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Review CARDIOLOGY ®
Abstract
Background: The increase in maximal oxygen consumption (VO2max) with endurance training is associated with that of
maximal cardiac output (Qmax), but not oxygen extraction, in young individuals. Whether such a relationship is altered
with ageing remains unclear. Therefore, we sought systematically to review and determine the effect of endurance
training on and the associations among VO2max, Qmax and arteriovenous oxygen difference at maximal exercise
(Ca-vO2max) in healthy aged individuals.
Design and methods: We conducted a systematic search of MEDLINE, Scopus and Web of Science, from their
inceptions until May 2015 for articles assessing the effect of endurance training lasting 3 weeks or longer on VO2max
and Qmax and/or Ca-vO2max in healthy middle-aged and/or older individuals (mean age 40 years). Meta-analyses were
performed to determine the standardised mean difference (SMD) in VO2max, Qmax and Ca-vO2max between post and
pre-training measurements. Subgroup and meta-regression analyses were used to evaluate the associations among SMDs
and potential moderating factors.
Results: Sixteen studies were included after systematic review, comprising a total of 153 primarily untrained healthy
middle-aged and older subjects (mean age 42–71 years). Endurance training programmes ranged from 8 to 52 weeks of
duration. After data pooling, VO2max (SMD 0.89; P < 0.0001) and Qmax (SMD 0.61; P < 0.0001) were increased after
endurance training; no heterogeneity among studies was detected. Ca-vO2max was only increased with endurance
training interventions lasting more than 12 weeks (SMD 0.62; P ¼ 0.001). In meta-regression, the SMD in Qmax was
positively associated with the SMD in VO2max (B ¼ 0.79, P ¼ 0.04). The SMD in Ca-vO2max was not associated with the
SMD in VO2max (B ¼ 0.09, P ¼ 0.84).
Conclusions: The improvement in VO2max following endurance training is a linear function of Qmax, but not Ca-vO2max,
through healthy ageing.
Keywords
Exercise training, maximal oxygen consumption, ageing, meta-analysis
Received 3 August 2015; accepted 21 October 2015
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2 European Journal of Preventive Cardiology 0(00)
must result in higher maximal cardiac output (Qmax) and/ ‘arteriovenous’ and ‘extraction’; the search strategy for
or arteriovenous oxygen difference at maximal exercise MEDLINE is shown in Supplementary Figure 1. We
(Ca-vO2max) –following the Fick principle, respectively, also performed hand searching in identified reviews, art-
and primarily reflecting convective oxygen delivery and icles included in meta-analysis, related citations in
extraction. However, whether the increase in VO2max MEDLINE and Google.
with ET is associated with that of Qmax and/or Ca-
vO2max remains to be established, despite related research
spanning over the past five decades.30–33
Article selection
To begin addressing this uncertainty, we adopted a To be included in the analysis, an original research art-
meta-analysis approach to determine the effects of ET icle had to assess VO2max along with Qmax and/or Ca-
on and associations between the components of VO2max vO2max with dynamic exercise involving a large muscle
in young adults (mean age <40 years), in order to limit mass (e.g. running, cycling), before and after an ET
the influence of ageing. We found that Qmax, but not intervention lasting 3 weeks or more in healthy
Ca-vO2max, was increased and linearly correlated with middle-aged and/or older subjects (mean age 40
the increase in VO2max following ET,34 suggesting that years). We excluded ET interventions of less than 3
oxygen extraction is not affected by ET in young indi- weeks’ duration because Qmax may not be significantly
viduals. In this sense, oxygen extraction may present increased by this very short ET period.9,24 Studies
near optimal levels in untrained youth, as it is sup- following the above criteria but including additional
ported by the approximate Ca-vO2max observed in interventions deemed likely to influence VO2max, Qmax
young athletes and sedentary individuals.35,36 Thus, or Ca-vO2max were excluded. In addition, VO2max
improvements in oxygen extraction may not occur as (and Qmax if applicable) absolute values (volume/time)
a result of a ‘ceiling effect’. With ageing, in turn, there had to be available or if normalised by anthropometri-
may be potential for improvement, in view of the higher cal variables (e.g. weight, body surface area) these latter
Ca-vO2max in master athletes versus healthy age- had to be not significantly altered by the training inter-
matched untrained individual.35,37,38 Accordingly, it vention. In the event of multiple publications pertaining
has been proposed that the increase in VO2max with to the same research, the first published or more com-
ET in aged individuals may be a function of the prehensive report was included. The inclusion of art-
improvement in Ca-vO2max.1,7 Such contention is, how- icles in our analysis was not limited by publication
ever, unclear based on individual studies in that a vari- status or language. Article selection was performed
able response to ET is apparently observed in VO2max independently and in duplicate by two investigators
components in healthy middle-aged and older individ- (DM and CD).
