Physical exercise and epicardial adipose tissue: A systematic review and meta-analysis of randomized controlled trials

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O B E S I T Y C O M O R B I D I T Y / M A N A G E M E N T

Physical exercise and epicardial adipose tissue: A systematic review and meta-analysis of randomized controlled trials

Gonzalo Saco-Ledo

¹

| Pedro L. Valenzuela

²

| Adrián Castillo-García

³

|

Joaquín Arenas

⁴

| Miguel León-Sanz

^4,5

| Luis M. Ruilope

^4,6

| Alejandro Lucia

^4,7

1Bioenergy and Motion Analysis Laboratory, National Research Center on Human Evolution (CENIEH), Burgos, Spain

2Department of Systems Biology, University of Alcalá, Madrid, Spain

3Physiology, Health and Physical Activity, Fissac, Madrid, Spain

4Research Institute of the Hospital Universitario 12 de Octubre (‘imas12’), Madrid, Spain

5Clinical Nutrition Unit, Hospital Universitario 12 de Octubre, Madrid, Spain

6Hypertension Unit and Cardiorenal Translational Laboratory, Hospital 12 de Octubre, Madrid, Spain

7Faculty of Sport Sciences, European University of Madrid, Madrid, Spain

Correspondence

Alejandro Lucia, MD, PhD, Faculty of Sport Sciences, European University of Madrid, C/Tajo S/N, 28670, Villaviciosa de Odón, Madrid, Spain.

Email: [email protected]

Funding information

European Union; Instituto de Salud Carlos III (Ministerio de Ciencia, Innovación y Universidades, Spain), Grant/Award Number:

PI18/00139; University of Alcalá, Grant/

Award Number: FPI2016

Summary

We performed a meta-analysis of the effects of exercise on epicardial adipose tissue (EAT). A systematic search was conducted in PubMed and Scopus (since incep- tion to 1 February 2020) of randomized controlled trials assessing the effects of exercise interventions alone (with no concomitant weight loss intervention) on EAT.

The standardized mean difference (Hedges'

g) and 95% confidence interval between

interventions were computed using a random effects model. Ten studies (including 521 participants who had, on average, overweight/obesity) met all inclusion criteria.

Interventions were supervised and lasted 2 to 16 weeks (

≥

3 sessions per week).

Exercise significantly reduced EAT (g = 0.82 [0.57

–

1.07]) irrespective of the duration of the intervention or the EAT imaging assessment method. Exercise benefits were separately confirmed for endurance (six studies,

n

= 287;

g

= 0.83 [0.52

–

1.15]) but not for resistance exercise training (due to insufficient data for quantitative synthesis). It was not possible to compare the effect of high-intensity interval training (HIIT) versus moderate-intensity continuous training (two studies, one reporting higher benefits with HIIT and the other no differences). Physical exercise interventions

—

particularly endurance training, with further evidence needed for other exercise modalities

—

appear as an effective strategy for reducing EAT in indi- viduals with overweight/obesity, which supports their implementation for cardiovas- cular risk reduction.

K E Y W O R D S

cardiovascular risk, epicardial fat, obesity, physical activity

1 | I N T R O D U C T I O N

The epicardial adipose tissue (EAT) is a visceral fat compartment located between the myocardial surface and the visceral layer of the pericardium, in direct contact with the coronary vasculature. It can be quantified with non-invasive imaging techniques (echocardiography, magnetic resonance imaging [MRI] or cardiac computed tomography).¹ EAT might exert cardioprotective effects, as it has a greater ability to

uptake and metabolize free fatty acids (FFA) compared to other visceral adipose tissues (VAT), being the main responsible for the oxidation of FFA from the coronary artery blood.^2,3Thus, EAT might act as a buffer protecting the heart against exposure of excessive FFA and formation of atherosclerotic plaques.^2,3 However, excessive levels of EAT are associated with an increased prevalence of cardiovascular disease (CVD) risk factors (visceral abdominal fat, hyper- cholesterolaemia, hypertension, insulin resistance or impaired glucose tolerance),^4–10as well as with a higher risk of CVD (coronary artery disease, heart failure or atrial fibrillation)^11–15 and mortality.^12,13,16 Gonzalo Saco-Ledo and Pedro L. Valenzuela contributed equally.

