This meta‐analysis showed that exercise significantly improved cardiorespiratory fitness and some cardiometabolic biomarkers. The effects of exercise were modified by age, sex, and health status. Findings from this study have significant implications for future design of targeted lifestyle interventions.

Two researchers selected 160 randomized controlled trials (7487 participants) based on literature searches of Medline, Embase, and Cochrane Central (January 1965 to March 2014). Data were extracted using a standardized protocol. A random‐effects meta‐analysis and systematic review was conducted to evaluate the effects of exercise interventions on cardiorespiratory fitness and circulating biomarkers. Exercise significantly raised absolute and relative cardiorespiratory fitness. Lipid profiles were improved in exercise groups, with lower levels of triglycerides and higher levels of high‐density lipoprotein cholesterol and apolipoprotein A1. Lower levels of fasting insulin, homeostatic model assessment–insulin resistance, and glycosylated hemoglobin A1c were found in exercise groups. Compared with controls, exercise groups had higher levels of interleukin‐18 and lower levels of leptin, fibrinogen, and angiotensin II. In addition, we found that the exercise effects were modified by age, sex, and health status such that people aged <50 years, men, and people with type 2 diabetes, hypertension, dyslipidemia, or metabolic syndrome appeared to benefit more.

Guidelines recommend exercise for cardiovascular health, although evidence from trials linking exercise to cardiovascular health through intermediate biomarkers remains inconsistent. We performed a meta‐analysis of randomized controlled trials to quantify the impact of exercise on cardiorespiratory fitness and a variety of conventional and novel cardiometabolic biomarkers in adults without cardiovascular disease.

Introduction

Cardiovascular disease (CVD) remains a leading cause of morbidity and mortality affecting ≈84 million people in the United States.1, 2, 3 Current guidelines recommend exercise for both primary and secondary prevention of CVD.4, 5, 6 Observational studies have associated exercise with lower CVD risk in populations free of preexisting CVD.7, 8, 9 Substantial evidence from secondary prevention studies also confirms better survival and reduced CVD recurrence after exercise interventions.10, 11 Because of apparent ethical and feasibility issues, however, no long‐term randomized controlled trials (RCTs) have directly investigated the benefits and risks of exercise training in relation to CVD incidence.12 Consequently, exercise interventions among healthy populations have focused on intermediate CVD biomarkers. Changes in circulating CVD biomarkers and cardiorespiratory fitness (CRF) are reasonable indicators for the favorable effects of exercise training on cardiovascular health.

An important component of health‐related fitness, CRF refers to the capacity of respiratory and cardiovascular systems to provide muscles with oxygen during sustained and/or intense exercise. Available evidence has shown that CRF can significantly improve the predictive ability of both short‐ and long‐term CVD risk when added to traditional risk factors.13 In addition to serving as a diagnostic and prognostic health indicator in clinical settings, CRF has been used as an indicator of habitual exercise.14, 15

Traditional CVD biomarkers, such as non–high‐density lipoprotein cholesterol and high‐sensitivity C‐reactive protein, may also have the potential to be used in CVD risk prediction.16, 17, 18, 19 Although most previous studies examining the relationship between exercise and circulating biomarkers focus on commonly measured CVD biomarkers, an increasing number of studies are evaluating novel biomarkers.20, 21 Evidence has implicated, for example, relevant biomarkers in insulin resistance and inflammation that contribute to CVD development.22, 23, 24, 25, 26

Nevertheless, much remains uncertain concerning the effects of exercise on both traditional and novel CVD biomarkers for targeted interventions and clinical evaluations.20, 21, 27 The primary objective of this meta‐analysis was to assess the effects of exercise training on CRF and a variety of both traditional and novel circulating CVD biomarkers. Furthermore, we aimed to investigate the sources of heterogeneity, especially by potential effect modifiers such as age, sex, obesity, lifestyle, preexisting conditions (type 2 diabetes, hypertension, hyperlipidemia, or metabolic syndrome), and intervention duration and intensity.

Methods

Data Sources and Searches

We developed and followed a standardized protocol to do this meta‐analysis in accordance with the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) guidelines.28 Two investigators (X.L., X.Z.) independently conducted literature searches of Medline, Embase, and the Cochrane Central Register of Controlled Trials published from January 1965 (index date) to March 2014, using keywords and Medical Subject Headings (Table 1). All relevant studies and review articles (including meta‐analysis) and the reference lists of the identified articles were checked manually. Any disagreements between 2 investigators were resolved by consensus. Institutional review board approval is not applicable because the current study is a systematic review and meta‐analysis, which is not considered research involving human subjects.

Table 1. Search Strategy for Medline 1. exp Exercise/ 2. physical activity.ab. 3. aerobic*.ab. 4. or/1 to 3 5. exp Biological Markers/ 6. Exercise Tolerance/ 7. Exercise Test/ 8. exp Oxygen Consumption/ 9. Physical Fitness/ 10. or/5 to 9 11. randomized controlled trial.pt. 12. controlled clinical trial.pt. 13. Randomized Controlled Trials/ 14. Random Allocation/ 15. Intervention Studies/ 16. or/11 to 15 17. 4 and 10 18. 17 and 16 19. limit 18 to English language 20. limit 19 to humans

Study Selection

Articles were included (1) if the study was an RCT that assigned at least 1 group of participants to exercise training and 1 group to control and (2) if CRF (absolute and relative maximal oxygen uptake) or circulating CVD biomarkers of lipid and lipoprotein metabolism, glucose intolerance and insulin resistance, systemic inflammation, or hemostasis were measured at baseline and at the end of the trial.

All abstracts about RCTs reporting the effect of exercise training on CVD‐related biomarkers or CRF were included for screening. We excluded studies (1) if the study design was not a RCT; (2) if the exercise intervention was acute (≤1 week), because we are interested in the effects of exercise interventions of moderate to long duration; (3) if interventions were based on education or counseling rather than a structured exercise training assignment; (4) if maximal oxygen consumption, or VO 2max , was indirectly calculated through heart rate or fixed time testing and no other biomarkers of interest to this study were reported; (5) if levels of circulating biomarkers were not directly measured; (6) if values of outcome measures at the end of trials were not reported; (7) if participants had severe chronic diseases (preexisting CVD, liver or kidney diseases, or cancers), any other conditions that could potentially compromise participants' capacity to exercise (disability, frailty, declined activities of daily living, or wheelchair dependency), or any mental conditions (depression, anxiety, schizophrenia, bipolar disorder, Parkinson's disease, or Alzheimer's disease); (8) if participants were identified as trained professionals, athletes, or soldiers; (9) if participants were infants, children, or adolescents; or (10) if participants were pregnant, postpartum, nursing, had recent surgery, or were undergoing rehabilitation exercise. If multiple articles were published based on the same trial, data were retrieved as 1 independent trial. If there were duplicate results from the same trial, the most updated and comprehensive ones were extracted.

