consis o in e mi en , sho high-in ensi y wo k pe iods (85–100% o VO
2
peak) wi h
ela i e es ing pe iods [13,14].
Exe cise in ensi y appea s o in luence he numbe o ca diop o ec i e bene i s achie ed
om ae obic exe cise [
15
,
16
]. The cu en consensus ecommends ha exe cise in ensi y
p esc ibed o pa ien s wi h CVD should be app oxima ely 60% o he maximal hea a e
(MHR), 50% o he hea a e ese e (HRR), o 12–13 on he Bo g scale. In ensi ies a ound
85% MHR, 80% HRR, o 15–16 on he Bo g scale should ep esen he uppe limi s [
6
]. Ad-
di ionally, high-in ensi y p o ocols (85–100% o VO
2
peak) appea o be o pa icula in e es
o scien is s, conside ing hei applica ion in pa ien s wi h CVD based on he e ec s on he
ca dio espi a o y and muscle sys ems [
7
]. High-in ensi y p o ocols elici a g ea e aining
s imulus han mode a e con inuous exe cise in imp o ing maximal ae obic capaci y [
8
–
19
].
In addi ion, high-in ensi y exe cise appea s o imp o e he limi ing ac o s o VO
2
peak,
and VO
2
peak i sel has been ound o be mo e e ec i e in imp o ing ca dio ascula isk
ac o s han mode a e-in ensi y exe cise [17,19].
T aining sessions based on mode a e-in ensi y con inuous exe cise ha e shown im-
p o emen s in HRR a e eigh weeks [
20
] and a e 12 weeks [
21
,
22
]. Mode a e- o high-
in ensi y con inuous exe cise (6 and 12 MET, co esponding o 21 and 42 mL-kg
−1
-min
−1
o VO
2
peak) has also been shown o educe all-cause mo ali y in heal hy indi iduals,
independen o ac i i y du a ion [
7
], and educe he isk o hea disease [
15
], suppo ing
he need o u he in es iga e he po en ial heal h e ec s o p o ocols based on highe
in ensi ies. The e o e, du ing he las wo decades, se e al s udies ha e demons a ed
ha high-in ensi y exe cise p o ocols induce mo e bene icial ca dio ascula adap a ions in
pa ien s wi h mild- o-se e e hea disease when compa ed o mode a e-in ensi y exe cise
p o ocols [8,17–19].
A ecen me a-analysis [
23
] epo ed highe imp o emen s in maximal ae obic capaci y
a e high-in ensi y in e al aining (HIIT) p og ams compa ed o mode a e-in ensi y
p og ams. Ne e heless, he op imum exe cise in ensi y p esc ip ion in pa ien s wi h CVD
is s ill a subjec o deba e. A ecen sys ema ic e iew on he opic [
24
] did no epo
op imal in ensi y p esc ip ion (e.g., he in ensi y in e al ha is mos e ec i e du ing
exe cise in e en ions o induce a o able changes in ae obic capaci y). Thus, despi e
he li e a u e being eple e wi h s udies showing ha egula and s uc u ed exe cise is
bene icial o CVD pa ien s, he op imal in ensi y and leng h o exe cise in e en ions
ha b ing abou g ea e bene i s emain equi ocal. Hence, he objec i e o his sys ema ic
e iew wi h me a-analysis was o iden i y, h ough Randomized Con olled T ials (RCTs) o
exe cise-based CR, he mos e ec i e exe cise in ensi y and in e en ion leng h o op imize
VO2peak in pa ien s wi h CVD.
2. Ma e ials and Me hods
This sys ema ic e iew was unde aken as de ailed in he p o ocol egis e ed wi h
PROSPERO (Regis a ion Numbe CRD42018097319).
2.1. Sea ch S a egy
The sea ch s a egies we e designed in acco dance wi h he me hods sugges ed by
he Coch ane Handbook o Sys ema ic Re iews o In e en ions [
25
]. The ollowing
da abases we e sea ched om hei incep ion o Janua y 2021: Coch ane Cen al Regis e
o Con olled T ials (CENTRAL), MEDLINE (O id), CINAHL (EBSCO) and SPORTDiscus.
Da a a e p o ided as he isk di e ence (95% CI), based on RCTs published un il Janua y
In . J. En i on. Res. Public Heal h 2021,18, 3574 3 o 19
2021, ensu ing ha all s udies ha e been included i epo ing da a on es ablished ou comes.
