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Scientific Review

The Effects of Exercise Training on Brachial Artery Flow-Mediated Dilation

A Meta-analysis

Early, Kate S. MA; Stewart, Abigail BS; Johannsen, Neil PhD; Lavie, Carl J. MD; Thomas, Jerry R. EdD; Welsch, Michael PhD

Author Information
Journal of Cardiopulmonary Rehabilitation and Prevention: March 2017 - Volume 37 - Issue 2 - p 77-89
doi: 10.1097/HCR.0000000000000206
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In the last decade, brachial artery flow-mediated dilation (BAFMD) utilized to assess endothelium-dependent vasodilatory function has become a popular barometer of vascular health, highly dependent on intact nitric oxide (NO) machinery.1,2 Cardiovascular (CV) risk and future CV events in both asymptomatic3,4 and diseased populations5–7 have been associated with the assessment of BAFMD. Endothelial dysfunction is considered an important early event in the development of atherosclerosis, preceding gross morphological signs and clinical symptoms of the inflammatory process and future CV disease.8

Growing evidence suggests that exercise training (ET) improves vascular structure and NO bioavailability and reduces CV disease risk factors,9 therefore making BAFMD assessment a common outcome measure to determine the efficacy of physical activity and ET.10 Resistance and aerobic ET have demonstrated improved BAFMD in short- and long-term ET programs.11,12 The mechanical effects of muscular contractions during ET contribute to an acute oscillatory shear stress thought to serve as a major stimulus for adaptations and release of NO, particularly in “flow-sensitive” arteries.13

To date, few statistical reviews have examined the effects of ET on BAFMD.1,14–16 These reviews were limited by a small special population including type 2 diabetics14 or children16 and lacked comprehension of potential inclusive studies and moderating factors (modality, length of program, exercise volume, fitness status) of ET.15 Thus, this systematic review will explore the effect of ET on BAFMD and potential ET and participant characteristic moderating factors.

METHODS

Search Strategy and Selection Criteria

In a systematic search of PubMed (from 1999 to 2013), 913 citations were obtained using the search terms “brachial artery flow-mediated dilation,” “vasodilation” or “endothelial function” or “vascular reactivity” and “exercise” or “training.” Because of technological advances and standardization of methods, articles prior to 1999 were excluded. In addition, reference lists of original and review articles were analyzed manually for full-text retrieval. The search of studies was not restricted by language, age, or publication status. After an initial screening of articles based on title and abstract, potentially relevant studies investigating BAFMD and ET were assessed for inclusion and quality in the current meta-analysis (Figure 1). This review is in accordance with PRISMA statement guidelines.17

Figure 1.
Figure 1.:
Study search and selection process. Abbreviation: FMD, flow-mediated dilation.

Original studies were included if they met the following criteria: (1) the use of human subjects; (2) duration of ET intervention was ≥1 week; (3) vascular function was evaluated by BAFMD with forearm occlusion; and (4) data concerning pre- and post-ET intervention BAFMD (mean and standard deviations) were reported. Studies involving manipulation (ie, blood flow restriction, functional electrical stimulation), detraining, or ET with additional interventions such as diet or pharmacological agents were excluded.

Quality Assessment and Data Extraction

Two reviewers independently selected studies, extracted data, and assessed the publications according to inclusion criteria. Discrepancies in inclusion/exclusion were resolved by a third-party reviewer. Reviewers judged the quality of studies by the Jadad et al18 3-item scoring instrument, which evaluates the study quality in terms of randomization quality, blinding, and reporting of withdrawals/dropouts. Studies scoring a 0 represented the lowest level of quality, with a possible score between 0 and 5. However, since the criterion item regarding blinding requirements was not applicable to ET interventions, the scoring was modified to assess the blinding of the outcome assessment (BAFMD); therefore, the highest possible Jadad score was 4.