Data Extraction and Quality Assessment

In total, 6135 articles were retrieved from the literature search. We excluded 5796 articles after abstract review and 170 after full‐text examination. Data extraction was conducted independently by 2 investigators (X.L., X.Z.), and discrepancies were resolved through consensus. The following information was extracted from all eligible studies: general information (first author's name, article title, and country of origin), study characteristics (study design, eligibility criteria, randomization, blinding, cointervention, dropout rate, and reason for dropping out), participant characteristics (age, sex, ethnicity, body mass index, life style, health status, and number of participants in each group), intervention and setting (exercise type, duration, intensity, and supervision), and outcome measures (definition of outcomes, statistical techniques, pre‐ and postintervention means, standard deviation, sample size of each arm, and adverse events). Maximal oxygen uptake VO 2max was measured directly and determined based on the highest VO 2 obtained prior to volitional fatigue. In this meta‐analysis, we focused on biomarkers in blood samples, including plasma, serum, and whole blood. All samples for fasting glucose and insulin measurement in the studies were collected after >10 hours of fasting.

Data Synthesis and Analysis

Methodological quality was assessed by 2 investigators (X.L., X.Z.) using the Cochrane Collaboration's tool for assessing risk of bias.29 This included random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective reporting, and other sources of bias. For each trial, the risk of bias was reported as low risk, unclear risk, or high risk. Disagreement was resolved by discussion. All eligible comparisons from each trial were extracted separately according to exercise intensity. The criteria for classifying exercise interventions as moderate exercise or vigorous exercise are summarized in Table 2. If the intensity measures were not reported in individual studies, maximum heart rate, maximum heart rate percentage, speed of running, metabolic equivalent, oxygen uptake, or relative metabolic rate were used to classify exercise intensity. To maintain independence, the most vigorous intervention and the control group in each trial were included in the primary analysis if multiple training groups of different intensities were compared with a single control group. Sensitivity analyses were performed by conducting separate analyses of all eligible comparisons for moderate and vigorous exercise interventions, respectively.

Table 2. Criteria Used for Exercise Intensity Classification Moderate Vigorous Maximum heart rate, beats/min <140 ≥140 Maximum heart rate, % <75 ≥75 Speed of running, m/s <6.8 ≥6.8 Metabolic equivalents Women: <6 Women: ≥6 Men: <8 Men: ≥8 Oxygen uptake (% of VO 2max ) <70 ≥70 Relative metabolic rate <8 ≥8

Mean levels and standard deviations of CRF and CVD biomarkers after the exercise interventions from individual trials were used to calculate weighted mean differences (WMDs) and 95% CIs using DerSimonian and Laird random‐effects models.30 Between‐study heterogeneity was examined using Q statistics and I2 statistics.31, 32 I2 ≈25%, 50%, and 75% is suggestive, respectively, of low, medium, and high heterogeneity. Egger's tests were used to formally test publication bias.33 If there was any evidence of publication bias, the trim and fill method was used to evaluate the impact of publication bias.34

All eligible trials were analyzed in subgroup analyses conducted within the strata of the predetermined potential modifiers, including age (mean or median <50 versus ≥50 years), sex (women versus men), body mass index (obese versus nonobese), lifestyle (active versus sedentary), health status (having at least 1 of the following comorbidities: type 2 diabetes, hypertension, hyperlipidemia, and metabolic syndrome versus none), and trial duration (≥16 versus <16 weeks). Obesity was defined as body mass index ≥30 kg/m2. Active lifestyle was defined according to the report of individual trials. Health status was confirmed by clinical diagnosis or reported medication use. Metaregressions were performed to evaluate the overall impact of potential modifiers.

Two‐sided P≤0.05 was used as the significance level except for the Q statistic and the Egger's tests (P=0.10).35 All statistical analyses were performed with Stata statistical software version 12 (Stata Corp).

Results

Figure 1 shows the number of trials included in the analysis for each outcome. A total of 7487 participants aged between 18 and 90 years, from 169 articles based on 160 RCTs, were included in the meta‐analysis. Characteristics of eligible studies are summarized in Table 3. Among all participants, 4276 (57.1%) were women; 3211 (42.9%) were men; 5845 (78.1%) were free of type 2 diabetes, hypertension, hyperlipidemia, or metabolic syndrome; and 1640 (21.9%) had at least 1 of those conditions. The median duration of trials was 12 weeks (range: 2 weeks to 2 years).