Re e ence lis s o eligible s udies we e also sys ema ically sea ched.
We used he PICO model [
26
] o iden i y ee ex e ms and con olled ocabula y
e ms o c ea e ou sea ches. The ollowing key concep s we e chosen: “Pa ien s wi h
ca dio ascula diseases” AND “Ca diac Rehabili a ion” AND “Exe cise In ensi y” AND
“Ca dio espi a o y Fi ness”. The sea ch s a egy o he MEDLINE (O id) da abase is
a ailable in he Supplemen a y Ma e ials o his manusc ip .
2.2. Inclusion C i e ia
The inclusion c i e ia we e ull-leng h esea ch a icles published in pee - e iewed
jou nals in he English language wi h no limi s se on he da e o i s publica ion o gende .
Only RCTs up o Janua y 2021 we e eligible. S udies included pa icipan s who we e
diagnosed wi h CVD, such as hose in ol ed in some exe cise p og ams, assessed by
analyzing expi ed ai du ing a maximal ca diopulmona y exe cise es a baseline and
pos in e en ion.
We included RCTs o compa e ae obic capaci y changes esul ing om exe cise in e -
en ions, wi h an exe cise g oup (o g oups), ha desc ibed exe cise in ensi ies, including
da a o isk a io and CI.
S udies we e equi ed o de ail he exe cise p esc ip ion in pa ien s wi h CVD, in-
cluding he equency, in ensi y and du a ion o each session, mode o exe cise and he
o e all leng h o in e en ion. The main au ho s o s udies and expe s in his ield we e
asked o any missed, un epo ed, o ongoing ials. The quan i a i e syn hesis included
s udies epo ing sample size and he mean and s anda d de ia ions (SDs) o VO
2
peak
p ein e en ion and pos in e en ion.
2.3. Exclusion C i e ia
Abs ac s, con e ence p esen a ions o pos e s, le e s o edi o s o book chap e s,
unpublished pape s, and e ospec i e design s udies we e excluded. In addi ion, s udies
we e excluded i pa icipan s had documen ed hea ailu e (ejec ion ac ion < 40%) o
a hy hmia, hey we e a ge ing a speci ic como bidi y (e.g., diabe es, ch onic obs uc i e
pulmona y disease, o s oke) and hey ea u ed in e en ions in ol ing esis ance exe cises
only. We also excluded s udies based on exe cise p esc ip ions including es ing ood
supplemen s and nu i ional o pha macological aids.
S udies we e also excluded i baseline o pos in e en ion da a we e no published,
and he au ho s we e no a ailable o con ac o did no wish o p o ide he missing da a.
2.4. S udy Selec ion and Da a Ex ac ion
All da a we e ex ac ed by he p incipal in es iga o and hei accu acy was assessed
by he second au ho . The EndNo e so wa e (Cla i a e Analy ics, Philadelphia, PA, USA)
was used o impo , manage and emo e duplica ed a icles o inal e iew. A e emo ing
he duplica es, he wo e iewe s independen ly e iewed i les and abs ac s agains he
inclusion/exclusion c i e ia. I in doub , he ull ex s we e e alua ed o e i y i hey me
he c i e ia. Subsequen ly, abs ac s we e selec ed o eligibili y, and ull manusc ip s we e
e ie ed o u he e alua ion o eligibili y. Disc epancies we e esol ed be ween bo h
au ho s, and a hi d expe , no in ol ed in he p e ious p ocedu es, was consul ed o
e i y he a ings. The selec ion p ocess was en e ed in o a P e e ed Repo ing I ems o
Sys ema ic Re iews and Me a-analysis (PRISMA) diag am [27] (Figu e 1).
In . J. En i on. Res. Public Heal h 2021,18, 3574 4 o 19
In . J. En i on. Res. Public Heal h 2021, 18, x FOR PEER REVIEW 4 o 18
Figu e 1. P e e ed Repo ing I ems o Sys ema ic Re iews and Me a-analysis (PRISMA) diag am
o li e a u e sea ch s a egies.
