International Journal of Cardiology 178 (2015) 69–76

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Review

Effect of combined aerobic and resistance training versus aerobic training on arterial stiffness David Montero a,b,c,⁎, Agnès Vinet a, Christian K. Roberts d a

Avignon University, LAPEC EA4278, F-84000 Avignon, France Department of Internal Medicine, Maastricht University Medical Centre (MUMC), Maastricht, the Netherlands Department of Internal Medicine, Cardiovascular Research Institute Maastricht (CARIM), Maastricht, the Netherlands d Exercise Physiology and Metabolic Disease Research Laboratory, Translational Sciences Section, School of Nursing, University of California, Los Angeles, CA, United States b c

a r t i c l e

i n f o

Article history: Received 15 June 2014 Received in revised form 4 September 2014 Accepted 18 October 2014 Available online 24 October 2014 Keywords: Arterial stiffness Combined exercise training Aerobic exercise training

a b s t r a c t Background: While aerobic exercise training may decrease arterial stiffness, the impact of combined aerobic and resistance training is unclear. Therefore, the aim of this study was to systematically review and quantify the effect of combined aerobic and resistance training on arterial stiffness, as determined by arterial pulse wave velocity (PWV), and compare it with aerobic training. Methods: MEDLINE, EMBASE and Web of Science were searched through November 2013 for randomized controlled trials evaluating the effect of aerobic or combined aerobic and resistance training on PWV. A metaanalysis was performed to determine the standardized mean difference (SMD) in PWV between exercise and control groups. Subgroup analyses were used to study potential moderating factors. Results: Twenty-one randomized controlled trials comparing exercise and control groups (overall n = 752), met the inclusion criteria. After data pooling, PWV was decreased in aerobic trained groups compared with controls (10 trials, SMD = −0.52, 95% CI = −0.76, −0.27; P b 0.0001) but did not reach statistical significance in combined trained groups compared with controls (11 trials, SMD = −0.23, 95% CI = −0.50, 0.04; P = 0.10). The effect in aerobic trained groups did not differ compared with combined trained groups (P = 0.12). In addition, aerobic training resulted in significantly lower SMD in PWV compared with combined training in interventions including a higher volume of aerobic training or assessing carotid–femoral PWV. Conclusions: These data suggest that combined aerobic and resistance training interventions may have reduced beneficial effects on arterial stiffness compared with control interventions, but do not appear to differ significantly with aerobic training alone. © 2014 Elsevier Ireland Ltd. All rights reserved.

1. Introduction Arterial stiffness is associated with high risk of cardiovascular morbidity and mortality and its prevalence is increasing rapidly [1,2]. Due to its clinical significance, several indices have been developed during the last two decades to assess arterial stiffness in a non-invasive manner [3,4]. The measurement of pulse wave velocity (PWV) in central arterial segments (i.e., aorta and its main branches) is considered as the ‘goldstandard’ estimate of arterial stiffness [4]. In brief, proximal and distal (pressure or distension or Doppler) sensors are placed on the skin at the ends of the arterial segment of interest. PWV is calculated as the (corrected) distance traveled by the pulse wave divided by the transit time [4]. PWV is an independent predictor of cardiovascular events in patients with established cardiovascular disease as well as in healthy adults [5,6]. ⁎ Corresponding author at: Department of Internal Medicine, CARIM, Universiteitssingel 50, 6229 ER Maastricht, the Netherlands. E-mail address: [email protected] (D. Montero).

http://dx.doi.org/10.1016/j.ijcard.2014.10.147 0167-5273/© 2014 Elsevier Ireland Ltd. All rights reserved.

There is a growing interest in therapeutical strategies aiming at reducing arterial stiffness [1]. Among them, regular aerobic exercise such as walking, jogging or cycling is known to prevent or even reverse arterial stiffening in healthy adults [7–12]. Arterial remodeling, decreased sympathetic tonus, enhanced endothelial function and improved profile of circulating factors have been suggested as changes underlying the beneficial impact of aerobic exercise training on arterial distensibility [8,13,14]. In contrast, resistance exercise training, which is associated with increased blood pressure that exceeds that expected due to oxygen requirements during exercise and sympathetic activation [15–17], does not appear to reduce arterial stiffness [18–24]. On the other hand, resistance training induces gains in strength and lean body mass, as well as greater increases in bone density compared with aerobic training [25,26]. Thus, prescribing aerobic and resistance training in conjunction is proposed as an optimum strategy to target cardiovascular as well as musculoskeletal functions in adults [27]. However, most previous randomized control trials that have measured the effect of combined aerobic and resistance training on PWV had small sample sizes and reported variable results [28–36]. Therefore, the main objective

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D. Montero et al. / International Journal of Cardiology 178 (2015) 69–76

Fig. 1. Flow diagram of the process of study selection.

of this study was to use the meta-analysis procedure to determine the effect of combined aerobic and resistance training on PWV and compare it with aerobic training.

study was included. Inclusion of studies in our analysis was not limited by publication status or language.