The primary outcome of this study was to investigate how ET impacts BAFMD. For each study, participant characteristics (age, sex, the number of participants); health status of participants (healthy, CV disease, metabolic diseases, hypertension, obesity, other); ET characteristics (length of ET, duration of ET bout, frequency of sessions, ET intensity, pre- and postfitness level); BAFMD characteristics (baseline and peak artery diameter, absolute change of FMD, FMD mean and standard deviation); and methodological considerations (probe strength, cuff placement) were retrieved. ET intensity (1 = very light-light; 2 = moderate; 3 = hard-near maximal), duration (<150 min/week; ≥150 min/week), and baseline fitness level (percentile category) were rated according to published guidelines.19 When necessary, corresponding authors were contacted for unpublished data that were not reported or displayed numerically in the content of the article.

Statistical Analysis

Statistical analysis was performed using SPSS 20.0 statistical software for Mac OS X (SPSS Inc, Chicago, IL). Descriptive data are reported as mean ± standard deviation (SD). BAFMD is determined as the percent change in brachial artery diameter after a 5-minute period of forearm occlusion and is displayed as absolute (mm) and relative (%) change. To facilitate comparison of results across studies, treatment and control effect sizes (ESs) were calculated by the differences in the means pre- and postintervention divided by the preintervention standard deviation.20 Each mean ES was calculated as a weighted mean difference with 95% CIs.20 Data were screened for normality using skewness, kurtosis, and normal quantile plots. Publication bias was examined by funnel plot asymmetry as well as 2 formal tests: Egger's weighted regression test21 and Begg and Mazumdar's rank correlation test.22 In the case of publication bias, the number of unpublished trials containing ES of 0 is defined as [K(dkdc)]/dc, where K = number of obtained studies, dk = mean ES of obtained studies, and dc = trivial ES to which the obtained ES would be reduced.20

Differences in effect of ET on BAFMD were assessed in the following subgroups: age of participants at baseline (≤30 vs 31-59 vs ≥60 years); disease status (diseased vs asymptomatic); fitness change; training type (aerobic vs resistance ET vs combined aerobic and resistance ET vs control); duration of ET program (≥12 weeks vs <12 weeks); ET intensity (very light-light, moderate, high-near maximal); and volume (<150 min/wk vs ≥150 min/wk), trial quality (≤2 vs >2). Age and duration of training subgroups were determined to equally distribute ES. Correlation between fitness and BAFMD ES was evaluated using the Spearman rank correlation analysis. To counteract multiple comparisons on the same data set, a Bonferroni correction was utilized to determine the critical P value for each comparison.

RESULTS

Literature Search and Publication Bias

A total of 191 related studies were identified from 1999 to 2013 for eligibility screening into this study (Figure 1). Of these, 125 studies were excluded because they were acute ET (n = 65) or detraining (n = 5) regimens; a manipulation or therapy was applied (ie, functional electrical stimulation) (n = 14); a quality assessment was performed (n = 9); ET plus additional interventions were applied (n = 3); flow-mediated dilation was not performed with forearm occlusion imaging the brachial artery (n = 13); or BAFMD data were not available after author contact (n = 16). Finally, of the 66 studies included in the final analysis, the sample size ranged between 7 and 146 participants with a total of 1865 ET intervention and 635 control subjects (Table 1). The mean and modal quality of studies (Jadad score) were 2 and 1 (range, 1-4), respectively.