Fo each RCT, he au ho , yea o publica ion, pa icipan cha ac e is ics (age, gende ,
and p ima y diagnosis), desc ip ion o he exe cise es ing p o ocol and desc ip ion o he
in e en ion (session equency and du a ion, in e en ion leng h, exe cise modali y, e-
sis ance aining, ype o aining (in e al/con inuous), supe ision (clinic/home) and in-
e en ion ype) we e ex ac ed. The p e- and pos -VO2peak alues and change in
VO2peak we e also ex ac ed o assess change in CRF. Ou comes we e ex ac ed in ela i e
(mL-kg−1-min−1) and absolu e (L-min−1) e ms. Ou comes epo ed in METs we e con-
e ed o ela i e e ms (METs × 3.5 mL-kg−1-min−1).
Figu e 1.
P e e ed Repo ing I ems o Sys ema ic Re iews and Me a-analysis (PRISMA) diag am o li e a u e
sea ch s a egies.
Fo each RCT, he au ho , yea o publica ion, pa icipan cha ac e is ics (age, gende ,
and p ima y diagnosis), desc ip ion o he exe cise es ing p o ocol and desc ip ion o
In . J. En i on. Res. Public Heal h 2021,18, 3574 5 o 19
he in e en ion (session equency and du a ion, in e en ion leng h, exe cise modal-
i y, esis ance aining, ype o aining (in e al/con inuous), supe ision (clinic/home)
and in e en ion ype) we e ex ac ed. The p e- and pos -VO
2
peak alues and change
in VO
2
peak we e also ex ac ed o assess change in CRF. Ou comes we e ex ac ed in
ela i e (mL-kg
−1
-min
−1
) and absolu e (L-min
−1
) e ms. Ou comes epo ed in METs we e
con e ed o ela i e e ms (METs ×3.5 mL-kg−1-min−1).
2.5. Assessmen o Po en ial Bias
The isk o bias was assessed using he modi ied Coch ane collabo a ion ool [
25
],
de eloped in 2005 o assess and epo he isk o bias in RCTs. Bias assessmen esul s
om he judgmen (high, low, o unclea ) o indi idual elemen s om se en sou ces o bias
co e ed six domains: andom sequence gene a ion (selec ion bias), alloca ion concealmen
(selec ion bias), blinding o pa icipan s and pe sonnel (pe o mance bias), blinding o
ou come assessmen (de ec ion bias), incomple e ou come da a (a i ion bias), selec i e
epo ing ( epo ing bias) and o he bias (c i e ia o selec ed pa ien s in he s udies and
he coun y in which he s udy was conduc ed). A de ailed desc ip ion o each sou ce
o bias and suppo o judgemen is a ailable elsewhe e [
25
]. The lead e iewe ound
16 s udies, and disc epancies we e discussed and esol ed.
2.6. Da a T ea men and Analysis
The sys ema ic e iew was s a i ied by in ensi ies based on p oposed cu -o s [
28
].
The eby, each exe cise p og am was anked as ligh -, mode a e- o igo ous-in ensi y
ae obic exe cise (Table 1).
Table 1.
Classi ica ion o exe cise in ensi y based on physiological and pe cei ed exe ion esponses.
%VO2max %HRpeak
%HR ese e/
%VO2 ese e Pe cei ed Exe ion *
Ligh 37–45 57–63 30–39 RPE 9–11
Mode a e 46–63 64–76 40–59 RPE 12–13
Vigo ous 64–90 77–95 60–89 RPE 14–17
Nea maximal o
maximal ≥91 ≥95 ≥90 RPE ≥18
Table adap ed om Ame ican College o Spo s Medicine (ACSM) [
28
] and Mi chell e al. [
23
]. * As pe he Bo g
6–20 RPE scale. %VO
2
max, pe cen age o maximal oxygen up ake; %HRpeak, pe cen age o peak hea a e;
%HR ese e, pe cen age o hea a e ese e; %VO
2
ese e, pe cen age o oxygen up ake ese e; RPE, a ing o
pe cei ed exe ion.
S udies epo ing an in ensi y ha co e s he ca ego ies o mode a e in ensi y and
igo ous in ensi y (e.g., 60–70% o VO
2
peak) we e classi ied as “mode a e- o- igo ous”
in ensi y [
28
]. A sepa a e me a-analysis was pe o med o each in ensi y ca ego y and
leng h o he ial—e.g., “sho - e m” (0–6 weeks), “medium- e m” (7–12 weeks), and
“long- e m” (>12 weeks).