2. Methods

The following variables were extracted into a pre-formatted spreadsheet: authors, year of publication, characteristics of study participants (n, age, gender, height, weight, body mass index (BMI), brachial systolic (SBP) and diastolic blood pressure (DBP), smoking subjects, morbidities, medication status), exercise training characteristics (modality, session length, intensity, frequency, duration of the intervention, timing of aerobic and resistance exercise, post-exercise time interval prior to assessment,) and vascular variables (arterial segment evaluated, type of pulse wave sensor, pre- and post-intervention PWV, change in PWV). In the majority of studies, the measure of variability of the change in PWV was not reported [28,31–33,38–44]. Thus, the formula SDc = √[(SDpre)2 + (SDpost)2 − (2 × corrpre,post × SDpre × SDpost)] was used for the calculation [45]. SDc, SDpre SDpost and corrpre,post represent the standard deviation of the change, the standard deviation of the pre-intervention value, the standard deviation of the post-intervention value, and the correlation coefficient between pre- and postintervention values, respectively. We assumed a conservative corrpre,post of 0.5 between the pre-intervention and post-intervention PWV values. The methodological quality of each included trial was evaluated using a validated 10-point scale to rate randomized controlled trials [46–48].

This study is reported according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines [37]. 2.1. Data sources and searches The search strategy was developed to identify all relevant randomized controlled trials assessing central or central–peripheral PWV that included a structured aerobic or combined aerobic and resistance exercise intervention and a parallel non-exercising control group. Our systematic search included MEDLINE, EMBASE and Web of Science, since their inceptions until November 2013. We used combinations of the subject headings “pulse wave velocity”, “exercise”, “training”, “intervention” and “program”; the search strategy for MEDLINE is shown in Supplemental Fig. 1. We also performed hand searching in reference citations of identified reviews and research articles selected for full-text retrieval.

2.3. Data extraction and quality assessment

2.2. Study selection 2.4. Data synthesis and analysis To be included in our analysis, an original research article had to meet the following criteria: (i) the research had to be a randomized controlled trial; (ii) central or central– peripheral PWV values had to be reported in relation to an aerobic or combined aerobic and resistance exercise training intervention; and (iii) the duration of the exercise intervention had to be ≥8 weeks. Studies following the above criteria but including other interventions deemed likely to influence PWV were excluded. In the event of multiple publications pertaining to the same research, the first published or more comprehensive

The meta-analysis and subgroup analyses were performed using Review Manager software (RevMan 5.2, Cochrane Collaboration, Oxford, UK). In each study, the effect size was calculated by the change (post- minus pre-intervention) mean difference in PWV between the exercise trained and control groups. Analysis of the change was preferred over that of post-intervention values because a significant difference was detected in preintervention values between aerobic exercise trained and control groups (P = 0.03).

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Table 1 Main characteristics of trials included in the meta-analysis. Study, year of publication

n

PWV assessment

Ctrl

Ex

Age (years)

♀ (%)

BMI (kg/m2)

SBP, DBP (mm Hg)

Morbidities

Arterial segment

Post-exercise interval (hours)

Training effecta

Aerobic training Madden et al. [71], 2013 Heydari et al. [40], 2012 Ohta et al. [72], 2012 Ciolac et al. A [38], 2010 Ciolac et al. B [38], 2010 Koh et al. A [41], 2010 Koh et al. B [41], 2010 Yoshizawa et al. [43], 2009 Madden et al. [42], 2009 Ferrier et al. [39], 2001