Table 1 • - Participant and Exercise Intervention Characteristics of Studies Included in the Meta-analysis
Study Characteristics Exercise Intervention Characteristics
Author Journal Population Age, y Males, % n (I/C) Length, wks Type Frequency (sessions/wk) Duration, min Intensity Ratinga
Clarkson et al23 J Am Coll Cardiol Healthy adults 20 ± 0 100 25/0 10 RA 7 ... ...
Maiorana et al24 J Am Coll Cardiol T2DM 52 ± 2 88 16/0 8 RA 3 60 3
Gokce et al25 Am J Cardiol CAD 59 ± 10 78 40/18 10 A 3 30-40 ...
Allen et al11 Med Sci Sport Exer Healthy adults 26 ± 6 100 14/14 4 R 5 20 2
Kobayashi et al26 Circ J CHF 55 ± 2 71 14/14 12 A 2-3 30 2
Walsh et al27 Eur Heart J HC 55 ± 2 73 11/11 8 RA 3 45-60 3
Walsh et al28 J Appl Physiol CAD 52 ± 2 100 10/0 8 RA 3 45-60 3
Guazzi et al29 J Appl Physiol CHF 52 ± 5 100 16/0 8 A 4 40 3
Kelly et al30 J Pediatr Overweight children 11 ± 4 45 10/10 8 A 4 50 3
Vona et al31 Am Heart J AMI 56 ± 6 77 28/24 12 A 3 60 2
Watts et al32 J Am Coll Cardiol Obese children 14 ± 2 65 23/0 8 RA 3 60 3
Watts et al33 J Pediatr Obese children 9 ± 2 43 14/14 8 A 3 60 2
Belardinelli et al34 Int J Cardiol HTN 56 ± 15 100 30/0 8 A 3 70 2
Moriguchi et al35 Hypertens Res HTN 43 ± 10 72 25/0 12 A 2 60 2
Rakobowchuk et al36 J Appl Physiol Healthy adults 23 ± 4 100 28/0 12 R 5 60 3
McGowan et al37 Eur J Appl Physiol HTN 66 ± 6 78 9/9 8 R 3 ... 1
Miche et al38 Clin Res Cardiol T2DM/CHF 67 ± 6 86 20/22 4 RA 3 ... 2
Olson et al39 Med Sci Sport Exer Overweight adults 38 ± 1 0 15/15 52 R 2 ... ...
Casey et al40 Exp Biol Med Healthy adults 21 ± 1 45 24/18 12 R 3 35 3
Casey et al41 Eur J Appl Physiol Healthy adults 59 ± 5 0 23/0 18 RA 2 35,35-40 2,3
McGowan et al42 Clin Sci Healthy adults 28 ± 14 78 9/9 8 R 3 ... 1
Westhoff et al43 J Hum Hypertens HTN 67 ± 5 51 24/27 12 A 3 33 2
Westhoff et al44 Kidney Blood Press Res HTN 68 ± 5 50 25/27 12 A ... ... 3
Belardinelli et al45 Circ Heart Fail CHF 59 ± 11 84 88/0 8 A 3 60,31 3
Sixt et al46 Eur J Cardiovasc Prev Rehabil IGT/CAD 64 ± 6 74 17/23 4 A 6 ... 7
Tinken et al47 J Physiol Healthy adults 22 ± 2 100 13/7 8 A 3 30 3
Westhoff et al48 J Hypertens HTN 53 ± 2 46 12/12 12 A 3 30 2
Baynard et al.49 Eur J Appl Physil MetSyn 52 ± 1 48 21/0 1 A 10 60 2
Dobrosielski et al50 Med Sci Sport Exerc Older adults 81±1 100 12/12 4 R 4 20 2
Munk et al51 Am Heart J PCI 57 ± 14 83 20/20 24 A 3 60 3
Murphy et al52 Int J Pediatr Obes Overweight children 10 ± 2 23/12 12 A 5 30 ...
Tjonna et al53 Clin Sci Overweight children 14 ± 0 20/22 12 A 2 40 3
Vona et al54 Circulation AMI 56 ± 6 65 159/50 4 A,R, RA 4 60 2
Wray et al55 Clin Sci HTN 71 ± 2 100 6/0 6 A 3 60 3
Xiang et al56 Eur J Endocrinol sHT 53 ± 8 0 53/0 24 A 4-6 40-45 2
Allen et al57 Free Radic Biol Med PAD 68 ± 10 55 33/0 12 A 3 30-40 3