uals.2–6,8–14 Presumably, the small sample size as well as
distinct training characteristics, study population and
methodology of individual studies may have com-
Data extraction and quality assessment
pounded the impact of ET on Qmax and Ca-vO2max. The following variables were summarised in a pre-for-
Therefore, the purpose of this study was systematic- matted spreadsheet: authors, year of publication, char-
ally to review and meta-analyse the effects of ET on acteristics of study participants (n, age, gender, height,
VO2max, Qmax and Ca-vO2max in healthy middle-aged weight, body surface area, body mass index, haemoglo-
and older subjects, as well as to determine the associ- bin concentration, haematocrit, fitness status, health
ations among VO2max, Qmax and Ca-vO2max and poten- status), cardiovascular/respiratory variables (heart
tial moderating factors. rate, blood pressure, total peripheral resistance, stroke
volume, Qmax, Ca-vO2max, VO2max), characteristics of
the assessment of VO2max, Qmax and Ca-vO2max (tech-
Methods
nique, test protocol) and ET features (type, modality,
The review is reported according to the meta-analysis frequency, intensity, session length, duration). The Fick
of observational studies in epidemiology group equation was used to calculate Ca-vO2max in studies
guidelines.39 reporting only VO2max and Qmax values.4,8 Missing
standard deviations (SD) of Ca-vO2max in the latter
studies were imputed from linear regression analysis
Data sources and searches of log (SD of Ca-vO2max) on log (mean Ca-vO2max)
Our systematic search included MEDLINE, Scopus and from studies that reported complete data,1–3,5–7,9–14,25
Web of Science, from their inceptions until May 2015. as previously described.40
We used combinations of the subject headings ‘healthy’, A systematic appraisal of quality for observational
‘middle’, ‘older’, ‘elderly’, ‘training’, ‘VO2max’, ‘max- research (SAQOR)41 previously applied in meta-analysis
imal’, ‘peak’, ‘oxygen’, ‘aerobic’, ‘cardiac output’, of observational studies evaluating cardiovascular
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Montero and Dı́az-Cañestro 3
function42,43 was performed to provide an assessment of New Jersey, USA). The primary outcomes were the stan-
study quality. The SAQOR was adjusted to assess: (a) dardised mean difference (SMD) in VO2max, Qmax and
the study sample; (b) quality of VO2max assessment; (c) Ca-vO2max between post and pre-ET measurements.
quality of Qmax assessment; (d) quality of Ca-vO2max The SMD summary statistic allowed us to standardise
assessment; (e) confounding variables and (f) data. values obtained using different methods into a uniform
Overall, the SAQOR was scored out of 16, quality scale to complete the meta-analysis.44 Each SMD was
deemed better with a greater score. Data extraction weighted by the inverse variance and they were pooled
and quality assessment were performed independently with a random effects model.44,45 Heterogeneity among
and in duplicate by two investigators (DM and CD). studies was assessed using the chi-squared test for hetero-
geneity and I2 statistics. Potential moderating factors
influencing the SMD in VO2max, SMD in Qmax and
Data synthesis and analysis SMD in Ca-vO2max (gender, weight, training characteris-
The meta-analysis and related analyses were performed tics, methodological quality) were evaluated by subgroup
using Review Manager software (RevMan 5.3; Cochrane analysis comparing studies grouped by dichotomous or
Collaboration, Oxford, UK) and Comprehensive continuous variables. Median values of continuous vari-
Meta-analysis software (version 2; Biostat, Englewood, ables were used as cut-off values for grouping studies.