27 18 13 12 12 15 15 12 17 10

25 20 13 16 16 13 14 12 18 10

69 25 72 25 26 52 52 48 71 64

42 0 100 100 100 40 34 100 ~50 50

29.7 28.7 22.4 23.6 24.2 28.0 28.1 23.2 28.9 29.5

144, 82 119, 63 146, 84 113, 70 112, 69 147, 82 144, 79 119, 74 145, 84 159, 80

T2DM, HTN, HYL None HTN, DM, HYL None None RF, HTN, DM, CVD RF, HTN, DM, CVD None T2DM, HTN, HYL HTN

Carotid–femoral Carotid–femoral Brachial-ankle Carotid–femoral Carotid–femoral Carotid–femoral Carotid–femoral Carotid–femoral Carotid–femoral Carotid–femoral

24 ≥24 N/A ≥24 ≥24 ≥24 ≥24 ≥48 24 ≥48

↔ ↓ ↓ ↓ ↔ ↔ ↔ ↔ ↓ ↔

Combined training Dobrosielski et al. [29], 2012 Figueroa et al. [30], 2011 Guimaraes et al. A [44], 2010 Guimaraes et al. B [44], 2010 Loimaala et al. [31], 2009 Miura et al. A [32], 2008 Miura et al. B [32], 2008 Cortez-Cooper et al. [28], 2008 Okamoto et al. A [33], 2007 Okamoto et al. B [33], 2007 Stewart et al. [34], 2005

70 12 11 11 24 12 11 12 6 5 42

70 12 16 16 24 29 25 12 11 11 40

57 54 49 45 54 69 69 53 19 19 64

42 100 63 77 0 100 100 71 67 66 49

33.3 23.7 27.5 28.3 29.6 23.1 23.6 26.4 22.5 22.9 29.6

127, 72 122, 73 125, 81 126, 81 144, 85 125, 73 123, 73 120, 67 114, 63 114, 64 141, 77

T2DM, HTN None HTN HTN T2DM, HTN None None None None None HTN

Carotid–femoral Brachial-ankle Carotid–femoral Carotid–femoral Aortic arch-popliteal Brachial-ankle Brachial-ankle Carotid–femoral Brachial-ankle Brachial-ankle Carotid–femoral

N/A ≥48 48 48 N/A ~24 ~24 24–48 N/A N/A ≥24

↔ ↓ ↔ ↔ ↔ ↔ ↔ ↔ ↔ ↓ ↔

Data are mean or n. Five trials presented two exercise subgroups [32,33,38,41,44], each of which had been independently compared with a single control group, thus they were evaluated as individual trials (distinguished by A or B) [45]. Ctrl, control group; CVD, cardiovascular disease; DBP, diastolic blood pressure; DM, diabetes mellitus; Ex, exercise group; HTN, hypertension; HYL, hyperlipidemia; N/A, data not available; PWV, pulse wave velocity; RF, renal failure; SBP, systolic blood pressure; T2DM, type 2 diabetes mellitus; ↔, no significant difference between groups; ↓, significant difference between groups. a Change in PWV in the exercise group compared with the control group.

Each mean difference was weighted according to the inverse variance method [45]. Since PWV was assessed by different methodologies, the mean differences were standardized by dividing them by the within-group standard deviation [45]. The standardized mean difference (SMD) in each study was pooled with a random effects model [49], which assumes that the effects determined in different studies are not identical\as opposed to a fixed effects model—but conform to some probability distribution [45]. According to Cohen guidelines [50], SMD of 0.2, 0.5, and 0.8 represents small, medium and large effect sizes, respectively. Heterogeneity between studies was assessed using the chi-squared test for heterogeneity and I2 statistics. Potential moderating factors were evaluated by subgroup analysis in aerobic and combined training trials grouped by dichotomous or continuous variables potentially influencing PWV. Median values of (changes in) continuous variables were used as cut-off values for grouping studies. Publication bias was evaluated by estimating Begg and Mazumdar's funnel plot asymmetry. A P value of less than 0.05 was considered statistically significant.

3. Results 3.1. Study selection and characteristics The flow diagram of the process of study selection is shown in Fig. 1. The search of MEDLINE, EMBASE and Web of Science, and manual review of articles cited in the identified and related publications retrieved 428 articles, remaining 226 after duplicate removal. Of these, 168 were excluded because they did not present PWV measurement (n = 50), investigated acute effects (n = 32), had a cross-sectional design (n = 29), were irrelevant to our present meta-analysis (n = 13), involved exercise training with other intervention (n = 12), did not involve exercise training (n = 12), were review articles and/or meta-analyses (n = 8), were protocols or conference proceedings (n = 6), were animal studies (n = 3) or pharmacological interventions (n = 3). We obtained and reviewed the full text of the remaining 58 articles and excluded 42 for the following reasons: no randomized controlled trials (n = 27), resistance training alone (n = 8), only peripheral PWV (n = 2) [51,52], unconventional PWV measurement (n = 1) [53], duplicate data (n = 2) [35,36] or data not available (n = 2) [54,55]. Finally, 16 articles were included in the meta-analysis. Five of these 16 articles presented a single control group independently compared with two exercise subgroups [32,33,38,41,44],