Credeur et al58 Med Sci Sport Exerc Healthy adults 22 ± 1 42 12/0 4 R 3 20 2
Desch et al59 Diabetes Obes Metab CAD 62 ± 6 73 14/12 24 A 7 30 2
Okada et al60 J Atheroscler Thromb T2DM 62 ± 9 55 21/17 12 RA 3-5 40 ...
Tinken et al61 Hypertension Healthy adults 22 ± 2 100 11/0 8 R 3 60 2
Van Craenenbroeck et al62 Basic Res Cardiol CHF 61 ± 2 79 21/17 24 RA 3 60 3
Anagnostakou et al63 J Card Fail CHF 53 ± 10 82 28/0 12 A,RA 3 40 2
Hermann et al64 Am J Transplant HTx 53 ± 11 81 14/13 8 A 3 60 3
Kwon et al65 Diabetes Metab J T2DM 56 ± 9 0 25/15 12 A,R 5 60 2,1
Molmen-Hansen et al66 Eur J Prev Cardiol HTN 52 ± 8 56 48/25 12 A 3 38,47 3,2
Okamoto et al67 Eur J Appl Physiol Healthy adults 19 ± 1 77 13/0 10 R 2 ... 2
Pierce et al68 Clin Sci Healthy adults 63 ± 1 42 26/10 8 A 6-7 45 2
Ramirez-Velez et al69 J Obstet Gynaecol Res Pregnant adults 20 ± 2 0 24/26 16 A 3 60 1
Seeger et al70 Diabetes Obes Metab T1DM 11 ± 2 7/0 18 A 2 40-60 ...
Akazawa et al71 Nutr Res Healthy adults 59 ± 5 0 11/10 8 A 3 40-60 2
Barone Gibbs et al72 Atherosclerosis T2DM 58 ± 5 62 49/63 26 RA 3 45 3
Billinger et al73 JNPT Stroke 61 ± 5 67 9/0 8 A 3 30-40 3
Cornelissen et al74 Eur J Prev Cardiol CAD 62 ± 1 84 146/0 12 A 3 90 3
Credeur et al75 Atherosclerosis CHF 62 ± 8 40 10/10 4 R 3 20 2
da Silva et al76 Diabetes Res Clin Pr MetSyn/T2DM 58 ± 6 35 20/11 6 A 4 50 1,3
Hopkins et al77 Eur J Prev Cardiol Twin children 14 ± 1 33 24/0 8 A 3 45 3
Hunt et al78 J Appl Physiol Healthy adults 26 ± 4 100 9/0 4 R 3 ... 1
Nualnim et al79 Am J Cardiol HTN 60 ± 2 12 A 4 40-50 2
Rakobowchuk et al80 Exp Physiol Healthy adults 24 ± 3 35 20/0 6 A 3 40 2,3
Swift et al12 Br J Sports Med Obese adults 57 ± 6 0 132/23 24 A 3-4 ... 1
Xiang et al81 Exp Clin Endocrinol Diabetes HT 45 ± 9 0 86/0 24 A 4 40-45 2
Beck et al82 Exp Biol Med Prehypertension 21 ± 3 70 28/15 8 A,R 3 60 3
Currie et al83 Med Sci Sport Exerc CAD 68 ± 8 11/11 12 A 2 30-50,35 2,3
Kitzman et al84 J Am Coll Cardiol HF 70 ± 7 24/29 16 A 3 60 3
Mitranun et al85 Scand J Med Sci Sports T2DM 61 ± 3 35 14/29 12 A 3 40 3
Spence et al86 J Physiol Healthy adults 27 ± 5 100 23/0 24 A,R 3 60 ...
Abbreviations: A, aerobic; AMI, acute myocardial infarction; C, control; CAD, coronary artery disease; CHF, chronic heart failure; HC, hypercholesterolemia; HF, heart failure; HT, Hashimoto's thyroiditis; HTN, hypertension; HTx, heart transplant; I, intervention; IGT, impaired glucose tolerance; MetSyn, metabolic syndrome; PCI, percutaneous coronary intervention; R, resistance; RA, combined aerobic and resistance; sHT, subclinical hyperthyroidism; T2DM, type 2 diabetes mellitus; T1DM, type 1 diabetes mellitus.
a1, very light-light; 2, moderate; 3, vigorous-near maximal.