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4 European Journal of Preventive Cardiology 0(00)
Wang et al., 201414 13 0 64 3 76 6 Moderately T 48 4 Cycle ergometer single-breath C2H2 fick equation
Fujimoto et al., 20103 9 33 71 3 76 9 UT 23 3 Treadmill C2H2 rebreathing fick equation
Murias et al. (1), 201010 6 100 69 7 72 6 UT 24 2 Cycle ergometer open-circuit C2H2 fick equation
Murias et al. (2), 20109 8 0 68 7 82 8 UT 28 7 Cycle ergometer open-circuit C2H2 fick equation
Morris et al. (A), 20028 10 0 63 3 81 7 N/A 27 4 Cycle ergometer C2H2 rebreathing fick equation
Morris et al. (B), 20028 10 0 65 3 83 10 N/A 28 3 Cycle ergometer C2H2 rebreathing fick equation
Marshall et al., 20016 9 11 58 7 80 7 N/A 33 5 Treadmill C2H2 rebreathing fick equation
McGuire et al., 20017 5 0 50–51 100 37 T/UT 36 treadmill C2H2 rebreathing fick equation
Beere et al., 19991 10 0 66 4 85 N/A 18 7 Cycle ergometer thermodilution catheterization
Hijazi et al., 19985 8 63 52 7 N/A N/A N/A Cycle ergometer N/A catheterization
Spina et al., 199813 10 0 65 3 84 12 UT 29 4 Treadmill/cycle C2H2 rebreathing fick equation
ergometer
Spina et al. (1A), 199311 15 0 63 12 83 12 N/A 28 Treadmill C2H2 rebreathing fick equation
Spina et al. (1B), 199311 16 100 64 12 65 12 N/A 21 Treadmill C2H2 rebreathing fick equation
Spina et al. (2), 19931,2 7 100 63 13 67 9 UT 18 4 Cycle ergometer radioactive fick equation
indicator-dilution
Ehsani et al., 19912 9 0 64 3 80 6 UT 30 4 Cycle ergometer radioactive fick equation
indicator-dilution
Haennel et al., 19894 8 0 42 12 83 24 N/A 33 8 Cycle ergometer radioactive fick equation
indicator-dilution
Data are n, % of women, mean SD, mean or range. Two articles presented separate study groups that were distinguished by A and B.8,11 Ca-vO2diff:
arteriovenous oxygen difference at maximal exercise; C2H2: acetylene; N/A: data not available; Qmax: maximal cardiac output; T: trained; UT: untrained;
VO2max: maximal oxygen consumption.
Meta-regression analyses were performed to evaluate the subjects,7,14 six studies only involved untrained sub-
associations among the SMD in VO2max, SMD in Qmax, jects,2,3,9,10,12,13 while eight studies did not report on
SMD in Ca-vO2max and potential moderating factors. In fitness status but presented poor to very poor mean
all meta-regression models, studies were weighted by the group VO2max baseline values1,4–6,8,11 conforming to
inverse variance of the dependent variable. Potential established guidelines.47 ET programmes consisted
moderating factors were entered as independent variables of endurance continuous training (ECT) and/or
in regression models with the SMD in VO2max, SMD in endurance interval training (EIT), respectively, of vari-
Qmax or SMD in Ca-vO2max as the dependent variable. able intensity performed through walking, running,
Publication and/or other biases were evaluated by the cycling and/or rowing exercise, ranging from 1.4 to
Begg and Mazumdar’s rank correlation test and 4.0 hours per week and from 8 to 52 weeks’ duration
Egger’s regression test.46 A P value less than 0.05 was (Table 2).
considered statistically significant. The mean quality of the studies was moderate
to high. The average score was 10.1 1.7 out of a pos-
sible 16 points (Supplementary Table 1). As for the
Results evaluation of potential biases, the funnel plot
(Supplementary Figure 2), Begg and Mazumdar’s
Study selection and characteristics rank correlation test and the Egger’s regression test
The flow diagram of the process of article selection is did not suggest the presence of publication bias and/
shown in Figure 1, which resulted in the inclusion of 14 or other biases for the SMD in VO2max in the studies
articles. Two of the articles presented separate study included in the meta-analysis (P ¼ 0.19, P ¼ 0.40,
groups,8,11 each of which was evaluated as an individ- respectively). Likewise, there was no evidence of publi-
ual study. Table 1 illustrates the main characteristics of cation and/or other biases with regard to the SMD in
the resulting 16 studies, comprising a total of 153 Qmax (Supplementary Figure 3) and the SMD in Ca-
healthy middle-aged and older subjects (mean age ran- vO2max (Supplementary Figure 4) in the studies
ging from 42 to 71 years). Two studies included trained included in the meta-analysis.