thus the control group of these articles was divided into two parts, so that the total numbers added up to the original size of the control group, and both exercise subgroups were then evaluated as individual trials [45]. Table 1 shows the characteristics of the resulting 21 trials, comprising a total of 752 subjects, of whom 423 subjects were assigned to exercise intervention groups and 329 subjects were assigned to control groups. The total sample size of trials ranged from 20 to 140. Seven trials comprised female subjects, 12 trials comprised male and female subjects and two trials comprised male subjects. The main reported clinical characteristics of all subjects in the included studies ranged from 19 to 72 years for age, 21.8 to 33.6 kg/m2 for BMI, 111 to 159 for SBP and 62 to 86 mm Hg for DBP. Eleven trials involved subjects presenting clinical conditions and 10 trials involved subjects without morbidities. Regarding training characteristics, 10 trials consisted in aerobic training interventions and 11 trials consisted in combined aerobic and resistance training interventions (Table 2), ranging from 8 to 103 weeks of duration. No significant differences were noted in any of the aforementioned clinical characteristics between aerobic training and combined training trials. The aerobic training in aerobic and combined training trials primarily comprised treadmill or cycle ergometer workouts, including a mean of 2.6 sessions per week lasting 39.2 min on average, in trials that reported any of these variables. Intensity of aerobic training approximately ranged from 60–90% of maximal heart rate. No significant differences were noted in any of the aforementioned aerobic training characteristics between aerobic and combined training trials. Resistance training involved different combinations of the upper and lower body exercises ranging from 1 to 5 sets, 8 to 20 repetitions, in a mean of 2.4 sessions per week lasting 31.3 min on average, in trials that reported any of these variables. Intensity of resistance training ranged from 50 to 80% of 1 repetition maximum. With respect to the timing of aerobic and resistance training, 5 trials implemented aerobic right after resistance training [30,32–34], whereas 3 trials implemented aerobic right before resistance training [33,44]. One trial had an inconsistent order of aerobic and resistance training [29] and 2 trials carried out aerobic

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Table 2 Exercise training characteristics of trials included in the meta-analysis. Study, year of publication

Aerobic training Madden et al. [71], 2013 Heydari et al. [40], 2012 Ohta et al. [72], 2012 Ciolac et al. A [38], 2010 Ciolac et al. B [38], 2010 Koh et al. A [41], 2010 Koh et al. B [41], 2010 Yoshizawa et al. [43], 2009 Madden et al. [42], 2009 Ferrier et al. [39], 2001 Combined training Dobrosielski et al. [29], 2012 Figueroa et al. [30], 2011 Guimaraes et al. A [44], 2010 Guimaraes et al. B [44], 2010 Loimaala et al. [31], 2009 Miura et al. A [32], 2008 Miura et al. B [32], 2008 Cortez-Cooper et al. [28], 2008 Okamoto et al. A [33], 2007 Okamoto et al. B [33], 2007 Stewart et al. [34], 2005

Aerobic training

Resistance training

Timing

Weeks (n)

Description

Length (min)

Intensity

n/week

Description

Length (min)

Intensity (% 1 RM)

n/week

Treadmill, cycling Cycling (IT) Bench step Treadmill (IT) Treadmill Cycling Walking Cycling Treadmill, cycling Cycling

60 30 N/A 60 60 30 30 30 60 40

60–75% HRR 88% HRmax LT 50–90%VO2max 60–70% VO2max 12–13 RPE 12–13 RPE 60–70% VO2max 60–75% HRR 65% HRR

3 3 N/A 3 3 3 2 2 3 3

– – – – – – – – – –

– – – – – – – – – –

– – – – – – – – – –

– – – – – – – – – –

– – – – – – – – – –

26 12 12 16 16 24 24 12 13 8

Treadmill, cycling, stairstepper Treadmill Treadmill Treadmill (IT) Jogging or walking Chair-based exercise Chair-based exercise Walking, cycling