Asymmetry of funnel plots suggests a potential publication bias. To confirm, the intercept of the regression relation effect between standard normal deviate and the inverse standard error was significantly different from zero (intercept = 0.22; P < .001), and the Kendall-tau correlation coefficient between the ES and its variance was also significant (r = 0.60; P < .001). The wide variation of sample size among the present studies and absence of “negative” studies potentially contributed to the bias. It is estimated that the number of unpublished studies needed to bring the mean effect to a nonsignificant level is 411 studies.20

Study Characteristics

The main demographic characteristics of the studies are described in Table 1. The mean age was 47 ± 19 (range, 9-81) years and percentage of men was 50%. Seven of the studies included children ranging from 8 to 14 years in age (median = 11 years).30,32,33,52,53,70,77 The populations of the studies primarily included CV-related diseases (n = 19), asymptomatic/healthy subjects (n = 18), metabolic-related diseases (n = 10), hypertension (n = 10), overweight and obesity (n = 7), and thyroid related issues (n = 2). Prior to ET intervention, the mean baseline artery diameter and BAFMD were 3.92 ± 0.50 mm (range, 2.61-5.33 mm) and 5.5 ± 2.4% (range, 0.9%-13.6%), respectively. Post-ET intervention groups mean BAFMD improved to 8.1 ± 3.9% (P < .0001), while there was no change in control group (5.4 ± 1.9%; P = .72). The absolute change of BAFMD in trained groups (n = 22) was significant from pre- to postintervention (0.26 ± 0.11 to 0.31 ± 0.13 mm; P = .01), and the control group (n = 11) absolute change in diameter decreased (0.24 ± 0.07 to 0.22 ± 0.07 mm; P = .23). However, baseline artery diameter remained the same postintervention in ET (3.92 ± 0.50 mm) and control groups (4.04 ± 0.56 mm). The mean ET intervention lasted 12 ± 8 (range, 1-52) weeks (Table 1). Exercise training modalities included aerobic (n = 58), resistance (n = 17), combined aerobic and resistance ET (n = 13), and control (n = 39) groups. Regardless of ET modality, the average ET intervention consisted of a mean 3.5 ± 1.5 (median = 3) sessions per week (n = 87) and 46.9 ± 13.8 (median = 45) minutes per session (n = 76). The median intensity was moderate (n = 84) and mean ET volume was 167 ± 93 (median = 159) minutes per week.

Effect of ET on BAFMD

One hundred twenty-three mean, weighted ESs were derived from 66 studies. Overall, ET induced a significant increase of BAFMD (trained ES, 8.38; 95% CI, 6.16-10.59; P < .0001). Eighty of the 88 training ESs (91%) were larger than zero. The control group mean ES was −0.61 (95% CI, −2.15 to 0.94) and suggests that control groups on average did not change during the interventional period (CI encompasses 0). No differences were observed between training modalities when compared to the control; aerobic ET tended to have the greatest ES (9.30; 95% CI, 6.29-12.31), followed by combined aerobic and resistance ET (ES, 7.62; 95% CI, 2.32-12.92) and resistance ET (ES, 5.80; 95% CI, 1.29-10.30) (Table 2). Of the 66 studies (71 ES) that reported a pre- and post-ET intervention fitness measure, 100% showed an improvement in fitness (peak oxygen uptake, 1−repetition maximum, maximal voluntary contraction). The mean percent change in fitness was 16 ± 12% (median = 12%). A modest relationship was found between the change in fitness and BAFMD ES (r = 0.51; P < .0001).

Table 2 • - Subgroup Analyses of Potential Moderating Factors
n Effect 95% CI L-Statistic P Value
Demographic characteristics
Age, yr 4.42 .11
≤30 28 4.63 2.91-6.35
31-59 38 10.68 7.11-14.24
≥60 22 9.17 2.84-15.49
Disease status 11.29 .0007
Asymptomatic/healthy 25 3.18 1.90-4.46
Diseased 63 10.44 7.53-13.34
Baseline level of fitness 0.21 .65
<50th percentile 52 4.19 3.31-7.63
≥50th percentile 6 8.63 −2.09 to 19.35
Vascular Indices
Baseline FMD 6.26 .01
<5% 54 8.23 5.28-11.17
≥5% 69 3.94 1.82-6.06
Baseline artery diameter 1.02 .31
<4.00 mm 52 4.80 2.69-6.92
≥4.00 mm 50 7.26 3.84-10.67
Methodological characteristics
Trial quality 9.11 .003
≤2 63 6.54 4.11-8.95
>2 25 13.01 8.59-17.42
Year of publication 3.63 .06
<2006 16 8.70 8.14-9.26
≥2006 72 8.30 5.76-10.96
Exercise Training Characteristics
Type of exercise 39.34 .0001
Control 35 −0.61 −2.11 to 1.00
Aerobic 58 9.31 6.08-12.31
Resistance 17 5.80 1.29-10.30
Aerobic and resistance 13 7.62 2.33-12.92
Length of training 37.77 .0001
Control 35 −0.61 −2.11 to 1.00
<12 weeks 43 8.09 5.06-11.13
≥12 weeks 45 8.65 5.23-12.06
Intensity 36.42 .0001
Control 32 −0.42 −2.06 to 1.21
Very light-light 9 3.63 −0.57 to 7.83
Moderate 38 8.96 5.39-12.53
Vigorous-near maximal 34 9.29 5.09-13.47
Volume 33.22 .0001
Control 31 −0.30 −1.99 to 1.39
<150 min/wk 48 4.80 3.08-6.51
≥150 min/wk 43 11.33 7.15-15.51
Abbreviation: FMD, flow-mediated dilation.