Table 3. Characteristics of the Trials Included in the Meta‐Analysis Study Age, y Sex BMI, kg/m2 Duration, wk Activity/Medical Condition Exercise Type, Intensity and Cointerventions N T /N C Marker Abderrahman, 201336 Mean: 20.6 Male only Mean: 22.8 7 NR/Health Running/Vigorous/No 9/6 Absolute CRF, Relative CRF Ahmaidi, 199837 53 to 74 NR NR 12 Sedentary/Health Walking/Jogging/Vigorous/No 11/11 Absolute CRF, Relative CRF Aldred, 199538 41 to 55 Female only T: 24.8±1.0 C: 26.8±0.8 12 Sedentary/Health Walking/Moderate/No 11/11 TC, HDL‐C2 LDL‐C, FFA Ashutosh, 199739 20 to 60 Female only Overweight or obesity 46 NR/Health Aerobic exercise/NR/Dietary intervention 9/6 Absolute CRF, Relative CRF Asikainen, 200240 48 to 63 Female only Mean: 26.2 24 Sedentary/Health Walking/Vigorous/No 20/38 Relative CRF Baker, 198641 Mean: 58.2 Male only NR 20 Sedentary/Health Aerobic training/Vigorous/No 20/14 Absolute CRF, Relative CRF, TC, HDL‐C, LDL‐C, VLDL‐C Balducci, 2010, 201242 C: 58.8±8.6 T: 58.8±8.5 NR C: 31.9±4.6 T: 31.2±4.6 52 Sedentary/Diabetes mellitus Aerobic and resistance training/Moderate/No 288/275 Relative CRF, TC, TG, HDL‐C, LDL‐C, CRP, Fasting glucose, Insulin, HOMA‐IR HbA1c Beavers, 201043 60 to 79 Female: 67% >28.0 78 Active/Health Walking and interactive, health education in control 97/93 Leptin Bell, 201044 Male: 49±11 Female: 50±9 NR Mean: 30 24 Sedentary/Health Walking/Moderate/No 43/45 Absolute CRF, Relative CRF, TC, TG, HDL‐C, LDL‐C, Fasting glucose Bermon, 199945 67 to 80 Male: 16 T: 24.9±0.5 C: 25.9±0.6 8 Sedentary/Health Strength training/Vigorous/No 16/16 IGF‐1, IGF‐BP Biddle, 201146 Mean: 34.8±12.6 Female 13 Mean: 36.3±6.7 4 Sedentary/Health Small‐sided games‐based exercise/NR/No 9/7 Absolute CRF, Relative CRF, TC, TG, HDL‐C, LDL‐C, CRP, Fasting glucose, HbA1c Blumenthal, 199147 60 to 83 Female: 50% NR 60 Sedentary/Health Aerobic exercise or yoga/Vigorous/No 15/15 Absolute CRF, Relative CRF Blumenthal, 199148 29 to 59 Male: 62% Mean: 26.9 16 NR/untreated mild hypertension Aerobic exercise training/Joging 39/22 Absolute CRF, Relative CRF Boardley, 200749 ≥65 Male: 27% NR 16 Sedentary/Health Resistance training and aerobic walking/Moderate/No 33/35 TC, TG, HDL‐C, LDL‐C Bobeuf, 201150 59 to 73 Female: 52.6% Mean: 26.2±2.6 24 Sedentary/Health Resistance training/Vigorous/Vitamins C/E supplementation 17/12 TC, TG, HDL‐C, LDL‐C Boreham, 200051 18 to 22 Female only NR 7 Sedentary/Health Stair climbing/Moderate/No 12/10 TC, HDL‐C Boudou, 200352 Mean: 45.4±7.2 Male only Mean: 29.6±4.6 8 NR/Diabetes mellitus Endurance exercise/Vigorous/No 8/8 Adiponectin, Leptin, Insulin Bourque, 199753 23 to 43 Female only Mean: 23.1±4.9 12 Sedentary/Health Endurance exercise/Vigorous/No 6/7 Relative CRF Braith, 199454 60 to 79 Female: 54.5% NR 24 Sedentary/Health Walking/Vigorous/No 14/11 Relative CRF Broeder, 199255 18 to 35 Male only Mean: 25.3 12 NR/Health Walk or jog/Vigorous/No 15/19 Relative CRF Broman, 200656 69±4 Female only NR 8 NR/Health In deep water running/Walking/Vigorous/No 15/9 Absolute CRF, Relative CRF Burr, 201157 Mean: 26 NR NR 6 Sedentary/Health Vehicle riding/Vigorous/No 34/12 Relative CRF, Fasting glucose Camargo, 200858 Mean: 29 Male only Mean: 27.3 12 Sedentary/Health Aerobic training/Moderate/No 7/7 Relative CRF Campbell, 200759 40 to 75 Female only 29.9 to 28.7 52 Sedentary/Health Aerobic Exercise/Moderate/No 17/15 Absolute CRF, Relative CRF, CRP Canuto, 201260 18 to 64 Female only Mean: 34.8 12 NR/Health Resistance training/Moderate/Education 29/30 TC, TG, HDL‐C, LDL‐C, CRP, Fasting glucose, Insulin, HbA1c Carroll, 201261 T: 39.3±7.8 C: 41.0±7.7 Female only T: 39.9±7.4 C: 41.0±7.7 12 Sedentary/Health Treadmill walking/Moderate/Lifestyle intervention 22/22 Absolute CRF, Relative CRF Chan, 201362 Mean: 54±11 Female only Mean: 31±7 10 Sedentary/Hypertension Treadmill walking/Vigorous/Education 10/13 Relative CRF, Chandler, 199663 60 to 79 Female: 38.6% NR 24 NR/Health Endurance training/Moderate/No 16/11 Relative CRF, PAI‐1 Cho, 201164 34 to 60 Female only Mean: 25.6 12 Sedentary/Health Walking/Moderate/No 13/10 Relative CRF,TG, HDL‐C FFA, Fasting glucose, Insulin, HOMA‐IR Christiansen, 201065 18 to 45 Female: 38 30 to 40 12 Sedentary/Health Aerobic exercise/Vigorous/Dietary intervention 21/19 Absolute CRF,TC, TG, HDL‐C, FFA, IL‐6, IL‐18, Adiponectin, Fasting glucose, Insulin, HOMA‐IR Church, 200766 45 to 75 Female only 25 to 43 24 Sedentary/Health Aerobic exercise/Moderate/No 103/102 Absolute CRF, relative CRF, TG, HDL‐C, LDL‐C, Fasting glucose Ciolac, 201167 20 to 30 Female only Mean: 23.78 16 Sedentary/Health Endurance exercise/Vigorous/No 11/12 Relative CRF,TC, TG, HDL‐C, LDL‐C, Fasting glucose, Insulin, HOMA‐IR Coker, 200968 65 to 90 Female: 50% 26 to 37 12 NR/Health Cycle ergometer/Moderate/No 6/6 Absolute CRF Cortez‐Cooper, 200869 40 to 80 Female: 73.8% <30 13 Sedentary/Health Aerobic exercise strength training vs stretching/Moderate/No 12/12 Relative CRF,TC, TG, HDL‐C, LDL‐C, Endothelin‐1, Fasting glucose Cox, 199370 20 to 45 Male only Mean: 26.3 (25.7 to 26.9) 4 Sedentary/Health Not report/Vigorous/Drink low‐alcohol beer or continue their normal drinking habits 19/16 TC, TG, HDL‐C, HDL‐C2, HDL‐C3, LDL‐C, Apo AI, Apo AII, Apo B Cox, 200371 Mean: 42.4±5.0 Male only Overweight or obesity 16 Sedentary/Hypertension NR/Moderate & vigorous/Dietary intervention and usual dietary 13/17 Absolute CRF Dalleck, 200972 45 to 75 year Female only Normal 12 Sedentary/Health NR/Moderate/No 8/10 Absolute CRF, Relative CRF,TC, TG, HDL‐C, LDL‐C, Fasting glucose De Vito, 199973 60 to 70 Female only NR 12 Sedentary/Health Walking/Moderate/No 11/9 Absolute CRF, Relative CRF Dimeo, 201274 42 to 78 Female: 58% Mean: 29.4 12 NR/Hyperlipidemia Walking on a treadmill/NR/No 22/25 Relative CRF Dipietro, 200675 62 to 84 Female only Mean: 27.3 36 Sedentary/Health Aerobic training/Moderate/No 9/7 Relative CRF,FFA, Fasting glucose, Insulin Duncan, 199176 20 to 40 Female only NR 24 