The ollowing subg oup analysis was conduc ed o explo e signi ican he e ogenei y:
pa icipan cha ac e is ics, including (1) age, (2) gende and (3) p ima y diagnosis; desc ip-
ion o he exe cise es ing p o ocol and desc ip ion o he in e en ion, including (4) session
equency and (5) du a ion, (6) in e en ion leng h, (7) exe cise modali y, (8) esis ance
aining, (9) ype o aining (in e al/con inuous), (10) supe ision (clinic/home), (11)
in e en ion ype (exe cise only/comp ehensi e); and (12) p e- and pos peak VO
2
alues
o change in VO2peak.
He e ogenei y amongs he included s udies was i s explo ed quali a i ely by com-
pa ing he cha ac e is ics o he included ials and hen by isually inspec ing o es plo s.
I was also assessed quan i a i ely by he Chi
2
and I
2
s a is ics. He e ogenei y was con-
side ed minimal i I
2
ell be ween 0–30%, mode a e i 30–50%, subs an ial i 50–90%, and
conside able i >90% [25]. I2and Chi2we e conside ed signi ican a p< 0.1.

In . J. En i on. Res. Public Heal h 2021,18, 3574 6 o 19
Due o he he e ogenei y o he p o ocol, mean di e ences (MDs) we e used, di iding
he mean alues be ween di e en in ensi ies. The di e ences in means we e g ouped
using he andom-e ec s model. A andom-e ec s model and a s anda dized means model
o a e ages we e used o explain he di e ences in he me hodology o he s udies included
bo h in he in ensi ies and leng h o in e en ion o ensu e a conse a i e es ima e was
calcula ed. A sensi i i y analysis was conduc ed o in es iga e he possible e ec s o
speci ic s udies on he e ogenei y and o e all e ec .
The dicho omous and con inuous a iables o he s udies we e compa ed wi h he
ex ac ed po en ial VO
2
peak mode a o ac o s. The e ec o ea men was calcula ed o
each s udy o he change in VO
2
peak o e he in e en ion using he pooled be ween-
subjec SD a bo h ime poin s. E ec s we e quan i ied as i ial (<0.20), small (0.21–0.60),
mode a e (0.61–1.20), la ge (1.21–2.00) and e y la ge (>2.00) [
29
], wi h he p ecision o
e ec size es ima es assessed using 95% CI. Pooled SMD was back- ans o med using
he pooled be ween-subjec SD a baseline wi hin each in ensi y ca ego y. I SD o he
mean change in VO
2
peak ac oss he in e en ion was no published [
30
], i was used o
p- alue en y. I no p- alues o s anda d de ia ions we e published, he s anda d e o
(SE) o he MD was inpu ed based on he co ela ion be ween p ein e en ion and pos in-
e en ion ou comes [
31
]. The impu ed SE was hen used o calcula e he 95% CI o he
s anda dized e ec o each s udy. Fo ou comes exp essed as change in ela i e VO
2
peak
(mL-kg
−1
-min
−1
), a co ela ion o = 0.54 om a simila me a-analysis [
32
] was used. A
sensi i i y analysis was pe o med using he es ima ed co ela ions o = 0.30 and 0.70.
Publica ion bias was analyzed using a unnel plo de i ed in Re Man5.3 so wa e [
30
].
The publica ion bias o he di e en condi ions analyzed (p e- s. pos in e en ion) was
assessed by examining he asymme y o a unnel plo using Egge ’s es , and p
≤
0.05 was
conside ed o be s a is ically signi ican .
3. Resul s
The ini ial sea ch esul ed in 221 s udies. All da a we e ex ac ed by he p incipal
in es iga o and hei accu acy was assessed by a second au ho . Sea ch esul s we e
en e ed in o EndNo e so wa e (Cla i a e Analy ics, Philadelphia, PA, USA), a e e ence
managemen ool, and duplica es we e emo ed. A e he duplica es we e emo ed, he
i les o 212 s udies we e e iewed. Following a sc eening o po en ial eco ds, 49 a icles we e
e iewed o eligibili y and hei e e ence lis s sc eened. Twen y- wo RCTs me eligibili y
c i e ia o he sys ema ic e iew and me a-analysis. Acco ding o ou inclusion c i e ia,
six een s udies [9–14,20–22,33–39] we e included in his sys ema ic e iew (Figu e 1).