Subgroup and Advanced Analyses

Results of subgroup analyses from BAFMD are summarized in Table 2. Overlapping CIs of each with-in comparison suggested no difference in age (≤30 vs 31-59 vs ≥60 years; P = .11), baseline fitness level (<50th percentile or ≥50th percentile; P = .65) and baseline artery diameter (<4.00 mm or ≥4.00 mm; P = .31) (Table 1). Compared to asymptomatic subjects, diseased patients had a significantly higher BAFMD ET effect (asymptomatic, 3.18; 95% CI, 1.90-4.46 vs diseased, 10.44; 95% CI, 7.53-13.34; P = .0007). When examining disease categories, CV disease (n = 25; 14.11; 95% CI, 7.63-20.59), overweight/obesity (n = 9; 9.93; 95% CI, 7.49-12.36), and hypertension (n = 13; 7.61; 95% CI, 3.82-11.41) groups had significantly greater BAFMD ES than the asymptomatic/healthy category (n = 24; 3.45; 95% CI, 1.28-4.73; P = .001). Subjects with a baseline BAFMD <5% appeared to have a larger ES than those with a baseline BAFMD ≥5% (8.23; 95% CI, 5.28-11.17 vs 3.94; 95% CI, 1.82-6.06, respectively; P = .01). Methodologically, studies with higher trial quality (ie, >2) showed statistically significant (P = .003) treatment effect, while studies conducted after 2006 (ES, 8.30; 95% CI, 5.76-10.96) tended to have a smaller effect than did studies conducted prior to 2006 (ES, 8.70; 95% CI, 8.14-9.26; P = .06).

Exercise training intervention groups had a significantly greater BAFMD ES than the control groups in regard to modality, length of ET as well as intensity and ET volume subgroups (all P < .0001; Table 2). Within subgroups, very light-light ET intensity was not different than the control group, but ET at a vigorous to near maximal ET intensity did result in a significant improvement in BAFMD (control, −0.42; 95% CI, −2.06 to 1.21 vs very light-light, 3.63; 95% CI, −0.57 to 7.83 vs vigorous-near maximal, 9.29; 95% CI, 5.09-13.47). Furthermore, study groups with an ET duration was ≥150 min/wk had a significant improvement in BAFMD compared with those with <150 min/wk (control, −0.30, 95% CI, −1.99 to 1.39 vs <150 min/wk, 4.79; 95% CI 3.08-6.51 vs ≥150 min/wk, 11.33; 95% CI, 7.5-15.51; Figure 2).

Figure 2.
Figure 2.:
Exercise intensity and volume weighted effect sizes displayed as mean and 95% CI. a P < .05 vs control; b P < .01 exercise intensity very light-light compared with vigorous-near maximal (Panel A) and volume ≥150 min/wk compared with <150 min/wk (Panel B).

DISCUSSION

The meta-analyses demonstrated that ET interventions contribute to a significant increase in BAFMD regardless of ET modality, length of ET, and intensity or volume of ET, supporting evidence that ET enhances endothelial function.13 In addition, BAFMD was associated independently with both ET intensity and duration in a dose-response fashion.