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Although the biological mechanisms underlying the aforementioned association remain to be clearly elucidated, an increased production of EAT-released adipocytokines (or ‘adipokines’, e.g., tumour necrosis factor alpha, resistin) in the context of deranged EAT adipogenesis is likely involved.¹⁷ The paracrine, pro-inflammatory effects of adipokines can indeed induce negative consequences in other tissues, contributing to systemic inflammation and to the development of atherosclerosis and other cardiovascular complications.^18,19

It is therefore important to develop strategies aimed at reducing EAT, especially in high-risk populations such as people with overweight/obesity or with other CVD risk factors. Some cross- sectional, prospective or randomized clinical trial (RCT) studies have analysed the effects of different weight loss strategies (physical exercise, diet, bariatric surgery or drugs) on EAT.^20,21Meta-analytical evidence from studies conducted until 2014 showed that, when pooled together, these weight loss strategies collectively decreased EAT, with the benefits dependent on the magnitude of body weight reduction.²¹In separate analyses, either bariatric surgery or diet alone reduced EAT, whereas physical exercise per se did not induce significant reductions. However, only three exercise studies (of which two were non-controlled) including a total of 43 participants could be meta-analysed.²¹More recently, some RCTs have assessed the effects of exercise alone on EAT,²²^–³¹ with some reporting promising results.26,27,29,31A recent systematic review that included both RCT and non-RCT studies assessed whether exercise—alone or combined with dietary intervention—affects EAT, with the results showing a significant reducing effect.³² However, some RCTs assessing the effects of exercise alone on EAT were not meta-analysed.^22,24,27

It was therefore the aim of this systematic review and meta- analysis to assess the effects of RCTs using only physical exercise intervention/s on EAT.

2 | M E T H O D S

The conduct and reporting of the current systematic review and meta-analysis conform to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA).³³This review was not prospectively registered.

2.1 | Data sources and search strategies

Two researchers (G.S.L. and P.L.V.) independently conducted a systematic review of relevant articles (first by title and abstract and then by full-text) in the electronic databases PubMed and Scopus (from inception to 1 February 2020) using the following search strategy: (Exercise OR‘physical activity‘OR training) AND (epicardial OR pericardial) AND (fat OR adipose). No search filters were applied.

The search was supplemented by a manual review of reference lists from included primary studies and review articles to find additional studies on the subject. References were stored and managed using Mendeley Desktop 1.19.4 (Elsevier, London, UK).

2.2 | Study selection

We applied no restrictions on the language of articles. Studies were eligible for inclusion if they met each of the following criteria: (i) RCT design, (ii) age of participants≥18 years, (iii) intervention consisting solely of physical exercise programme(s) (e.g., studies with both diet andexercise interventions were excluded) and (iv) assessing EAT as one of the study end points. Abstracts, conference proceedings, letters, editorials, case studies, reviews and books/book chapters were excluded.

2.3 | Data extraction

Two reviewers (G.S.L. and P.L.V.) independently extracted the following data from each study: number of participants within each group, participants' characteristics, exercise intervention characteristics, end points, EAT assessment method and results. Data were extracted, when available, as mean and standard deviation (SD). When data were provided as intervention effects and/or using other measures of dispersion (e.g., standard error, 95% confidence intervals), the required information was estimated following the guidelines available elsewhere.³⁴A specific software (WebPlotDigitizer 4.2, San Francisco, CA) was used to extract data when provided as a figure,^22,24,26and we contacted the authors of two studies because the required data had not been reported for the control group.^27,28 However, the authors of one study²⁸ could not be contacted and thus we were unable to include their data in quantitative synthesis—the study was nevertheless included in the qualitative results.