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Montero and Dı́az-Cañestro 5
Wang et al., 201414 Cycling, EIT 4 min 90–95% HRmax, 5.0 1.40 8.0 56.0
3 min 70% HRmax
Fujimoto et al., 20103 Walking/running, 75–90% HRmax 3.0 2.38 52.1 372.3
ECT/EIT
Murias et al. (1), 201010 Cycling, ECT/EIT 70% VO2max (10 wk); 4.0 2.06 12.0 98.9
1 min 90–100% Wattmax,
1 min rest (2 wk)
Murias et al. (2), 20109 Cycling, ECT/EIT 70% VO2max (10 wk); 4.0 2.06 12.0 98.9
1 min 90–100% Wattmax,
1 min rest (2 wk)
Morris et al. (A), 20028 Cycling, ECT 87% HRmax 3.5 1.45 10.0 50.8
Morris et al. (B), 20028 Cycling, ECT 66% HRmax 1.0 1.45 10.0 14.5
Marshall et al., 20016 Cycling, ECT 75–80% VO2max 3.5 1.67 8.0 46.7
McGuire et al., 20017 Walking/running/cycling, 75% HRmax 3.0 2.86 19.6 168.2
ECT
Beere et al., 19991 (Arm–leg) cycling, ECT 75–90% HRmax 3.5 1.50 12.9 67.5
Hijazi et al., 19985 Cycling, ECT 65% VO2max 3.0 2.50 8.0 60.0
Spina et al., 199813 Walking/running/ 85% HRmaxb 3.5 4.00 36.0 504.0
cycling/rowing,
ECT/EIT
Spina et al. (1A), 199311 Walking/running/ 81% HRmax 3.0 2.93 45.0 396.0
cycling/rowing,
ECT/EIT
Spina et al. (1B), 199311 Walking/running/ 77% HRmax 3.0 2.91 45.0 393.5
cycling/rowing,
ECT/EIT
Spina et al. (2), 199312 Walking/running/ 81% HRmax 3.0 3.85 45.0 519.8
cycling/rowing,
ECT/EIT
Ehsani et al., 19912 Walking/running/ 60–80% VO2max, 93% 3.5 4.00 50.6 708.0
cycling, ECT/EIT VO2max (short bouts)
Haennel et al., 19894 Cycling, ECT 80% HRR 3.5 1.35 9.0 42.5
Weighted mean – – 3.3 2.39 25.5 236.3
Data are mean or range. Two articles presented separate study groups that were distinguished by A and B.8,11
a
Calculated by multiplying intensity status, hours/week and duration (weeks) of training. bDuring last 3 months of the exercise intervention. AU:
arbitrary units; ECT: endurance continuous training; EIT: endurance interval training; HRmax: maximal heart rate; HRR: heart rate reserve; VO2max:
maximal oxygen consumption; Wattmax: maximal power output; wk: week.