45

60–90% HRmax

3

7 exe, 2 sets, 10–15 reps

N/A

50

3

Variable

26

20 60 60 N30

60% HRmax 60% HRR 50–80% HHR 65–75% VO2max

3 3 3 2

9 exe, 1 set, 12 reps – – 8 exe, 3–4 sets, 10–12 reps

N/A 20 20 N 30

60 b100 b100 70

3 3 3 2

12 16 16 103

20

75.4% HRmax

1

6–8 exe, 3–5 sets, 15–20 reps

40

50a

1

R-A A-R A-R Separate days R-A

a

2

R-A

12

Separate days A-R R-A R-A

13

Treadmill Treadmill Treadmill, cycling, stairstepper

20

75.4% HRmax

2

6–8 exe, 3–5 sets, 15–20 reps

40

50

30–45

60–75% HRR

2

10 exe, 2 sets, 8–12 reps

30–45

60

2

20 20 43

60% HRR 60% HRR 60–90% HRmax

2 2 3

7 exe, 5 sets, 8–10 reps 7 exe, 5 sets, 8–10 reps 7 exe, 2 sets, 10–15 reps

N/A N/A N/A

80 80 50

2 2 3

12

8 8 26

Data are mean, range or n. Five trials presented two exercise subgroups [32,33,38,41,44], each of which had been independently compared with a single control group, thus they were evaluated as individual trials (distinguished by A or B) [45]. A, aerobic training; exe, exercises; HRmax, maximum heart rate; HRR, heart rate reserve (estimated as: HRmax − resting heart rate [73]); IT, interval training; LT, lactate threshold; N/A, data not available; reps, repetitions; R, resistance training; RM, repetition maximum; RPE, rate of perceived exertion; VO2max, maximal oxygen consumption. a Estimated according to the number of repetitions and manuscript description.

and resistance training each on separate days [28,31]. As regards the post-exercise time interval prior to assessment, subjects rested 24 h or more from the last bout of exercise in 16 trials, while 5 trials did not report on this issue. 3.2. Quality assessment and potential bias The quality of the trials according to a previously validated scale [46–48] was moderate. The mean score was 5.3 (SD 1.3) out of a possible ten points (Supplemental Table 1). As for the evaluation of potential bias, the Begg and Mazumdar's plot for SMD in PWV was generally symmetrical (Supplemental Fig. 2), suggesting the absence of significant publication bias. 3.3. Pulse wave velocity (PWV) Pulse wave velocity was determined in all of the included trials in central or central–peripheral arterial segments. Fourteen trials assessed carotid–femoral PWV, 6 trials evaluated brachial-ankle PWV and 1 trial determined aortic arch-popliteal PWV (Table 1). After data pooling, the meta-analysis revealed a decreased PWV in aerobic trained groups compared with control groups (10 trials, SMD = −0.52, 95% CI = −0.76, −0.27; P b 0.0001) but not between combined trained groups and control groups (11 trials, SMD = −0.23, 95% CI = −0.50, 0.04; P = 0.10) (Fig. 2). The SMD in PWV did not differ between aerobic and combined training trials (P = 0.12) (Fig. 2). No significant heterogeneity was found among aerobic or combined training trials with respect to the SMD in PWV (I2 = 0%, P = 0.76; I2 = 41%, P = 0.08, respectively) (Fig. 2). Similar results were obtained when the trial that implemented a 103-week intervention [31] was excluded.

Subgroup analyses were conducted in aerobic and combined training trials presenting similar potential moderating factors of PWV (Table 3). Subgroups of trials below vs. above the median value for volume of aerobic training exhibited a significantly lower SMD in PWV in aerobic compared with combined training trials (P = 0.002). In addition, assessment of carotid–femoral PWV (P = 0.007) and change in BMI (P = 0.03) also differed in above/below median subgroups. No other potential moderating factor (n, age, gender, SBP, DBP, health status, duration of training, pre-intervention PWV, methodological quality, year of publication) modified the comparison between aerobic and combined training trials regarding the SMD in PWV. In addition, subgroup analyses were performed in aerobic and combined training trials irrespective of the comparison between training modalities (Supplemental Table 2). Subgroups of trials below the median value in change in SBP or in healthy subjects presented a significantly lower SMD in PWV compared with their complementary subgroups (P = 0.001, P = 0.04, respectively). Furthermore, the timing of aerobic and resistance sessions did not significantly influence the SMD in PWV in the subgroup of trials consisting in combined aerobic and resistance training. 4. Discussion In this systematic review and meta-analysis, we pooled and analyzed data from 21 randomized controlled trials assessing the effect of aerobic or combined aerobic and resistance training interventions on arterial stiffness, determined by PWV (central or central–peripheral arterial segments) in a total of 752 subjects presenting diverse clinical characteristics. The meta-analysis revealed a decreased PWV in exercise groups, which reached statistical significance in aerobic but not in combined trained groups compared with controls. The effect in aerobic