2.4 | Quality assessment

Two authors (G.S.L. and P.L.V.) independently assessed the methodological quality of the included studies with the PEDro scale.³⁵A 0–10 total score was determined by counting the number of criteria satis- fied by each study. Study quality was rated as poor (PEDro score≤3), fair (4–5) or high (>5). All studies were used for data synthesis independently of their methodological quality.

2.5 | Statistical analysis

A meta-analysis was performed when a minimum of three studies analysed EAT. The pooled standardized mean difference (Hedges'g, post-minuspre-intervention data) between the different intervention groups was compared along with 95% confidence interval (CI) using a random effects model. Subanalyses were performed attending to the EAT assessment method and the type of exercise intervention: endurance (‘aerobic’) training (ET) or resistance training (RT). A conservative correlation Pearson's coefficient (r) of 0.7 between pre- and post- intervention data was used for the computation of the within-group differences.³⁶Sensitivity analyses with anr-value of 0.2 and 0.5 were

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performed when a significant result was found. A meta-regression analysis using the random effects model (method of moments) was also performed to assess the association between the magnitude of the effects (Hedges'g) and the duration (weeks) of the interventions.

The Begg's test was used to determine the presence of publication bias, and theQandI² statistics were used to assess heterogeneity across studies. All statistical analyses were performed using the statistical software package Comprehensive Meta-analysis 2.0 (Biostat; Englewood, NJ) setting the level of significance at 0.05.

3 | R E S U L T S

3.1 | Studies' characteristics

From the retrieved studies (see Data S1 for list of excluded studies), 10 (n= 521 participants) met all inclusion criteria and were included in the systematic review (Figure 1).

The characteristics of the included studies are summarized in Table 1. All were conducted in individuals who had, on average, overweight or obesity (body mass index >25 kgm⁻²), with mean age ranging from 23 to 68 years. However, other participants' characteristics differed across studies, with four of them specifically conducted in individuals with overweight or obesity,^27–29,31two in individuals with metabolic syndrome,^23,30one in individuals with high CVD risk

(e.g., Framingham 10-year risk score >20%),²⁴ one in patients on hemodialysis,²² one in individuals with depressive disorders,²⁶ and one combining people who were healthy and individuals with defective glucose tolerance.²⁵

Exercise interventions were supervised in all cases and included three sessions per week (30–60 min per session) in the majority of cases except for one study, in which training frequency was not specified.²⁴However, other characteristics such as length of the intervention (which lasted between 2 and 16 weeks) differed considerably between studies. Moreover, studies included different types of ET, moderate-intensity continuous (MICT)22,24,26,29,30

or high-intensity interval training (HIIT),^23,25,31or RT interventions (e.g., circuit of seven to 10 exercises with three to five sets of10 repetitions),^27,28,31and one study also assessed the effects of exergaming (i.e., exercising [in this case running and jumping] while playing a video game).²⁴None of the studies reported any adverse event related to the exercise interventions (e.g., no musculoskeletal injury).

3.2 | Quality assessment and publication bias

The quality of the included studies was overall fair (median PEDro score = 5, range 3–7; Table 2). One study showed poor methodological quality,²⁸seven had fair quality,^22–27,29and two were deemed to have a high quality.^30,31

F I G U R E 1 Flowchart of literature search

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TABLE1Maincharacteristicsoftheincludedstudies Study Samplesizebygroup afterrandomization Samplesizebygroupatthe endofthestudyParticipantsExerciseintervention Imaging procedureMainresults Joetal.23-HIIT(n=18) -MICT(n=19)

-HIIT(n=17) -MICT(n=17) Patients(51%men)withhypertension andmetabolicsyndrome(meanage, 51years)

-Modality:ET(treadmill;HIITor MICT). -Totalduration:8weeks -Frequency:3sessions/week -Durationpersession:30–40min -Intensity:HIIT,80%HRR(witha 3-minactiverecoverybetween intervalsat40%HRR);MICT,60% HRR

EchoHIIT:##EAT MICT:#EAT Christensenetal.31-HIIT(n=16) -RT(n=16) -Control(n=18)

-HIIT(n=14) -RT(n=13) -Control(n=12) Inactiveadults(26%men)with abdominalobesity(meanage, 38–47years).