Age did not serve as a moderator to the changes in BAFMD with ET, suggesting that the vasculature remains modifiable throughout the lifespan. The older age groups (>31 years) tended to have greater BAFMD improvement, suggesting that ET can prevent age-related loss in endothelial function. However, since age tended to be a potential moderator (P = 0.11), it is possible that age-specific responses to ET may be masked because of the combining of sexes. Previous research suggests that sedentary, middle-aged, and older men can prevent age-associated loss in endothelial function with regular aerobic ET87 while healthy postmenopausal women have no improvements in BAFMD with endurance ET.88 Disease status was found to impact the ES of BAFMD with ET, in particular CV diseases, overweight/obesity, and hypertension, likely due to their higher propensity for vascular disease and therefore more potential gain from effective therapies. In clinical studies of diabetes mellitus,72,85 obesity12 and hypertension,37 patients have shown a blunted BAFMD. In addition, this analysis found the greater change in fitness the greater ES of BAFMD, suggesting that modifying fitness is important to vascular health. Low cardiorespiratory fitness is an established risk factor for the CV and total mortality independent of CV risk factors.89 Therefore, as ET interventions are applied to patients with CV risk factors, it is important to consider that ET is important to improving fitness and clinical symptoms and slow the progression of atherosclerosis, as measured by BAFMD.

Evidence supports a significant effect of ET on BAFMD independent of modality or length of ET. The modality with the greatest BAFMD ES was aerobic ET, suggesting that regular aerobic exercise may be the most beneficial mode to improve vascular function.15 There were no differences in the magnitude of ES between studies up to 12 weeks versus studies longer than 12 weeks in duration. The ES of BAFMD on ET is associated with both ET intensity and volume suggests a dose-response stimulus. The association with ET intensity may be due to greater shear stimulus triggered by increasing intensity.90 Such shear stress has been shown to upregulate NO production via NO synthase.91 These findings demonstrated that high-intensity ET might be beneficial to optimally improve vascular function.92,93 However, no difference was seen between moderate and vigorous ET intensity, suggesting that moderate intensity can sufficiently improve BAFMD. Despite the popular trend of high-intensity interval training, there appears to be no benefit of higher, potentially riskier, ET intensity for vascular improvement. Furthermore, maximal effort ET for a sustained period of time has been shown to generate reactive oxygen species, which hinders vascular function.94,95 Reduced BAFMD may be the consequence of an increase in circulating vasoconstrictor agonists (ie, Angiotensin-II, vasopression, and endothelin)82,96 and increased oxidative stress.97 Nitric oxide is believed to play a significant role in buffering against oxygen radicals. If the oxygen stress is elevated as in high-intensity exercise, the role of NO may shift from a vasodilator to a radical scavenger.

Although we believe this to be the most comprehensive review of evidence supporting the impact of ET-based intervention on vascular function, variations in the methods of BAFMD assessment and reporting of ET characteristics may lead to detectable differences and explain the wide variation in the measurement. Several studies that met the minimum inclusion criteria were of poor methodological quality, and few described the process of random assignment and blinding of the outcome assessment (BAFMD). Additional factors that may potentially influence BAFMD including menopause, diet, and smoking could not be examined because of the lack of reporting in the included studies. Future studies should include age and gender information in their report to further clarify the evidence supporting different BAFMD responses to ET. Interestingly, trials over the last decade (published ≥2006) are typically of lower quality, which is potentially a consequence of methodological and physiologic guidelines that have been published and the popularity of the measurement.8,98 Few of the included studies were longitudinal; 9 of the 66 studies reviewed were longer than 20 weeks. Further research is necessary to establish optimal ET interventions for improvement in vascular health, measured by BAFMD.

In conclusion, a meta-analysis of 66 studies found that ET interventions contribute to a significant increase in BAFMD. Age did not modify BAFMD, suggesting that the vasculature is modifiable and age-associated changes in BAFMD can be improved with ET. The ES of BAFMD is associated with both ET intensity and duration in a dose-response fashion. Larger effects were seen with higher-intensity, longer duration exercise. This meta-analysis provides evidence that ET interventions improve BAFMD, supporting its marked benefits in the primary and secondary prevention and treatment of a variety of CV and metabolic disorders.

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                                                                                                            Keywords:

                                                                                                            exercise training; flow-mediated dilation; meta-analysis; vascular function

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