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Fig. 2. Forest plot of the change in PWV in exercise and control groups. The squares represent the SMD in PWV for each trial. The diamond represents the pooled SMD in PWV across trials. Subgroups are divided according to the modality of training. CI, confidence interval; df, degrees of freedom; IV, inverse variance; PWV, pulse wave velocity; SD, standard deviation; SMD, standardized mean difference.

trained groups did not differ compared with combined trained groups. Moreover, aerobic training resulted in a more pronounced decreased PWV than combined training in interventions that were associated with a higher volume of aerobic training or assessed the ‘gold standard’ carotid–femoral PWV. The present meta-analysis indicates that combined aerobic and resistance training, while yielding a non-significant decrease in PWV, has less impact on arterial stiffness than aerobic training alone. Accordingly, it is reasonable to suppose that the resistance training component of combined training may limit, to a certain degree, the improvement in arterial distensibility. In this regard, previous studies assessing the effect of resistance training programs found either increased [56–58] or unaltered [19–24] arterial stiffness following the intervention. Interestingly, resistance exercise, despite being associated with disproportionate increases in blood pressure during exercise [16,17], result in decreased blood pressure as a training adaptation [19,23,59], which could favor a decrease in PWV. This suggests that the resistance training-related factor(s) contributing to arterial stiffness are complex, and although some studies suggest that higher intensity resistance training is associated with increased arterial stiffness [18], other studies suggest no effect [19] and our subgroup analyses suggest, if any, greater decreases in PWV with intensity of resistance training ≥60% of 1 RM (Supplemental Table 2). Nonetheless, it is unknown whether the increased arterial stiffness observed with resistance training in some studies is related to vascular alterations similar to those occurring in pathological conditions or simply a physiological adaptation [60,61]. Alternatively, increased lean body mass with resistance training may contribute to PWV independently of changes in the arterial wall. Regardless, this meta-analysis demonstrates that the addition of resistance training to aerobic training did not negatively impact arterial stiffness. Furthermore, from a more comprehensive perspective, the prescription of combined training may still be encouraged given its superiorly beneficial effects on body composition and musculoskeletal health as well as its metabolic benefits compared with aerobic training alone [62,63].

The impact of exercise training on PWV could be influenced by the health status of the study subjects. Herein we found a greater impact of training on PWV in (i) healthy vs. morbid (hypertensive) subjects or (ii) subjects showing a reduction in SBP above vs. those below the median value, when aerobic and combined training trials were analyzed collectively (Supplemental Table 2). These findings concur with recent meta-analyses on the effect of aerobic training on arterial stiffness in hypertensive and obese populations [64,65]. Taken together, these findings suggest that the beneficial effect of exercise training on arterial stiffness might be lost or attenuated in populations with a high baseline arterial wall stress or when the exercise intervention is not successful in reducing such stress. With regard to the comparison between aerobic and combined training trials according to health status, the current study—plausibly underpowered—found a trend (P = 0.06) for a higher impact of aerobic vs. combined training on PWV in morbid subjects (Table 3). This would support the prescription of aerobic vs. combined training in subjects with a presumably high baseline arterial wall stress. An interesting observation of this study was the greater effect of aerobic relative to combined training on arterial stiffness depending on particular moderating factors (Table 3). A significant effect of aerobic vs. combined training on arterial stiffness was found in trials that included a volume (hours/week) of aerobic training above the median value, thus agreeing with recent data indicating that the exercise dose is a determining factor of cardiovascular adaptations to aerobic training [66]. Ultimately, the difference between aerobic and combined training was observed in trials that evaluated PWV in the carotid–femoral arterial segment, which has the largest support as a predictor of adverse cardiovascular events and is considered the ‘gold-standard’ measure of arterial stiffness [4]. 4.1. Study limitations There are some limitations in the present meta-analysis worth addressing. First, cross-sectional comparisons may be misleading when

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Table 3 Subgroup analyses in aerobic and combined training trials presenting similar potential moderating factors of the SMD in change in PWV between exercise and control groups. Group