-Modality:ET(cycling;HIIT)orRT -Totalduration:12weeks -Frequency:3sessions/week -Durationpersession:45min -Intensity:HIIT,75%–85%ofVO2 max;RT,60%–80%of1RM

MRIHIIT:#EAT RT:#EAT Control:No changeinEAT Joetal.24-Exergaming(n=22) -MICT(n=22) -Control(n=21)

-Exergaming(n=21) -MICT(n=13) -Control(n=13) Postmenopausalwomenwithhigh CVDrisk(meanage,57–63years).

-Modality:ET(treadmill walking/jogging,orExergaming; MICT) -Totalduration:12weeks -Frequency:7sessions/week -Durationpersession:40min -Intensity:Exergaming,HRof120 ±19bpm;MICT,60%–80%ofHRR EchoExergaming:# EAT MICT:#EAT Control:No changeinEAT Fernandez-del-Valle etal.27-RT(n=6) -Control(n=6)

-RT(n=6) -Control(n=5)

Obesewomen(meanage,24years)-Modality:RT -Totalduration:3weeks -Frequency:3sessions/week -Durationpersession:50min -Intensity:7exercises,3setsof10 repetitionsperexercise(70%–75% of1RM)

MRIRT:#EAT Control:No changeinEAT Bairapareddyetal.29-MICT(n=85) -Control(n=85)

-MICT(n=66) -Control(n=64) Overweightandobesepeople(39% men;meanage,31years).

-Modality:ET(treadmill;MICT) -Totalduration:12weeks -Frequency:≥3sessions/week -Durationpersession:40–60min -Intensity:40%–60%ofHRR EchoMICT:#EAT Control:No changeinEAT Honkalaetal.25-HIIT(n=23) -MICT(n=21)

-HIIT(n=23) -MICT(n=21) Physicallyinactivehealthymen(n=28) ormenwithdefectiveglucose tolerance(DGT)(n=16)(meanage, 47years).

-Modality:ET(cycling;HIITorMICT). -Duration:2weeks -Frequency:3sessions/week -Durationpersession:HIIT, 4–6×30s,with4minofrecovery betweensets;MICT,40–60min

CT-HIIT:#EAT -MICT:#EAT (Continues)

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TABLE1(Continued) Study Samplesizebygroup afterrandomization Samplesizebygroupatthe endofthestudyParticipantsExerciseintervention

Imaging procedureMainresults -Intensity:HIIT,all-out;MICT,60%OF VO2peak Kahletal.26-MICT(n=22) -Control(n=20)

-MICTgroup(n=20) -Controlgroup(n=10) Patients(60%men)withdepression (meanage,38–44years).

-Modality:ET(cycling+cross-trainer; MCIT) -Totalduration:6weeks -Frequency:3sessions/week -Durationpersession:45min -Intensity:50%ofthemaximum workload

MRIMICT:#EAT Control:No changeinEAT Rosetyetal.28-RT(n=12) -Control(n=12)

-RT(n=12) -Control(n=12) Obesewomen(meanage67years).-Modality:RT -Totalduration:12weeks -Frequency:3sessions/week -Durationpersession:Notreported -Intensity:40%–65%of1RM EchoRT:#EAT Control:No changeinEAT FornielesGonzález etal.30-MICT(n=30) -Control(n=30)

-MICT(n=30) -Control(n=30) Postmenopausalwomenwith metabolicsyndrome(meanage, 50years).