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6 European Journal of Preventive Cardiology 0(00)
Post training Pre training Std. Mean difference Std. Mean difference
Study or subgroup Mean SD Total Mean SD Total Weight IV, random, 95% CI IV, random, 95% CI
1.1.1 Effect of endurance training on maximal oxygen consumption
Wang et al, 2014 3.9 0.24 13 3.69 0.3 13 8.9% 0.75 [–0.05, 1.55]
Fujimoto et al, 2010 1.97 0.31 9 1.73 0.3 9 6.1% 0.75 [–0.22, 1.71]
Murias et al 1, 2010 2.01 0.29 6 1.73 0.25 6 3.8% 0.95 [–0.27, 2.18]
Murias et al 2, 2010 2.95 0.48 8 2.29 0.49 8 4.7% 1.29 [0.18, 2.39]
Morris et al A, 2002 2.48 0.25 10 2.21 0.32 10 6.6% 0.90 [–0.03, 1.83]
Morris et al B, 2002 2.57 0.22 10 2.3 0.22 10 6.1% 1.18 [0.21, 2.14]
Marshall et al, 2001 2.85 0.54 9 2.64 0.51 9 6.5% 0.38 [–0.55, 1.32]
McGuire et al, 2001 3.26 0.64 5 2.96 0.65 5 3.6% 0.42 [–0.84,1.68]
Beere et al, 1999 1.84 0.53 10 1.57 0.54 10 7.2% 0.48 [–0.41, 1.38]
Hijazi et al, 1998 1.23 0.25 8 1 0.25 8 5.3% 0.87 [–0.17, 1.91]
Spina et al, 1998 2.87 0.35 10 2.39 0.35 10 5.9% 1.31 [0.33, 2.30]
Spina et al 1 A, 1993 2.8 0.39 15 2.35 0.39 15 9.4% 1.12 [0.34, 1.90]
Spina et al 1 B, 1993 1.66 0.4 16 1.36 0.4 16 11.1% 0.73 [0.01, 1.45]
Spina et al 2, 1993 1.27 0.16 7 1.08 0.16 7 4.3% 1.11 [–0.04, 2.27]
Ehsani et al, 1991 2.05 0.26 9 1.85 0.2 9 6.0% 0.82 [–0.15, 1.79]
Haennel et al, 1989 3.22 0.28 8 2.82 0.25 8 4.5% 1.42 [0.29, 2.56]
Subtotal (95% CI) 153 153 100.0% 0.89 [0.65, 1.12]
Heterogeneity: Tau2 = 0.00; Chi2 = 5.77, df = 15 (P = 0.98); I2 = 0%
Test for overall effect: Z = 7.26 (P < 0.00001)
–4 –2 0 2 4
Decrease Increase
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Montero and Dı́az-Cañestro 7
Table 3. Subgroup analyses of the effect of endurance training on VO2max, Qmax and a-vO2diff at maximal exercise.
VO2max Qmax Ca-vO2max
Gender
Women (n ¼ 3) 0.86 (0.31, 1.41) 0.002 0 0.75 0.31 (–0.21, 0.83) 0.24 0 0.16 0.92 (0.34, 1.50) 0.002 7 0.07
Men (n ¼ 10) 0.96 (0.66, 1.26) <0.001 0 0.74 (0.44, 1.04) <0.001 0 0.31 (0.01, 0.60) 0.04 2
Training characteristics
Type
Cycling (n ¼ 9) 0.87 (0.54, 1.19) <0.001 0 0.86 0.75 (0.41, 1.09) <0.001 0 0.23 0.22 (0.11, 0.56) 0.18 10 0.20
Including 0.91 (0.56, 1.26) <0.001 0 0.46 (0.11, 0.80) 0.009 0 0.58 (0.15, 1.01) 0.008 30
weight-bearing
(n ¼ 7)
Modality
ECT (n ¼ 7) 0.79 (0.41, 1.17) <0.001 0 0.54 0.62 (0.21, 1.02) 0.003 0 0.96 0.32 (0.06, 0.69) 0.10 2 0.71
Including EIT (n ¼ 9) 0.95 (0.64, 1.25) <0.001 0 0.60 (0.30, 0.91) <0.001 0 0.42 (0.02, 0.83) 0.04 42
Intensity status
>3.5 (n ¼ 3) 0.94 (0.37, 1.51) 0.001 0 0.84 0.88 (0.31, 1.45) 0.002 0 0.30 0.12 (0.52, 0.77) 0.71 26 0.37