The main cha ac e is ics o he s udies and aining in e en ions a e desc ibed in
Tables 2and 3, espec i ely.
Table 2.
Subg oup analyses assessing po en ial mode a ing ac o s o VO
2
peak inc ease in s udies included in he
me a-analysis by popula ion cha ac e is ics.
Resea ch S udies Peak VO2
G oup N Re e ences MD (95% CI) I2pap-Di e ence b
No. o
pa icipan s
<20 4 Gh oubi e al. [20], Tambu us e al.
[14], Wu e al. [33], Chuang e al. [34]2.62 (1.65, 3.58) 88 <0.001
0.78
≥20 12
Abolah a i-Shi azi e al. [9],
Blumen hal e al. [21], Giallau ia e al.
[10–12,36], Ki zman e al. [22],
K aal e al. [36], Kubo e al. [38],
Leg aman e e al. [37],
Villelabei ia e al. [13],
Zheng e al. [35]
2.75 (2.58, 2.93) 97 <0.001
In . J. En i on. Res. Public Heal h 2021,18, 3574 7 o 19
Table 2. Con .
Resea ch S udies Peak VO2
G oup N Re e ences MD (95% CI) I2pap-Di e ence b
Age, yea s
<60 9
Abolah a i-Shi azi e al. [9],
Gh oubi e al. [20], Giallau ia e al.
[10,12,36], K aal e al. [39], Kubo e al.
[38], Tambu us e al. [14],
Villelabei ia e al. [13]
4.40 (0.79, 8.01) 97 0.02
0.75
≥60 6
Blumen hal e al. [21], Chuang e al.
[34], Giallau ia e al. [11],
Ki zman e al. [22], Leg aman e e al.
[37], Wu e al. [33]
3.48 (2.09, 4.87) 79 <0.001
No
epo ed 1 Zheng e al. [35] 3.10 (2.06, 4.14) 0 <0.001
Diagnosis
CAD only 3 Blumen hal e al. [21], Tambu us e al.
[14], Villelabei ia e al. [13]6.41 (−2.70, 15.53) 99 0.17
0.03
CABG
only 4Chuang e al. [34], Gh oubi e al. [20],
Leg aman e e al. [37], Wu e al. [33]4.27 (1.60, 6.94) 85 0.002
PCI only 1 Abolah a i-Shi azi e al. [9] 8.20 (4.68, 11.72) 0 <0.001
CABG/PCI
1 K aal e al. [39] 3.20 (0.36, 6.04) 0 0.03
MI 6 Giallau ia e al. [10–12,36], Kubo e al.
[38], Zheng e al. [35]2.65 (0.56, 4.74) 91 0.01
FMD 1 Ki zman e al. [22] 1.60 (−0.13, 3.33) 0 0.07
S udy loca ion
Ame ica 2 Ki zman e al. [22],
Tambu us e al. [14]1.38 (0.39, 2.36) 0 0.006
0.01
A ica 1 Gh oubi e al. [20] 1.70 (−1.07, 4.47) 0 0.23
Asia 5
Abolah a i-Shi azi e al. [9], Chuang
e al. [34], Kubo e al. [38], Wu e al.
[33], Zheng e al. [35]
5.33 (2.90, 7.76) 80 <0.001
Eu ope 8
Blumen hal e al. [21], Giallau ia e al.
[10–12,36], K aal e al. [39],
Leg aman e e al. [37],
Villelabei ia e al. [13]
4.23 (1.50, 6.95) 98 0.002
95% CI, 95% con idence in e al. I2, he e ogenei y. MD, mean di e ence. Peak VO2, peak oxygen up ake. Condi ions: MI, myoca dial
in a c ion. CABG, co ona y a e y bypass g a . PCI, pe cu aneous co ona y in e en ion. CAD, co ona y a e y disease. FMD, endo helial-
dependen low-media ed a e ial dila ion. Ce ain en olled s udies we e no included because he alue used o subg oup analysis was
no epo ed in hem. a Tes o o e all e ec . b Tes o subg oup di e ences.
In . J. En i on. Res. Public Heal h 2021,18, 3574 8 o 19
Table 3.
Subg oup analyses assessing po en ial mode a ing ac o s o VO
2
peak inc ease in s udies included in he
me a-analysis by popula ion cha ac e is ics.