-Modality:ET(treadmill;MICT) -Totalduration:16weeks -Frequency:3sessions/week -Durationpersession:30–40min -Intensity:60%–75%ofpeakHR EchoMICT:#EAT Control:No changeinEAT Wilundetal.22-MICT(n=8) -Control(n=9)

-MICT(n=7) -Control(n=8) Haemodialysispatients(47%;mean age,60years) -Modality:ET(cycling;MICT) -Frequency:3sessions/week -Durationpersession:45min -Intensity:RPEof12–14ina6to20 scaleduration:16weeks EchoMICT#EAT Control:No changeinEAT Abbreviations:1RM,onerepetitionmaximum;CT,computedtomography;ET,endurance(‘aerobic’)exercisetraining;EAT,epicardialadiposetissue;Echo,echocardiography;HIIT,high-intensityintervaltraining; HR,heartrate;HRR,heartratereserve;MICT,moderate-intensitycontinuoustraining;MRI,magneticresonanceimaging;RT,resistancetraining;VO2peak,peakoxygenuptake.

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3.3 | Synthesis 3.3.1 | Overall effect

From the 10 included studies, eight22,24,26–31assessed the effects of exercise interventions compared to a non-exercise control group.

Data from seven studies22,24,26,27,29–31 (nine exercise interventions, n= 357) could be used for quantitative synthesis. Pooled analyses showed that physical exercise interventions significantly reduced EAT (Figure 2A,g= 0.82, 95% CI 0.57 to 1.07,p< 0.001) with no signs of heterogeneity (Q = 7.048, I² = 0%) or publication bias (Begg's p= 0.459, funnel plot available as Figure S1A). The effect remained significant in sensitivity analyses (allps < 0.001), as well as when removing the study (i.e., Bairapareddy et al.²⁹) with the greatest influence on the results (g= 0.96, 95% CI 0.68 to 1.23,p< 0.001). There was no association between the total duration of the intervention and the magnitude of the effect (p= 0.205) (Figure S2). The one study that could not be included in quantitative synthesis also reported a beneficial effect of exercise training over EAT.²⁸

3.3.2 | Exercise modality

Six studies (n= 287 participants) compared the effects of ET against a non-exercise control group,20,22,24,27–29

and pooled analysis confirmed the benefits of this exercise modality on EAT with no signs of heterogeneity (Figure 2B,g= 0.83, 95% CI 0.52 to 1.15,p< 0.001, Q = 4.158, I² = 0%, Begg's p = 0.354, funnel plot available as Figure S1B). The effect remained significant in sensitivity analyses (all ps < 0.001), as well as when removing the study with the greatest influence on the results (g= 1.02, 95% CI 0.69 to 1.35,p< 0.001).

There was no association between the total duration of the intervention and the magnitude of the effect (p= 0.162).

Three studies compared the effects of RT against a non-exercise control group.^27,28,31 Although all three studies found significant benefits, only two reported results that could be included in quantitative synthesis, and thus, it was not possible to conduct a meta-analysis of RT interventions. One study found a significant EAT reduction after an exergaming intervention, although the benefits over a non-exercise control group did not reach statistical significance.²⁴ Two studies compared the effects of HIIT versus MICT,^23,25 with one finding superior benefits with HIIT²³ and the other reporting no differences.²⁵ One study compared the effects of ET and RT and found no differences.³¹

3.3.3 | EAT assessment method

Exercise benefits on EAT were confirmed in separate analyses of those studies that used either MRI (g= 0.64, 95% CI 0.22 to 1.05, p= 0.002,Q= 0.587,I²= 0%, Begg'sp= 0.367) or echocardiography for EAT quantification (g= 0.97, 95% CI 0.58 to 1.36, p< 0.001, Q= 2.938,I²= 0%, Begg'sp= 0.403).