Sedentary/Health Walk/Moderate/No 12/13 Relative CRF,TC, TG, HDL‐C, LDL‐C Duscha, 200577 40 to 65 NR 25 to 35 36 NR/Hyperlipidemia Walking/Moderate/No 25/37 Absolute CRF, Relative CRF Eguchi, 201278 20 to 65 Female only Mean: 25.1±3.9 12 NR/Health Endurance training using bicycle ergometers/Moderate/No 8/10 Absolute CRF, Relative CRF,TC, TG, HDL‐C, LDL‐C, Fasting glucose, HbA1c Fatouros, 200579 65 to 78 Male only 28.7 to 30.2 24 Sedentary/Health Resistance exercises/Moderate/No 12/10 Relative CRF, Adiponectin, Leptin, Fasting glucose, HOMA‐IR Finucane, 201080 67.4 to 76.3 Female: 44% Mean: 27.2 12 NR/Health Cycle ergometer/Moderate/No 48/48 TC, TG, HDL‐C, LDL‐C, Fasting glucose, HbA1c Friedenreich, 201181 50 to 74 Female only 22 to 40 52 Sedentary/Health Aerobic exercise/Vigorous/No 154/154 Adiponectin, Leptin, Fasting glucose, Insulin, HOMA‐IR, IGF‐1, IGF‐BP Garber, 199282 24 to 50 Female: 75% NR 8 Sedentary/Health Walk‐jog/Moderate/No 13/9 Relative CRF Geogiades, 200083 ≥29 Female: 44% 25 to 37 24 Sedentary/Hypertension Aerobic exercise/Vigorous/No 36/19 Relative CRF Gormley, 200884 18 to 31 Female: 65.5% Mean: 24.3 6 Sedentary/Health Aerobic/Moderate/No 14/13 Relative CRF Gram, 201085 25 to 80 Female: 45.6% NR 52 NR/Diabetes mellitus Strength training and aerobic exercise/Moderate/No 21/20 Absolute CRF,TC, HDL‐C, LDL‐C, HbA1c Grandjean, 199686 NR Female only NR 24 Sedentary/Health Walking and jog and cycling/Vigorous/No 20/17 Absolute CRF,TC, TG, HDL‐C, LDL‐C, VLDL‐C Gray, 200987 18 to 65 Female: 77% Mean: 28.6 12 Sedentary/Health Pedometer‐based walking/Moderate/No 24/24 CRP, IL‐6, TNF‐α, Fasting glucose, Insulin, HOMA‐IR Guadalupe‐Grau, 200988 Mean: 23.9±2.4 Female: 34.8% C: 24.0±3.6 T: 22.8±2.0 9 Active/Health Strength combined with plyometric jumps training/Vigorous/No 8/15 Leptin Hagan, 198689 Mean: 36.6 Female: 50% Normal 12 Sedentary/Health Aerobic training/Moderate/Dietary training 12/12 Absolute CRF, Relative CRF,TC, TG, HDL‐C, LDL‐C, VLDL‐C Hass, 200190 35 to 55 Female: 50% NR 12 Sedentary/Health NR/Moderate/No 17/9 Absolute CRF, Relative CRF Hendrickson, 201091 18 to 26 Female only NR 12 Active/Health Aerobic endurance and strength training/Vigorous/No 13/10 Relative CRF Heydari, 201392 Mean: 24.9±4.3 Male only Mean: 28.7±3.1 12 Sedentary/Health High‐intensity intermittent exercise/Vigorous/No 20/18 Absolute CRF, Relative CRF Heydari, 201392 Mean: 24.9±4.3 Male only Mean: 28.7 12 Active/Health High‐intensity intermittent exercise/Vigorous/No 25/21 Absolute CRF, Relative CRF Hilberg, 201393 T: 49±6 C: 48±6 Male only NR 12 NR/Health NR/Vigorous/No 22/22 Relative CRF Hiruntrakul, 201094 18 to 25 Male only C: 21.35±3.54 T: 20.99±3.35 12 Sedentary/Health Aerobic exercise/Moderate/No 19/18 Relative CRF, HDL‐C Ho, 201295 40 to 66 Female: 83.5% 25 to 40 12 Sedentary/Health Aerobic resistance training/Moderate/No 15/16 Relative CRF, TC, TG, HDL‐C, LDL‐C, Fasting glucose, Insulin Hu, 200996 20 to 45 Male only NR 10 Sedentary/Health Progressive strength training/Moderate/No 48/21 Absolute CRF, Relative CRF, Huttunen, 197997 40 to 45 Male only NR 16 Sedentary/Health Walking, Jogging, Swimming, Skiing, or Cycling/Moderate/No 44/46 Relative CRF, HDL‐C, Apo AI, Apo AII Tsuji, 200098 60 to 81 Female: 53% NR 25 Active/Health Endurance session with a bicycle ergometer, and a resistance exercise training session using rubber films/Moderate/Education 31/33 Relative CRF Irwin, 201299 59 to 86 Female: 61% NR 9 Sedentary/Health Tai Chi Chih vs health education/Moderate/No 46/37 CRP, IL‐6, IL‐18 Larose, 2011100 39 to 70 Female 36.2% Mean: 34.9 24 Sedentary/Diabetes mellitus Aerobic or resistance training/Vigorous/No 60/63 Relative CRF, HbA1c Jessup, 1998101 61 to 77 Female: 52% NR 16 Sedentary/Health Treadmills and stair‐climbers/Vigorous/No 11/10 Relative CRF Kadoglou, 2012102 Mean: 61.3±2.1 Female: 67.6% T: 32.74±4.05 C: 31.58±5.71 12 NR/Diabetes mellitus Resistance Exercise/Vigorous/No 23/24 Relative CRF, TC, TG, HDL‐C, LDL‐C, Fasting glucose, Insulin, HOMA‐IR, HbA1c, Fibrinogen Karstoft, 2013103 C: 57.1±3.0 T: 60.8±2.2 Female: 31% NR 16 NR/Diabetes mellitus Walking/Moderate/No 12/8 Absolute CRF, Relative CRF,TC, TG, HDL‐C, LDL‐C, Fasting glucose, Insulin, HbA1c King, 1989104 Male 49±6 Female 47±5 Female: 50% NR 24 Sedentary/Health Aerobic/Exercise/Training/Moderate/No 29/28 Relative CRF Kirk, 2003105 19 to 30 Male only 27 to 32 36 Sedentary/Health Aerobic exercise/Moderate/No 16/15 Absolute CRF, Relative CRF Kirk, 2003105 19 to 30 Female only 27 to 32 36 Sedentary/Health Aerobic Exercise/Moderate/No 25/18 Absolute CRF, Relative CRF Kiviniemi, 2007106 T: 31±6 C 35±8 Male only T: 24±2 C: 25±1 4 Active/Health Running/Vigorous/No 9/10 Absolute CRF, Relative CRF Kokkinos, 1998107 35 to 76 Male only T: 30±4 C: 31±5 16 Sedentary/Hypertension Aerobic/Exercise/Moderate/No 15/19 TC, TG, HDL‐C, HDL‐C2, HDL‐C3, LDL‐C, Apo AI, Apo B Kraemer, 1997,108 1999109 Mean: 35.4±8.5 Female only C: 28.2±4.0 T: 28.3±4.2 12 NR/Health Aerobic endurance exercise/Vigorous/Dietary intervention 9/8 Absolute CRF, Relative CRF, TG, Fasting glucose Krogh, 2012110 18 to 60 Female: 67% NR 12 NR/Health Aerobic exercise/Vigorous/No 56/59 Relative CRF, TC, TG, HDL‐C, Fasting glucose, Insulin Krustrup, 2009111 20 to 43 Male only Mean: 25.7 12 Sedentary/Health Recreational soccer/Vigorous/No 12/10 Relative CRF, TC, HDL‐C, LDL‐C,Absolute CRF, CRP, Fasting glucose, Insulin Kukkonen‐Harjula, 1998112 31 to 52 Female: 53% 18.5 to 32.7 15 Sedentary/Health Walking/Training/Moderate/No 58/58 Absolute CRF, Relative CRF, Fibrinogen Kurban, 2011113 T: 53.77±8.2 C: 53.57±6.6 Female: 51.7% T: 30.90±4.64 C: 30.23±4.74 12 Sedentary/Diabetes Mellitus Walking/Moderate/No 30/30 Fasting glucose, HbA1c Laaksonen, 2000114 20 to 40 Male only Mean: 24.4 16 Active/Diabetes mellitus Sustained running/Moderate/No 20/22 Relative CRF, TC, TG, HDL‐C, LDL‐C, Apo AI, Apo B, HbA1c Labrunee, 2012115 Mean: 52.7±8.2 Female: 82.6% Mean: 38.5±7.6 