Clinical characteristics n ≥ 24 Aerobic Combined n b 24 Aerobic Combined Mean age ≥ 52.5 years Aerobic Combined Mean age b 52.5 years Aerobic Combined Gender ≥ 66.66% females Aerobic Combined Gender b 66.66% females Aerobic Combined Change in BMI ≥ −0.09 kg/m2b Aerobic Combined Change in BMI b −0.09 kg/m2b Aerobic Combined Change in SBP ≥ −1.05 mm Hgb Aerobic Combined Change in SBP b −1.05 mm Hgb Aerobic Combined Change in DBP ≥ −1.05 mm Hgb Aerobic Combined Change in DBP b −1.05 mm Hgb Aerobic Combined Healthy subjects Aerobic Combined Morbid subjects Aerobic Combined Subjects with HTN Aerobic Combined Subjects with T2DM and HTN Aerobic Combined Training characteristics Volume of aerobic training ≥1.5 h/week Aerobic Combined Volume of aerobic training b1.5 h/week Aerobic Combined Duration of intervention ≥13 weeks Aerobic Combined Duration of intervention b13 weeks Aerobic Combined Arterial assessment Carotid–femoral PWV Aerobic Combined Brachial-ankle PWV Aerobic Combined Pre-intervention SMD in PWV ≥0.04 Aerobic Combined

Studies

Pulse wave velocity

Numbera

References

SMD (95% CI)

I2

5 7

[40,42,43,71,72] [28–32,34]

−0.58 (−0.89, −0.28) −0.21 (−0.52, 0.09)

0 48

0.0002 0.17

0.09

5 4

[38,39,41] [33,44]

−0.41 (−0.82, 0.01) −0.29 (−0.96, 0.37)

0 41

0.05 0.39

0.78

4 7

[39,42,71,72] [28–32,34]

−0.44 (−0.79, −0.09) −0.21 (−0.52, 0.09)

0 48

0.01 0.17

0.34

6 4

[38,40,41,43] [33,44]

−0.60 (−0.95, −0.25) −0.29 (−0.96, 0.37)

0 41

0.0007 0.39

0.43

4 6

[38,43,72] [28,30,32,33,44]

−0.76 (−1.21, −0.32) −0.37 (−0.83, 0.08)

0 43

0.0007 0.11

0.23

5 5

[39–41,71] [29,31,33,34,44]

−0.35 (−0.67, −0.02) −0.08 (−0.37, 0.22)

0 28

0.04 0.61

0.23

2 5

[39,42] [28,30,32,33]

−0.40 (−1.08, 0.27) −0.39 (−1.01, 0.22)

34 58

0.24 0.21

0.98

4 3

[40,43,71,72] [29,32,34]

−0.55 (−0.89, −0.21) −0.01 (−0.35, 0.33)

0 39

0.001 0.97

0.03

4 6

[38,39,41] [28,29,33,34,44]

−0.35 (−0.80, 0.11) 0.03 (−0.20, 0.26)

0 0

0.14 0.80

0.15

6 4

[38,40,42,43,71,72] [30,32,33]

−0.59 (−0.88, −0.30) −0.64 (−1.17, −0.11)

0 39

b0.0001 0.02

0.87

5 5

[41,43,71,72] [28,32,33,44]

−0.40 (−0.74, −0.07) −0.15 (−0.53, 0.24)

0 0

0.02 0.45

0.33

5 5

[38–40,42] [29,30,32–34]

−0.65 (−1.01, −0.30) −0.36 (−0.85, 0.14)

0 70

0.0004 0.16

0.34

4 6

[38,40,43] [28,30,32,33]

−0.75 (−1.17, −0.34) −0.42 (−0.91, 0.06)

0 49

0.0004 0.09

0.31

6 5

[39,41,42,71,72] [29,31,34,44]

−0.39 (−0.70, −0.09) −0.02 (−0.25, 0.20)

0 0

0.01 0.84

0.06

1 3

[39] [34,44]

0.00 (−0.88, 0.88) −0.04 (−0.52, 0.44)

N/A 25

1 0.87

0.94

2 1

[42,71] [29]

−0.43 (−0.86, −0.00) 0.02 (−0.31, 0.35)

0 N/A

b0.05 0.90

0.10

8 4

[38–42,71,72] [29,34,44]

−0.54 (−0.81, −0.28) 0.03 (−0.22, 0.28)