3.5 (n ¼ 13) 0.87 (0.61, 1.14) <0.001 0 0.55 (0.28, 0.81) <0.001 0 0.45 (0.14, 0.75) 0.004 25
Duration
>12.4 weeks (n ¼ 8) 0.85 (0.53, 1.18) <0.001 0 0.77 0.42 (0.10, 0.74) 0.01 0 0.08 0.62 (0.25, 1.00) 0.001 20 0.06
12.4 weeks (n ¼ 8) 0.92 (0.57, 1.28) <0.001 0 0.85 (0.49, 1.22) <0.001 0 0.14 (0.20, 0.47) 0.42 0
Load
>98.9 AU (n ¼ 7) 0.91 (0.56, 1.26) <0.001 0 0.86 0.46 (0.11, 0.80) 0.009 0 0.23 0.58 (0.15, 1.01) 0.008 30 0.20
98.9 AU (n ¼ 9) 0.87 (0.54, 1.19) <0.001 0 0.75 (0.41, 1.09) <0.001 0 0.22 (0.11, 0.56) 0.18 10
Maximal exercise test
Cycle ergometer 0.97 (0.67, 1.27) <0.001 0 0.37 0.78 (0.47, 1.10) <0.001 0 0.08 0.26 (0.02, 0.55) 0.07 0 0.43
(n ¼ 10)
Treadmill (n ¼ 5) 0.74 (0.35, 1.14) <0.001 0 0.35 (–0.01, 0.71) 0.05 0 0.56 (0.11, 1.24) 0.10 63
Methodological quality
>10 points (n ¼ 7) 0.96 (0.63, 1.29) <0.001 0 0.52 0.63 (0.30, 0.96) <0.001 0 0.84 0.41 (0.09, 0.91) 0.10 55 0.80
10 points (n ¼ 9) 0.80 (0.46, 1.15) <0.001 0 0.58 (0.22, 0.93) 0.001 0 0.34 (0.01, 0.67) <0.05 0
Median values of continuous variables were used as cut-off values for grouping studies. AU: arbitrary units; Ca-vO2max: arteriovenous oxygen difference
at maximal exercise; CI: confidence interval; ECT: endurance continuous training; EIT: endurance interval training; I2: index of heterogeneity; n: number
of studies; Qmax: maximal cardiac output; SMD: standardised mean difference between post and pre-endurance training measurements; VO2max:
maximal oxygen consumption.
P < 0.0001), whereas maximum heart rate (HRmax) was between studies (I2 ¼ 26 %, P ¼ 0.17). In subgroup ana-
not altered (mean difference 0.52 beats/min, 95% CI – lyses, Ca-vO2max was not increased following ET in
2.17, 3.21, I2 ¼ 17%; P ¼ 0.71) after ET. In subgroup ana- studies (a) consisting of only cycling exercise training
lyses (Table 3), Qmax was not enhanced after ET in studies (n ¼ 9) (SMD 0.22, 95% CI –0.11, 0.56; P ¼ 0.18) or
only comprising women (n ¼ 3) (SMD 0.31, 95% CI – ECT (n ¼ 7) (SMD 0.32, 95% CI –0.06, 0.69;
0.21, 0.83; P ¼ 0.24). Moreover, the increase in Qmax P ¼ 0.10), (b) with an intensity status above the
after ET in studies that assessed maximal exercise on a median value (n ¼ 3) (SMD 0.12, 95% CI –0.52, 0.77;
treadmill (n ¼ 5) did not reach statistical significance P ¼ 0.71), (c) with a duration or load of training below
(SMD 0.35, 95% CI –0.01, 0.71; P ¼ 0.05). the median value (n ¼ 8 and n ¼ 9, respectively) (SMD –
0.14, 95% CI –0.20, 0.47; P ¼ 0.42; SMD 0.22, 95% CI
–0.11, 0.56; P ¼ 0.18, respectively) and (d) with a meth-
Effect of ET on Ca-vO2max odological quality score above the median value (n ¼ 7)
The Fick equation was used to calculate Ca-vO2max in (SMD 0.41, 95% CI –0.09, 0.91; P ¼ 0.10).