12 NR/Diabetes mellitus Cyclergometer training/NR/No 11/12 Relative CRF, TC, TG, HDL‐C, LDL‐C, Fasting glucose, HOMA‐IR, HbA1c Lake, 1996116 18 to 28 Male only NR 6 Active/Health Running training/Moderate/No 8/7 Relative CRF LaPerriere, 1994117 18 to 40 Male only NR 10 Sedentary/Health Aerobic exercise/Vigorous/No 7/7 Relative CRF Lee, 2003118 18 to 30 Male only NR 2 Sedentary/Health Cycle ergometer/Vigorous/No 12/12 Relative CRF Lee, 2012119 30 to 50 Female only ≥25 14 NR/Health NR/Moderate/No 8/7 Relative CRF, TC, TG, HDL‐C, LDL‐C, CRP, IL‐6, TNF‐α LeMura, 2000120 Mean: 20.4±1 Female only T: 20.8±2.1 C: 21.8±2.3 16 Sedentary/Health Resistance training and aerobic training/Vigorous/No 10/12 Relative CRF,TC, TG, HDL‐C, LDL‐C Libardi, 2012121 T 48.6+5.0 C 49.1+5.5 Male only T: 27.5+4.1 C: 24.7+3.3 24 Sedentary/Health Resistance training/Moderate/No 12/13 Relative CRF, TC, TG, HDL‐C, LDL‐C, CRP, IL‐6, TNF‐α, Fasting glucose de Lima, 2012122 20 to 35 Female only C: 23.0±2.4 T: 22.8±3.6 12 Sedentary/Health Muscular endurance/Moderate/No 10/8 Relative CRF Lovell, 2011123 70 to 80 Male only NR 20 Active/Health Cycle ergometer and stretching/Vigorous/No 12/12 Absolute CRF, Relative CRF Martin, 1990124 T: 58.6±4.6 C 60.6±7.4 Female only NR 12 Sedentary/Health Cycle ergometer training/Vigorous/No 14/14 Absolute CRF, Relative CRF McAuley, 2002125 25 to 70 Female: 67% <27 16 NR/Health NR/Moderate/Dietary intervention 29/23 TC, TG, HDL‐C, LDL‐C, Fasting glucose, Insulin Meckling, 2007126 20 to 62 Female only 25 to 30 12 NR/Health Resistance training and endurance training/Moderate and vigorous/Dietary intervention or high protein 11/8 TC, TG, HDL‐C, Fasting glucose, Insulin Meyer, 2006127 30 to 60 Female: 47% NR 12 Sedentary/Health Walking or running/Vigorous/No 12/13 Relative CRF Miyaki, 2012128 Mean: 60±6 Female only NR 8 Sedentary/Health Walking and cycling/Moderate/No 11/11 Relative CRF, TC, TG, HDL‐C, LDL‐C, Fasting glucose Morey, 2012129 60 to 89 Female: 3% 25 to 45 kg/m2 52 NR/Health Enhanced fitness intervention/NR/No 180/122 TC, TG, HDL‐C, LDL‐C, Fasting glucose, Insulin, HOMA‐IR HbA1c Morgan, 2010130 50 to 70 Females: 73.3% NR 15 Sedentary/Health Walk/Moderate/No 14/15 TC, HDL‐C Morton, 2010131 T: 61+10 C: 63+9 Females: 22.2% T: 32+7 C: 30.9+7.0 7 Sedentary/Diabetes mellitus Walking/Vigorous/No 15/12 Absolute CRF, Relative CRF, Fasting glucose, HbA1c Murphy, 2006132 Mean: 41.5±9.3 Female: 64.9% T: 26.8±5.6 C: 24.4±3.6 8 Sedentary/Health Walking/Moderate/No 21/12 TC, TG, HDL‐C, LDL‐C, CRP Murtagh, 2005133 Mean: 45.7±9.4 Female: 64.6% <30 12 Sedentary/Health Walking/Vigorous/No 18/11 Relative CRF, TC, TG, HDL‐C, LDL‐C Musa, 2009134 21 to 36 Male only Normal 8 Sedentary/Health Interval running/Moderate/No 20/16 TC, HDL‐C Nemoto, 2007135 Mean: 63±6 Female: 75.6% C: 22.8 T moderate: 22.8 vigorous: 22.9 20 NR/Health Walking/Moderate/No 43/37 Absolute CRF Nicklas, 2009136 50 to 70 Female only 25 to 40 20 Sedentary/Health Calorie restriction and aerobic exercise/Moderate/dietary intervention 36/29 TG, HDL‐C, LDL‐C, Fasting glucose, Insulin Niederseer, 2011137 T: 66.6±2.1 C: 67.3±4.4 Female: 47.6% T: 27.1±3.3 C: 25.4±2.8 12 Active/Health Skiing/Moderate/No 22/20 Relative CRF, TC, TG, HDL‐C, LDL‐C, CRP VCAM‐1, ICAM‐1, Endothelin‐1, e_selectin Nieman, 1993138 67 to 85 Female only Mean: 23.7 12 Sedentary/Health Walk/Moderate/No 14/16 Relative CRF, TC, TG, HDL‐C, LDL‐C, Nieman, 1998139 Mean: 45.6±1.1 Female only Mean: 33.1±0.6 12 Active/Health Walking/Moderate and vigorous/dietary intervention 22/26 Absolute CRF, TC, Fasting glucose Nordby, 2012140 20 to 40 Male only 25 to 30 12 Sedentary/Health Endurance training (cycling, running, cross‐training, or rowing)/Moderate/Dietary intervention 12/12 Absolute CRF, Relative CRF, Fasting glucose, Insulin, HbA1c O'donovan, 2005141 30 to 45 Male only NR 24 Sedentary/Health NR/Moderate/No 14/15 Absolute CRF, Relative CRF, TC, TG, HDL‐C, LDL‐C, Fibrinogen Panton, 1990142 Pollock, 1991143 70 to 79 Female: 53.1% NR 24 Sedentary/Health Aerobic and resistance training/NR/No 13/15 Relative CRF Phillips, 2012144 62 to 67 Female only Overweight or Obesity 12 Active/Health Aerobic training/Vigorous/No 11/12 Leptin Poehlman, 2000145 18 to 35 Female only C: 22±2 T: 22±2 24 Sedentary/Health Endurance training (N=14), resistance training/Vigorous/No 14/20 Absolute CRF Posner, 1992146 60 to 86 Female: 61.9% NR 16 Sedentary/Health Cycle ergometer/Moderate/No 166/81 Absolute CRF, Relative CRF Probart, 1991147 ≥70 Female only Mean: 24.6 26 NR/Health Walking on a treadmill/Vigorous/No 10/6 Absolute CRF, Relative CRF Pyka, 1994148 64 to 78 Female: 60% NR 104 NR/Health Resistance exercise (walking and stretching)/Moderate/No 8/6 IGF‐1 Chow, 1987149 50 to 62 Female only NR 52 NR/Health Aerobic exercise or aerobic and strengthening exercises/Vigorous/No 17/15 Relative CRF Raz, 1988150 24 to 26 Male only Mean: 22.8 9 Sedentary/Health Aerobic exercise/Vigorous/No 28/27 Relative CRF, TC, TG, HDL‐C, HDL‐C2, HDL‐C3, LDL‐C, HbA1c Ready, 1996151 ≥50 Female only NR 24 Sedentary/Health Walk/Moderate/No 17/18 Absolute CRF, Relative CRF, TC, TG, HDL‐C, LDL‐C Romero‐Arenas, 2013152 55 to 75 NR Mean: 29.9 12 Active/Health Resistance training/Moderate/No 16/10 Relative CRF Santa‐Clara, 2003,153 2006154 45 to 70 Female only Caucasian‐American T: 25±3 C: 27±5 African‐American T: 29±7 C: 29±6 24 Sedentary/Health Treadmill walking/Jogging, stationary cycling, and rowing/Vigorous/No 17/16 Relative CRF, IGF I Santiago, 1995155 22 to 40 Female only ≥31 40 Sedentary/Hyperlipidemia Walking/Vigorous/No 16/11 Relative CRF, TC, TG, HDL‐C, LDL‐C Scanga, 1998156 Mean: 38±7 Female only C: 35.2±3.9 T: 36.6±4.3 8 NR/Health Aerobic and resistance training/Moderate/Dietary intervention 10/12 Absolute CRF, Relative CRF Seifert, 2009157 C: 30±5 T: 32±6 Male only 25 to 30 12 Sedentary/Health Endurance training/Moderate/Endurance training 10/7 Fasting glucose Lamina, 2011158 50 to 70 Male only 20 to 