0 0

b0.0001 0.82

0.002

2 6

[41,43] [28,30,32,33]

−0.39 (−1.00, 0.22) −0.42 (−0.91, 0.06)

0 49

0.21 0.09

0.94

5 6

[38,41,71] [28,29,31,34,44]

−0.41 (−0.77, −0.05) −0.05 (−0.26, 0.17)

0 0

0.02 0.67

0.09

5 5

[39,40,42,43,72] [30,32,33]

−0.62 (−0.96, −0.28) −0.44 (−1.04, 0.16)

0 59

0.0003 0.15

0.62

9 5

[38–43,71] [28,29,34,44]

−0.49 (−0.74, −0.23) 0.00 (−0.24, 0.23)

0 0

0.0002 0.98

0.007

1 5

[72] [30,32,33]

−0.85 (−1.66, −0.04) −0.44 (−1.04, 0.16)

N/A 59

0.04 0.15

0.43

7 4

[38,40–42,71] [29,30,32]

−0.53 (−0.82, −0.25) −0.37 (−0.88, 0.14)

0 63

0.0003 0.16

0.59

P

PDifference

D. Montero et al. / International Journal of Cardiology 178 (2015) 69–76

75

Table 3 (continued) Group

Arterial assessment Pre-intervention SMD in PWV b0.04 Aerobic Combined Methodological quality ≥5 points Aerobic Combined b5 points Aerobic Combined Year of publication ≥2010 Aerobic Combined b2010 Aerobic Combined

Studies

Pulse wave velocity

Numbera

References

SMD (95% CI)

I2

P

PDifference

3 7

[39,43,72] [28,31,33,34,44]

−0.49 (−0.97, −0.01) −0.16 (−0.50, 0.19)

0 30

b0.05 0.38

0.27

8 8

[38,40–42,71,72] [29–31,33,34,44]

−0.57 (−0.83, −0.30) −0.22 (−0.58, 0.13)

0 54

b0.0001 0.22

0.14

2 3

[39,43] [28,32]

−0.29 (−0.89, 0.31) −0.31 (−0.73, 0.11)

0 0

0.34 0.15

0.95

7 4

[38,40,41,71,72] [29,30,44]

−0.54 (−0.83, −0.25) −0.45 (−1.05, 0.16)

0 61

0.0003 0.15

0.78

3 7

[39,42,43] [28,31–34]

−0.46 (−0.92, −0.01) −0.15 (−0.48, 0.18)

0 34

0.04 0.37

0.27

Median values of continuous variables were used as cut-off values for grouping studies. BMI, body mass index; DBP, diastolic blood pressure; HTN, hypertension; N/A, data not available; PWV, pulse wave velocity; SBP, systolic blood pressure; SMD, standardized mean difference; T2DM, type 2 diabetes mellitus. a Certain enrolled studies were not included because the value used for subgroup analysis was not reported in them. b Change in the exercise trained group minus change in the control group.

addressing the impact of exercise training [67]. In this respect, a comprehensive evaluation of potential moderating factors was performed through subgroup univariate analyses, which in turn are susceptible to the effect of confounding variables. Second, we only included randomized controlled trials assessing arterial stiffness by means of PWV, which is considered to improve the precision of the pooled estimates at the cost of excluding evidence based on different study designs and/or measures of arterial stiffness [3,4]. Third, the heterogeneity of the SMD in PWV in combined training trials, albeit not significant, was higher than that of aerobic training trials (Fig. 2). The main cause(s) of such increased heterogeneity remains uncertain considering the presence of distinct potential moderating factors (Table 3), nonetheless, we can speculate that a heterogeneous training load between combined training trials could be associated, to some extent, with a variable PWV response. Fourth, we could not accurately determine the post-exercise time interval prior to PWV assessment in the included trials, which may have an impact on the results of this meta-analysis [68]. Likewise, the phase of menstrual cycle in which PWV was assessed was scarcely reported, although this variable may not affect PWV outcomes [69,70]. Finally, the methodological quality of the included trials was determined as moderate, although there was no evidence of publication bias (Supplemental Fig. 2).

5. Conclusions This meta-analysis suggests that combined aerobic and resistance training may not be as effective as aerobic training alone to reduce arterial stiffness. Further research is needed to elucidate the prognostic relevance of such different impacts of combined vs. aerobic training on arterial stiffness.

Funding None. Conflict of interest The authors have no conflicts to disclose.

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