4 | D I S C U S S I O N

This systematic review and meta-analysis of RCTs shows that short- to middle-term supervised physical exercise interventions (2 to 16 weeks,≥3 sessions per week) result in significant and large reductions in EAT among individuals who had, on average, overweight or obesity (Figure 3). Given that excess EAT represents a CVD risk factor per se,^5,6,8,9the present results provide further support to the overall beneficial effects of physical exercise on cardiovascular health.³⁷A previous meta-analysis assessed the combined effects of different weight-loss strategies—physical exercise, diet and bariatric T A B L E 2 Methodological quality of the included studies

Items

Study 1 2 3 4 5 6 7 8 9 10 11 Total score^a

Jo et al.²³ + + ? + − − − + − + + 5

Christensen et al.³¹ + + + + − − + − + + + 7

Jo et al.²⁴ + + ? + − − − + − + + 5

Fernandez-del-Valle et al.²⁷ + + ? + − − − − − + + 5

Bairapareddy et al.²⁹ + + ? + − − − + − + + 5

Honkala et al.²⁵ + + − − − − − + − + + 4

Kahl et al.²⁶ + + ? + − − − + − + + 5

Rosety et al.²⁸ + + ? + − − − + − − − 3

Fornieles González et al.³⁰ + + + + − − − + − + + 6

Wilund et al.²² + + ? + − − − + − − + 4

Note: Column numbers correspond to the following criteria on the PEDro scale: 1, eligibility criteria were specified; 2, subjects were randomly allocated to groups; 3, allocation was concealed; 4, groups were similar at baseline; 5, subjects were blinded; 6, therapists who administered the treatment were blinded; 7, assessors were blinded; 8, measures of key; outcomes were obtained from more than 85% of subjects; 9, data were analysed by intention to treat; 10, statistical comparisons between groups were conducted; 11, point measures and measures of variability were provided.

aA total score out of 10 is determined from the number of criteria that are satisﬁed, except for Item 1 (which is not used to generate the total score).

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F I G U R E 2 Effects of physical exercise on epicardial adipose tissue. Reduction of epicardial adipose tissue with physical exercise interventions in general (endurance training [ET], resistance training [RT] or exergaming) (A) and with ET in particular (B), compared with a control group.

Results are shown as Hedges'galong with 95% confidence interval (CI)

F I G U R E 3 Summary of study findings. Results are shown as Hedges'galong with 95% confidence interval (CI). Abbreviations: RCTs, randomized controlled trials

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surgery—on EAT, reporting an overall benefit (standardized difference = 1.12, 95% CI 0.54 to 1.71), which was slightly superior to the one found here for physical exercise alone.²¹However, only three studies (n= 43 participants) were included (of which only one was an RCT), whereas here we included 10 exercise RCTs (n= 521). A recent systematic review³² of both RCTs and non RCTs—including studies of exercise intervention alone or combined with diet—reported a reduction of EAT (standardized difference = 0.57, 95% CI 0.18 to 0.97).³²These results were based on five studies that did not include three RCTs meta-analysed here.^22,24,27Thus, to our knowledge, ours is the first and largest meta-analysis to assess the effects of exercise alone on EAT based solely on RCTs, which is expected to provide the highest level of evidence.

According to Rabkin et al.,²¹ the magnitude of weight loss— together with the type of intervention—explains up to 71% of the variance in the reduction of EAT. These authors found a significant association between the magnitude of weight loss and that of EAT reduction for both dietary interventions and bariatric surgery, but not for exercise training. Meta-analytic evidence supports the weight-loss reducing effects of exercise interventions.^38,39However, these effects seem to be overall modest (2 kg for interventions lasting six to 12 months) and heterogeneous, and for this reason, the effectiveness of exercise interventions for inducing clinically meaningful total weight reductions in overweight/individuals with obesity has been questioned.^39,40On the other hand, hypocaloric diets can induce a larger weight loss than exercise training, but the latter tends to result in greater reductions of visceral adipose tissue (VAT).³⁸ Moreover, exercise seems to induce a larger reduction of EAT than bariatric surgery despite resulting in a lower weight loss.⁴¹ Importantly, as opposed to caloric restriction, exercise training can reduce VAT (by6%) in the absence of weight loss.³⁸

Although the benefits of physical exercise on EAT could only be confirmed in separate analyses for ET and not for RT interventions, preliminary evidence supports the benefits of the latter exercise modality.^27,28,31 For instance, Christensen et al.³¹ reported EAT reductions of 32% and 24% on average after 12 weeks of ET and RT, respectively, with no significant differences between conditions.