the majority of the studies (Table 1). Two studies dir-
ectly determined Ca-vO2max by means of invasive tech-
Meta-regression analyses
niques.1,5 After data pooling, Ca-vO2max was increased
after ET (SMD 0.38, 95% CI 0.11, 0.66; P ¼ 0.006) A positive association was found between the SMD in
(Figure 2). There was no significant heterogeneity Qmax and the SMD in VO2max (B ¼ 0.79, 95% CI 0.02,
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8 European Journal of Preventive Cardiology 0(00)
(a) 2.00
1.80
1.60
1.40
SMD in Qmax 1.20
1.00
0.80
0.60
0.40
0.20
0.00
0.28 0.40 0.53 0.65 0.78 0.90 1.02 1.15 1.27 1.40 1.52
(b) 2.00
1.74
1.48
SMD in Ca-vO2max
1.22
0.96
0.70
0.44
0.18
–0.08
–0.34
–0.60
0.28 0.40 0.53 0.65 0.78 0.90 1.02 1.15 1.27 1.40 1.52
SMD in VO2max
Figure 3. Meta-regression plots of the SMD in VO2max according to the SMD in Qmax (B ¼ 0.79, 95% CI 0.02, 1.56; P ¼ 0.04) (a) and
the SMD in Ca-vO2max (B ¼ 0.09, 95% CI –0.84, 1.03; P ¼ 0.84) (b). The size of each circle is proportional to the study’s weight.
Ca-vO2max: arteriovenous oxygen difference at maximal exercise; Qmax: maximal cardiac output; SMD: standardised mean difference
between post and pre-endurance training measurements; VO2max: maximal oxygen consumption.
1.56; P ¼ 0.04) (Figure 3(a)). Likewise, the SMD in Over the inconsistent findings reported by previous
SVmax, but not the mean difference in HRmax, was posi- studies,1–14 this meta-analysis demonstrates increases in
tively associated with the SMD in Qmax (B ¼ 0.67, 95% the VO2max components after ET in aged subjects, with
CI 0.16, 1.19; P ¼ 0.01) and the SMD in VO2max null or low heterogeneity among studies. This indicates
(B ¼ 0.81, 95% CI 0.03, 1.58; P ¼ 0.04). the presence of statistical limitations (e.g. type II errors)
In contrast, the SMD in Ca-vO2max was not asso- in prior research, which are common to scientific fields
ciated with the SMD in VO2max (B ¼ 0.09, 95% CI – based on small sample size studies48 – and furthermore,
0.84, 1.03; P ¼ 0.84) (Figure 3(b)). None of the assessed corroborates the adequacy of our meta-analytic
potential moderating factors were significantly asso- approach. In addition, we found that (a) a linear func-
ciated with the SMD in VO2max, the SMD in Qmax or tion related the ET-induced increases in VO2max and
the SMD in Ca-vO2max. Qmax but not Ca-vO2max, and (b) the increase in Qmax
entirely resulted from that of SVmax because HRmax was
not altered with ET, all concurring with pooled evi-
Discussion dence in young individuals.34 Potential mechanisms
In this systematic review and meta-analysis, we pooled underlying the increase in SVmax induced by ET in
and analysed data from 16 studies assessing the effects aged individuals comprise adaptations in left ventricu-
of ET interventions lasting 8 to 52 weeks on VO2max lar structure/function,17 blood volume19 as well as
and Qmax and/or Ca-vO2max in a total of 153 healthy decreased peripheral vascular resistance,28 plausibly
middle-aged and older subjects. The main finding of due to enhanced muscle capillarisation,22 vascular
this meta-analysis is that despite both Qmax and Ca- endothelial and/or smooth muscle dilator function.49,50
vO2max being increased with ET, only Qmax is linearly Taken together, the above findings suggest that the
associated with the increase in VO2max. effect of ET on VO2max is proportional to the increase
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Montero and Dı́az-Cañestro 9
in SVmax throughout adulthood and healthy ageing, intensity status below the median value. In this line, it
regardless of the pre-training level of oxygen extraction, has been demonstrated that isoenergetic ET of lower
which is reduced in aged individuals.35,37,38 Of note, versus higher intensity is more effective in enhancing
such a relationship might differ according to skeletal muscle capillary density, vascular conductance
gender,10–12 albeit this remains uncertain on the basis and thereby Ca-vO2max.56 In turn, Ca-vO2max was posi-
of scarce data in women (three studies, n ¼ 29) in the tively influenced by the load of ET (calculated by multi-
present meta-analysis. plying intensity status and total hours of training). As
The observation that oxygen extraction is increased Ca-vO2max was not positively associated with intensity
with ET contrasts with our previous meta-analysis in status, it is implied that the increase in oxygen extrac-
young individuals.34 Both meta-analyses, however, tion in studies with a higher load of training was pri-