30 8 Sedentary/Hypertension Bicycle ergometer/Vigorous/No 112/105 Relative CRF Sillanpaa, 2009,159 2010160 39 to 64 Female only Normal 21 NR/Health NR/Vigorous/ 15/12 TC, TG, HDL‐C, LDL‐C, Fasting glucose, Insulin Sloan, 2013161 T: 54.1±5.8 C: 54.1±4.9 Female only T: 29.2±4.9 C: 27.1±5.9 16 Sedentary/Health Walking/Moderate/No 16/16 Relative CRF Spence, 2013162 NR Male only T: 73.0±16.9 C: 81.7±15.23 24 Active/Health Endurance vs resistance/Moderate/No 10/13 Absolute CRF, Relative CRF Stachenfeld, 1998163 > 65 Female only NR 24 Active/Health Aerobic training/Vigorous/No 9/8 Relative CRF Stein, 1992164 T: 46.2±6.1 C: 45.0±6.1 Male only NR 8 Sedentary/Health Aerobic exercise training/Moderate/No 19/14 Absolute CRF Stensel, 1993165 42 to 59 Male only Normal 52 Sedentary/Health Brisk/Walking/Moderate/No 24/24 TC, TG, HDL‐C, LDL‐C, VLDL‐C, Apo AI, Apo B, Lp‐A Stensvold, 2010166 Mean: 50.2±9.5 Female: 39.5% C: 31.9±4.1 T: 32.2±4.2 12 Sedentary/Health Strength training vs aerobic interval training/Vigorous/No 11/10 Relative CRF, TC, TG, HDL‐C, Fasting glucose, C‐peptide, HbA1c Strasser, 2009167 >70 Females: 55.6% Mean: 26.9 24 Sedentary/Health Endurance training or–and resistance training/Vigorous/No 13/14 Relative CRF Sung, 2012168 >70 Female: 65% NR 24 NR/Diabetes mellitus Walking/Moderate/No 22/18 TC, TG, HDL‐C, LDL‐C, Fasting glucose, HbA1c Takeshima, 2002169 60 to 75 Female only NR 7 Sedentary/Health Stretching, endurance‐type exercise (walking and dancing, 30 min), Resistance exercise/Vigorous/No 15/15 TC, TG, HDL‐C, LDL‐C Takeshima, 2004170 60 to 83 8 Males and 10 Females NR 12 Sedentary/Health Progressive accommodating circuit exercise/Vigorous/No 18/17 Absolute CRF, TC, TG, HDL‐C, LDL‐C Thomas, 1984171 18 to 32 Female only NR 12 Active/Health Running/Vigorous/No 9/6 Absolute CRF, Relative CRF, TC, TG, HDL‐C Thompson, 2010172 45 to 64 Male only C: 28.0±2.7 T: 28.5±2.9 24 Sedentary/Health NR/Moderate/Dietary intervention 20/21 Relative CRF,TC, TG, HDL‐C, CRP, IL‐6, Fasting glucose, Insulin, HOMA‐IR Tjonna, 2008173 Mean: 52.3±3.7 Female: 53.6% C: 32.1±3.3 T: 29.4±4.9 16 NR/Health Aerobic interval training/Vigorous/No 8/9 Relative CRF, TG, HDL‐C, Adiponectin, Fasting glucose, Insulin, HOMA‐B Toledo, 2008174 >30 Female: 62.5% T: 34.8±1.1 C: 33.4±1.2 16 Sedentary/Health Walking/Moderate/Dietary training 9/7 FFA, Fasting glucose, Insulin Tseng, 2013175 18 to 29 Male only 12 NR/Health Aerobic, resistance or combined aerobic and resistance training/Moderate/ 10/10 TG, HDL‐C, Fasting glucose Tulppo, 2003176 35±10 Male only Moderate: 25±3 Vigorous: 25±2 C: 25±3 8 Sedentary/Health Walking and Jogging/Vigorous/No 16/11 Absolute CRF, Relative CRF Utter, 1998177 25 to 75 Female only 25 to 65 12 Sedentary/Health Walk/Moderate and vigorous/Dietary intervention 21/22 Absolute CRF, Relative CRF Van Aggel‐Leijssen, 2001,178 2001179 C: 38.6±6.5 T: 39.3±7.7 Male only C: 32.6±2.5 T: 32.0±2.1 12 Sedentary/Health Cycling on an ergometer, walking, and aqua‐jogging/Moderate/Energy restriction and dietary intervention 20/17 Absolute CRF, FFA, Fasting glucose, Insulin Van Den Berg, 2010180 18 to 30 Male only NR 7 Sedentary/Health Motor‐driven treadmill/Moderate/No 9/13 Absolute CRF, Relative CRF Vicente‐Campos, 2012181 62 to 67 Female: 60% NR 28 Sedentary/Health Aerobic training/Vigorous/No 22/21 TC, TG, HDL‐C, LDL‐C Vincent, 2002182 60 to 83 Female and Male NR 24 Sedentary/Health Resistance training/Moderate/No 24/16 Relative CRF Vissers, 2010183 C: 44.8±11.4 T: 44.7±13.0 Female: 74.7% C: 29.8±2.6 T: 33.1±3.4 52 Active/Health Bicycle ergometer/Vigorous/No 20/20 TG, HDL‐C Vitiello, 1997184 Male: 66.9±1.0 Female: 67.1±1.7 Female: 40.3% NR 24 Sedentary/Health Endurance or stretching/Flexibility/Moderate/No 30/22 Relative CRF, IGF‐1 Volpe, 2008185 Mean: 44.2±7.2 Female only Mean: 30.5±2.7 52 Sedentary/Health Skiing/NR/Dietary intervention 14/14 TC, TG, HDL‐C, LDL‐C Waib, 2011186 47 to 56 Training: 60.8% T: 30.0 (28.8 to 31.2) C: 29.6 (27.8 to 31.5) 15 Sedentary/Hypertension Aerobic training jogging on an electronic treadmill/Moderate/No 55/24 Relative CRF, HOMA‐IR, C‐peptide Wallman, 2009187 18 to 64 Female: 75% Mean: 30±2 8 Sedentary/Health Aerobic Exercise/Vigorous/Dietary education 6/8 TC, TG, HDL‐C, LDL‐C Wang, 2005188 C: 24.7±2.3 T: 23.5±1.6 Male only C: 22.7±1.7 T: 23.1±0.6 8 Sedentary/Health Bicycle ergometer/Moderate/No 15/15 Relative CRF Wang, 2011189 T: 21.5±0.7 C: 22.9±0.4 Male only T: 22.9±0.4 C: 23.3±0.7 4 Sedentary/Health Bicycle ergometer/Moderate/No 10/10 Relative CRF Warner, 1989190 27 to 63 Female: 35.3% NR 12 Sedentary/Hyperlipidemia Aerobic training/Vigorous/Fish oil intervention 7/7 Relative CRF, LDL‐C, Apo B Warren, 1993191 Mean: 73.6±0.7 Female only Normal 12 Sedentary/Health Walking or calisthenics control/Moderate/No 14/16 Relative CRF Watkins, 2003192 NR NR T: 33.4±4.5 C: 34.0±5.2 24 Sedentary/Health Aerobic training/Vigorous/Weight lost 14/9 Relative CRF,TC, TG, HDL‐C, LDL‐C, Fasting glucose, Insulin Wong, 1990193 Mean: 62.7±3.1 Male only Normal 52 NR/Health Treadmill walking/Moderate/No 69/69 Absolute CRF, Woods, 1999194 Mean: 65±0.8 NR NR 24 Sedentary/Health Aerobic exercise/Moderate/No 14/15 Absolute CRF, Relative CRF Wu, 2011195 45 to 64 Female: 71.9% 16.0 to 33.3 36 NR/Health Aerobic exercise, stretching exercise/Vigorous/No 68/67 TG, Adiponectin, Fasting glucose, Insulin, HOMA‐IR Yoshizawa, 2009196 50 to 65 Female only Mean: 23.7 8 Sedentary/Health Resistance training/Moderate/No 12/13 Relative CRF, TC, TG, HDL‐C, LDL‐C Yoshizawa, 2009197 32 to 59 Female only T: 24.6±1.1 C: 21.8±1.0 12 Sedentary/Health Aerobic exercise training/Moderate/No 12/12 Relative CRF, TC, HDL‐C, LDL‐C You, 2006198 50 to 70 Female only 25 to 40 20 Sedentary/Health Treadmill/Moderate/Dietary intervention 13/14 Absolute CRF, Relative CRF Ziemann, 2011199 T: 21.6±1.1 C: 21.0±0.9 Male only T: 24.5±1.8 C: 23.0±1.9 6 Active/Health NR/Vigorous/Physical education 10/11 Absolute CRF, Relative CRF