Resea ch S udies Peak VO2
G oup N Re e ences MD (95% CI) I2pap-Di e ence b
Leng h, weeks
<6 1 Leg aman e e al. [37] 2.60 (2.41, 2.79) 0
<0.001
0.42
6–12 9
Abolah a i-Shi azi e al. [9],
Chuang e al. [34], Gh oubi e al. [20],
Giallau ia e al. [
10
,
36
], K aal e al. [
39
],
Kubo e al. [38], Villelabei ia e al. [13],
Wu e al. [33]
5.31 (1.24, 9.38) 97 0.01
>12 6
Blumen hal e al. [21], Giallau ia e al.
[11,12], Ki zman e al. [22],
Tambu us e al. [14], Zheng e al. [35]
2.50 (1.60, 3.41) 52
<0.001
F equency, sessions/week
1–2 2 Chuang e al. [34], K aal e al. [39] 3.98 (1.96, 6.01) 0
0.001
0.17
3–4 13
Abolah a i-Shi azi e al. [9],
Blumen hal e al. [21], Gh oubi e al.
[20], Giallau ia e al. [10–12,36],
Ki zman e al. [22], Kubo e al. [38],
Tambu us e al. [14], Villelabei ia e al.
[13], Wu e al. [33], Zheng e al. [35]
4.21 (1.82, 6.60) 96
0.006
5–7 1 Leg aman e e al. [37] 2.60 (2.41, 2.79) 0
<0.001
Supe ision
Clinic 12
Blumen hal e al. [21], Chuang e al.
[
34
], Gh oubi e al. [
20
], Giallau ia e al.
[10–12], Ki zman e al. [22], Kubo e al.
[38], Leg aman e e al. [37], Tambu us
e al. [14], Villelabei ia e al. [13],
Zheng e al. [35]
4.01 (2.30, 5.72) 96
<0.001
0.02
Home 1 Wu e al. [33] 8.50 (5.78, 11.22) 0
<0.001
Mixed 3 Abolah a i-Shi azi e al. [9], Giallau ia
e al. [36], K aal e al. [39]2.99 (−2.89, 8.87) 94 0.32
In e en ion ype
Con inuous 13
Abolah a i-Shi azi e al. [9],
Blumen hal e al. [21], Chuang e al.
[34], Giallau ia e al. [11,12,36],
Ki zman e al. [22], K aal e al. [39],
Kubo e al. [38], Leg aman e e al. [37],
Wu e al. [33], Zheng e al. [35]
3.27 (2.23, 4.32) 87
<0.001
0.44
In e al 2 Tambu us e al. [14],
Villelabei ia e al. [13]8.67 (−5.86, 23.21) 99 0.24
Mixed 1 Gh oubi e al. [20] 1.70 (−1.07, 4.47) 0 0.23
In . J. En i on. Res. Public Heal h 2021,18, 3574 9 o 19
Table 3. Con .
Resea ch S udies Peak VO2
G oup N Re e ences MD (95% CI) I2pap-Di e ence b
Mode
Cycle
e gome e 7
Gh oubi e al. [20], Giallau ia e al.
[10–12], Tambu us e al. [14],
Villelabei ia e al. [
13
], Zheng e al. [
35
]
4.90 [1.52, 8.27) 97
0.005
0.23
T eadmill 1 Chuang e al. [34] 4.80 (1.91, 7.69) 0
0.001
Walking 1 Blumen hal e al. [21] 1.90 (0.20, 3.60) 0 0.03
Mixed
( eadmill,
walking,
cycling,
calis henics
o /and
a m/leg
e gome e )
7
Abolah a i-Shi azi e al. [9], Giallau ia
e al. [36], Ki zman e al. [22],
K aal e al. [39], Kubo e al. [37],
Leg aman e e al. [37], Wu e al. [33]
3.28 (1.17, 5.39) 92
0.002
Exe cise ype
Ae obic 13
Blumen hal e al. [21], Chuang e al.
[
34
], Gh oubi e al. [
20
], Giallau ia e al.
[10,12,36], Ki zman e al. [22],
K aal e al. [39], Kubo e al. [38],
Tambu us e al. [14], Villelabei ia e al.