coincide in that Ca-vO2max is only improved with marily driven by their prolonged duration, as discussed
longer (>12 weeks) ET interventions.34 Importantly, above. Furthermore, it should be noted that Ca-vO2max
the average duration of ET in studies in aged subjects was only significantly increased in studies with moder-
was seemingly higher compared with studies in young ate to low methodological quality, which is also
subjects (25.5 vs. 8.6 weeks), thus, this may explain, at observed in young individuals.34 Ultimately, consider-
least in part, the aforementioned discrepancy. ing the nature and relatively small number of studies
Moreover, the fact that Ca-vO2max is improved with comprising the subgroup analyses here applied, these
ET after, but not prior to, a given period of time in should be considered exploratory and not as proof of
young and aged individuals is intrinsically noteworthy. causality.57
This highlights the existence of prevalent temporal
boundaries for the effect of ET on the determinants
Limitations
of oxygen extraction in healthy individuals, which
may explain, to some degree, the dissociation between There are some limitations and strengths in this meta-
Ca-vO2max and VO2max. As for the mechanisms, the analysis. First, the findings were derived from studies
increase in Ca-vO2max with ET in aged individuals mostly comprising men, thus our conclusions should be
could be solely attributed to the improvement in primarily limited to male individualss. Second, the Ca-
blood flow distribution to exercising limbs, given that vO2max was calculated by means of the Fick equation
leg Ca-vO2max may not be affected by ET.1 However, (Ca-vO2max ¼ VO2max/Qmax) in the majority of the stu-
further invasive studies in aged subjects are required to dies, which could have reduced the statistical power to
discard any contribution of peripheral adaptations detect the association between Ca-vO2max and VO2max,
exclusively enhancing microvascular oxygen delivery because of the combined error in Qmax and VO2max
and/or diffusion from capillaries in to muscle to the measurements.58,59 However, such a source of con-
improvement in VO2max, as previously debated.51 founding may have been attenuated by the use of the
Nonetheless, this meta-analysis buttressed the notion SMD (between post and pre-ET) as the summary stat-
that VO2max is primarily governed by the convective istic, which is suggested by the null heterogeneity in
oxygen delivery to the exercising limbs.20,52,53 VO2max and Qmax among studies. Finally, the mean
Although the ET programmes of the included stu- methodological quality of the included studies was
dies presented substantial diversity, the effects asso- determined as moderate to high, and the presence of
ciated with distinct training features were certainly publication and/or other biases was discarded.
homogeneous, except for those regarding oxygen
extraction. Other than duration, the type, modality,
intensity and load of ET influenced Ca-vO2max in sub-
Conclusions
group analyses (Table 3). With respect to type and The current meta-analysis demonstrates that the
modality, the increase in Ca-vO2max reached statistical improvement in VO2max with ET is a linear function
significance in studies including, but not limited to, of Qmax, but not Ca-vO2max, in primarily untrained
weight-bearing exercise (walking, running) or EIT but healthy aged individuals, a finding that is similarly pre-
not in those comprising only cycling or ECT. While sent in young individuals. This suggests that any
speculative, the effect of ET on Ca-vO2max may be increase in systemic oxygen delivery with ET contrib-
facilitated by the interaction of multiple adaptations utes, in a proportional manner, to the enhancement of
potentially improving blood flow distribution such as VO2max, independent of healthy ageing and its related
enhanced skeletal muscle capillarisation, vascular con- decrease in oxygen extraction capacity. Due to the
ductance and sympathetic activity, among others, small number of women in the studies included in the
induced by different types and modalities of exercise meta-analysis, further research is needed to elucidate
in aged individuals.54–56 Moreover, Ca-vO2max was the determinant(s) of VO2max improvement with ET
increased with ET interventions characterised by an in women.
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10 European Journal of Preventive Cardiology 0(00)
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