Figure 1. Summary of study selection process. In total, 6135 articles were retrieved from the literature search that evaluated the effect of exercise interventions on CRF or cardiometabolic biomarkers. We excluded 5796 articles after abstract review and 170 after full text examination. After exclusion, 160 RCT s reported in 169 articles were included in the meta‐analysis. Apo AI indicates apolipoprotein A1; Apo AII, apolipoprotein A2; Apo B, apolipoprotein B; CRF, cardiorespiratory fitness; CRP, C‐reactive protein; FFA, free fatty acid; HbA1c, glycosylated hemoglobin A1c; HDL ‐C, high‐density lipoprotein cholesterol; HOME‐B, homeostatic model assessment‐beta cell function; HOMA‐IR, homeostatic model assessment–insulin resistance; HOMA‐S, homeostatic model assessment‐insulin sensitivity; ICAM‐1, intercellular adhesion molecule 1; IGF‐1, insulin‐like growth factor 1; IGF‐BP, insulin‐like growth factor binding protein; IL, interleukin; LDL ‐C, low‐density lipoprotein cholesterol; Lp(a), lipoprotein(a); PAI‐1, plasminogen activator inhibitor‐1; RCTs, randomized controlled trials; TC , total cholesterol; TG , triglycerides; TNF‐α, tumor necrosis factor α; VCAM‐1, vascular cell adhesion molecule 1; VLDL‐C, very low‐density lipoprotein cholesterol.