[13], Wu e al. [33], Zheng e al. [35]
3.94 (1.55, 6.34) 96
0.001
0.86
Ae obic and
Resis ance 3Abolah a i-Shi azi e al. [9], Giallau ia
e al. [11], Leg aman e e al. [37]4.24 (1.82, 6.67) 81
0.001
In ensi y
Mode a e 3 Giallau ia e al. [10], Kubo e al. [38],
Villelabei ia e al. [13]2.90 (1.64, 4.16) 0
<0.001
0.03
Mode a e- o-
igo ous 10
Abolah a i-Shi azi e al. [9], Chuang
e al. [34], Giallau ia e al. [11,12,36],
Ki zman e al. [
22
], K aal e al. [
39
], Wu
e al. [33], Zheng e al. [35]
5.07 (3.43, 6.72) 92
<0.001
Vigo ous 3
Blumen hal e al. [21], Gh oubi e al.
[20], Giallau ia e al. [10],
Leg aman e e al. [37], Tambu us e al.
[14], Villelabei ia e al. [13]
2.43 (1.33, 3.54) 75
<0.001
95% CI, 95% con idence in e al. I
2
, he e ogenei y. MD, mean di e ence. Peak VO2, peak oxygen up ake. Ce ain en olled s udies we e no
included because he alue used o subg oup analysis was no epo ed in hem.
a
Tes o o e all e ec .
b
Tes o subg oup di e ences.
3.1. Risk o Bias
Six een s udies we e sco ed by wo e iewe s, and an absolu e ag eemen ( = 0.94)
was ob ained om he in aclass co ela ion coe icien (ICC). Bias was assessed as a
judgmen (high, low, o unclea ) o indi idual elemen s om se en sou ces o bias and he
ollowing ICCs o absolu e ag eemen be ween he wo e iewe s we e ob ained: andom
sequence gene a ion o selec ion bias ( = 0.90), alloca ion concealmen o selec ion bias
( = 0.92), blinding o pa icipan s and pe sonnel o pe o mance bias ( = 0.98), blinding o
ou come assessmen o de ec ion bias ( = 0.94), incomple e ou come da a o a i ion bias
( = 0.79), selec i e epo ing o epo ing bias ( = 0.98) and inclusion c i e ia o pa ien s
in he s udies and he coun y in which he s udy was conduc ed o o he bias ( = 0.88).
The isk o bias in he 16 included ials is summa ized in Figu e 2.
In . J. En i on. Res. Public Heal h 2021,18, 3574 16 o 19
Fu u e s udies would bene i om being be ween 6 and 12 weeks in leng h wi h
an in e en ion ac i i y ca ied ou a leas h ee imes weekly, ensu ing ha he co ec
in ensi y is main ained. Fo example, app op ia e goals o igo ous-in ensi y exe cise
include
≥
85% VO
2
peak o
≥
85% HRR o
≥
90% HRM and, o mode a e in ensi y, 50–75%
VO
2
peak o 50–75% HRR o 50–80% HRM. In addi ion, la ge anges o exe cise in ensi ies
should no be p esc ibed based on HR esponses o exe cise. This would allow a mo e
accu a e calcula ion o he exac e ec s o in ensi ies on CRF and o de e mine he ideal
and mos e ec i e “dose” o people wi h hea p oblems. Fu u e esea ch should include
me hods o app op ia ely desc ibe he compliance o pa icipan s wi h he p esc ibed
exe cise in ensi y and a endance o exe cise sessions.
S udies should epo s anda d de ia ions, conceal alloca ion, and blind assesso s o
imp o e s udy quali y. Mo eo e , u u e s udies should aim o ec ui mo e women and
olde pa icipan s (<76 yea s) o ensu e igo ous-in ensi y in e en ions a e mo e e ec i e
han mode a e-in ensi y ones in imp o ing CRF o a b oade ange o pa ien s wi h
CVD. Finally, u he s udies ha in es iga e he longe - e m bene i s o igo ous-in ensi y
in e en ions and whe he hese adap a ions a e main ained would also be bene icial.
5. Conclusions
The mos e ec i e doses o exe cise in ensi y o op imize CRF we e mode a e- o-
igo ous and igo ous exe cise. In e en ions o enhance CRF in pa ien s wi h CVD a e
mos e ec i e i conduc ed o 6 o 12 weeks. Mo e esea ch is needed o unde s and wi hin
he mode a e- o- igo ous-in ensi y ca ego y which pe cen age esul s in inc eased CRF,
assis ing in he design o speci ic p esc ip ion p o ocols.