Fernandez del Valle et al. found a significant reduction in EAT (by 11.3%) in women with obesity after an RT intervention of only 3-week duration.²⁷ On the other hand, controversy exists on the potential superiority of ET over RT for the promotion of weight loss, with some studies reporting larger benefits with the former⁴² and other finding no differences.⁴³A meta-analysis reported similar benefits for both ET and RT on VAT in adults with overweight.⁴³Of note, programmes including RT seem to provide larger benefits on other health markers such as lean body mass or muscle strength, and thus, the combination of both exercise training modalities might be an opti- mal strategy.^42–44 Further evidence is therefore needed to confirm the effects of different exercise modalities (particularly RT) on EAT.

Regarding ET subtypes, more evidence is needed on the differences between MICT and HIIT for the reduction of EAT. Although Jo et al.²³recently reported that the latter could induce larger benefits (EAT loss of 10.9% vs. 19.6%, respectively), other authors observed

no differences between these training methods.²⁵Some studies sug- gest that HIIT might be a more effective⁴⁵—or at least more effi- cient⁴⁶—strategy than MICT for reducing overall fat mass, and higher exercise intensities induce larger reductions in abdominal, subcutaneous, and VAT than lower ones.⁴⁷However, more research is needed to determine which is the most effective ET subtype, MICT or HIIT, for EAT reduction.

Further evidence is also needed to compare the exercise training effects on EAT with those of other lifestyle interventions such as calo- rie restriction or with those induced by more‘aggressive’strategies such as drugs and bariatric surgery. A recent meta-analysis concluded that physical exercise might be more effective than pharmacological interventions (at least when expressed relative to the magnitude of body weight loss) for reducing VAT.⁴⁸ Both drugs (glucagon-like peptide-1 and receptor agonists, or long acting insulin analogue, recombinant hormone)^20,49,50 and bariatric surgery⁵¹ have been reported to produce large reductions (36%⁴⁹ and 27%,⁵¹ respectively) in EAT, but they are not free of potential complications. By contrast, exercise interventions are associated with minimal adverse effects (mainly musculoskeletal problems after exhaustive running or weight lifting). For this reason, clinicians should be encouraged to rec- ommend lifestyle interventions and particularly exercise programmes as a safe, effective strategy for the reduction of EAT and the overall improvement of cardiovascular health.

Several physiological mechanisms support the beneficial effects of exercise-induced reductions of EAT on cardiovascular health.

Excess levels of EAT are associated with an increased release of pro-inflammatory adipokines,¹⁷which can promote the development of atherosclerosis and other cardiovascular complications.^18,19 In turn, endurance exercise is not only associated with a reduced EAT—as confirmed in the present meta-analysis—but also with a reduced concentration of adipokines that can be released from EAT such as resistin.⁵²^–⁵⁴ Moreover, physiological levels of EAT have been reported to display the cardioprotective functions that are characteristic of brown adipose tissue (e.g., thermogenesis, lipid storage preventing atherosclerotic plaque development).^55,56 Thus, the reduction of EAT down to normal levels might be one of the different mechanisms by which physical exercise helps to prevent CVD.

It must be noted that a large heterogeneity was found across studies in terms of the type of participants/patients they assessed.

Thus, although most study participants had overweight or obesity, the included studies analysed individuals with and without associated cardiometabolic comorbidities (e.g., metabolic syndrome and defective glucose tolerance), or even patients undergoing haemodialysis²² or with depressive disorders.²⁶ The intervention characteristics also appeared to differ across studies, with different durations (2 to 16 weeks) and exercise modalities (MICT, HIIT, RT or exergaming) reported. However, no heterogeneity was found in the meta-analysis results (I²= 0% for all the meta-analyses performed), and meta-regression showed no association between the studies' duration and the magnitude of the benefits, which suggests that despite the abovementioned differences in sample or intervention

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characteristics, exercise resulted similarly beneficial for EAT reduction. Indeed, all of the individual studies reported a significant reduction in EAT from baseline to post-intervention,²²^–³¹ and even very short interventions (2–3 weeks) have been reported to provide meaningful beneficial effects (5%–11%) on EAT.^25–27 Further evidence is however warranted to assess the specific influence of differences in participant or intervention characteristics on the effects of exercise in EAT.

The present study has some limitations, notably the lack of a prospective registration—which can be viewed as a potential bias— and the abovementioned heterogeneity found between studies in terms of participants' characteristics or type of exercise interventions. Moreover, the fact that the present meta-analytical findings were based on aggregate data instead of individual participant data might potentially limit their validity. The present findings should be therefore considered exploratory, and large RCTs and individual participant data meta-analyses are needed to confirm the present conclusions—particularly regarding the effect of different types and durations of exercise interventions on EAT. Moreover, analyses were conducted using a random effects model, and because the included studies reported results in different units, our meta-analysis results were presented as standardized differences, which precludes us from drawing strong conclusions on the actual clinical importance of our findings.⁵⁷Finally, in the present study, we did not report exercise effects on pericardial adipose tissue (PAT, the fact deposit between visceral and parietal pericardium, with close proximity to coronary arteries). This is an important question because PAT has been suggested to be a stronger indicator of CVD risk than EAT,⁵⁸and it might also be reduced with exercise training.^25,31 Future research should thus determine how do the benefits observed here for EAT compare to the exercise effects on PAT.

5 | C O N C L U S I O N S

Supervised physical exercise interventions (2 to 16 weeks,≥3 sessions per week) reduces EAT in patients with overweight/obesity. These results were separately confirmed for ET and were independent of the EAT assessment method or the intervention duration.

Although further evidence is needed to determine which is the most effective exercise modality as well as to confirm the clinical relevance of exercise-induced EAT reductions in the long-term, the present results support the implementation of supervised exercise programmes—particularly ET—in individuals with an unfavourable cardiometabolic profile.

A C K N O W L E D G E M E N T

We would like to express our appreciation to Dr. Fernandez-del-Valle (Department of Applied Health, Southern Illinois University Edwardsville USA) for providing the required data.

C O N F L I C T O F I N T E R E S T

The authors declare no conflict of interest.

A U T H O R S ' C O N T R I B U T I O N S

Gonzalo Saco-Ledo, Pedro L. Valenzuela and Alejandro Lucia were responsible for the study concept and design, methodology and supervision, interpretation of data and drafting of the manuscript.

Pedro L. Valenzuela was responsible for statistical analysis. All authors were responsible for the critical revision of the manuscript for important intellectual content. All authors approved the final version of the manuscript.

D A T A A C C E S S , R E S P O N S I B I L I T Y A N D A N A L Y S I S

G.S.L. and P.L.V. had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

F U N D I N G I N F O R M A T I O N

The work of Pedro L. Valenzuela is supported by University of Alcalá (FPI2016). Research by Alejandro Lucia is funded by Instituto de Salud Carlos III (Ministerio de Ciencia, Innovación y Universidades, Spain) (PI18/00139) and FEDER funds from the European Union.

O R C I D

Alejandro Lucia https://orcid.org/0000-0002-5565-0997

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S U P P O R T I N G I N F O R M A T I O N

Additional supporting information may be found online in the Supporting Information section at the end of this article.

How to cite this article:Saco-Ledo G, Valenzuela PL, Castillo- García A, et al. Physical exercise and epicardial adipose tissue:

A systematic review and meta-analysis of randomized controlled trials.Obesity Reviews. 2021;22:e13103.https://

doi.org/10.1111/obr.13103