This e iew may sugges ha coun ies wi hou guidelines o pa ien s wi h CVD
ega ding he in ensi y o exe cise p og ams, as well as coun ies wi h guidelines ha
ecommend lowe in ensi y exe cise, should include mode a e- o- igo ous in ensi y and
igo ous in ensi y.
Wha is al eady known:

Ca dio ascula diseases a e he leading causes o mo ali y in oday’s socie y. They
a e esponsible o up o 30% o all dea hs wo ldwide and 48% o dea hs in Eu ope,
and i is expec ed ha hese igu es will inc ease in he coming yea s.

Exe cise p og ams in pa ien s wi h ca dio ascula disease ha e se e al bene icial
e ec s on ca dio ascula unc ional capaci y, quali y o li e, isk ac o s modi ica ion,
psychological p o ile, hospi al eadmissions, and mo ali y.

Exe cise-based in e en ions seem o signi ican ly imp o e ca dio espi a o y i ness
in pa ien s ollowing a ca diac e en o su ge y, bu li le is known ega ding he
di e en ial e ec s o p esc ibed exe cise in ensi y.
Wha a e he new indings?

Exe cise in e en ions o pa ien s wi h ca dio ascula disease end include la ge
anges o exe cise in ensi ies based on hea a e esponses o exe cise.

The mos e ec i e doses o exe cise in ensi y o op imize ca dio espi a o y i ness
we e mode a e- o- igo ous and igo ous-in ensi y exe cises, being mo e e ec i e
when conduc ed o 6 o 12 weeks.

Mo e esea ch is needed o unde s and wi hin he mode a e- o- igo ous- and igo ous-
in ensi y ca ego ies he pe cen age ha speci ically helps o inc ease ca dio espi a o y
i ness and he abili y o es ablish speci ic p esc ip ion p o ocols.
Supplemen a y Ma e ials:
The ollowing a e a ailable online a h ps://www.mdpi.com/a icle/10
.3390/ije ph18073574/s1, Table S1: Comple e sea ch s a egy o MEDLINE, sea ched om incep ion
un il Janua y 2021; Figu e S2: Summa y o s udy cha ac e is ics; Figu e S3: Ou come o he isk o
bias assessmen ; Figu e S4: Lis o e e ences o included s udies.
Au ho Con ibu ions:
Concep ualiza ion, C.G., J.B., A.A. and A.R.; me hodology, C.G. and J.B.;
so wa e, C.G.; alida ion, C.G. and J.B.; o mal analysis, C.G. and J.B.; in es iga ion, C.G. and

In . J. En i on. Res. Public Heal h 2021,18, 3574 17 o 19
J.B.; esou ces, C.G. and J.B.; da a cu a ion, C.G. and J.B.; w i ing—o iginal d a p epa a ion, C.G.;
w i ing— e iew and edi ing, C.G., J.B., A.A. and A.R.; isualiza ion, C.G., J.B., A.A. and A.R.;
supe ision, C.G., J.B. and A.R.; p ojec adminis a ion, C.G., J.B. and A.R.; unding acquisi ion, C.G.,
A.A. and A.R. All au ho s ha e ead and ag eed o he published e sion o he manusc ip .
Funding:
This esea ch was unded by Fundação pa a a Ciência e Tecnologia (Po ugal), g an
numbe SFRH/BD/138326/2018.
Ins i u ional Re iew Boa d S a emen : No applicable.
In o med Consen S a emen : No applicable.
Da a A ailabili y S a emen :
The da a ha suppo he indings o his s udy a e a ailable om he
co esponding au ho , C.G., upon easonable eques .
Acknowledgmen s:
This wo k was suppo ed by he Fundação pa a a Ciência e a Tecnologia
(Po ugal). We hank all au ho s o he o iginal wo ks ci ed in he p esen s udy, who eadily assis ed
us by sha ing hei manusc ip s o his sys ema ic e iew wi h me a-analysis.
Con lic s o In e es :
The au ho s decla e no con lic o in e es . The unde s had no ole in he design
o he s udy; in he collec ion, analyses, o in e p e a ion o da a; in he w i ing o he manusc ip , o
in he decision o publish he esul s.
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