Description of Study Quality

The quality of studies included was heterogeneous (Figure 2). Random sequence generation was reported in 50 trials, and allocation concealment was reported in 20 trials; only 1 of these trials showed a high probability of selection bias because the random allocation was not concealed. The risk of potential performance bias was high in all trials because it was not possible to blind participants and trainers in exercise interventions. Among 26 trials reporting the blinding of outcome assessment, the risk of detection bias was high in only 1 trial. The risk of other bias was high in 46 trials because of poor compliance, the use of intention‐to‐treat analysis, limited sample sizes, or limitations discussed in individual articles.

Figure 2. Assessment of risk of bias: summary for items of bias.

Cardiorespiratory Fitness

A total of 67 and 123 independent comparisons were included in the primary analysis for absolute and relative CRF, respectively (Table 4). Both measures were significantly raised by exercise interventions (both P<0.001). The WMDs comparing exercise groups and control groups were 0.28 L/min (95% CI 0.23 to 0.33; I2=93.7%; P<0.001 for heterogeneity) for absolute CRF and 3.90 mL/kg per minute (95% CI 3.45 to 4.35; I2=91.4%; P<0.001 for heterogeneity) for relative CRF. The Egger's tests showed evidence of publication bias in both instances (P<0.05). When applying the trim and fill method, the conclusion regarding the associations between exercise training and CRF did not change (filled analysis for absolute CRF: WMD 0.14 L/min, 95% CI 0.20 to 5.28, P<0.001; filled analysis for relative CRF: WMD 2.56 mL/kg per minute, 95% CI 3.06 to 10.16, P<0.001).

Table 4. WMDs in Cardiorespiratory Fitness and Circulating Concentrations of Biomarkers Between Exercise Groups and Control Groups Outcome No.a Number of Participants WMD 95% CI P WMD Exercise Control Cardiorespiratory fitness Absolute, L/min 67 1448 1272 0.28 0.23 to 0.33 <0.001 Relative, mL/kg per minute 122 2543 2249 3.94 3.48 to 4.39 <0.001 Lipid and lipoprotein markers TC, mg/dL 68 1754 1604 1.16 −9.28 to 11.99 0.82 TG, mg/dL 66 1851 1703 −5.31 −10.63 to −0.89 0.02 HDL‐C, mg/dL 74 1967 1800 2.32 1.16 to 3.87 <0.001 HDL 2 ‐C, mg/dL 5 91 92 0.39 −1.93 to 2.32 0.8 HDL 3 ‐C, mg/dL 3 62 62 −0.08 −1.55 to 1.55 0.94 LDL‐C, mg/dL 59 1681 1525 3.87 −8.12 to 0.39 0.08 VLDL‐C, mg/dL 7 130 102 −3.09 −8.51 to 2.32 0.29 Apo AI, g/L 5 63 62 0.03 0.02 to 0.04 <0.001 Apo AII, g/L 2 140 126 0.01 −0.01 to 0.03 0.2 Apo B, g/L 5 103 87 0.01 −0.01 to 0.03 0.4 FFA, mmol/L 6 70 62 −0.06 −0.14 to 0.03 0.21 Adipokine and inflammatory markers CRP, mg/L 13 598 554 −0.22 −0.78 to 0.34 0.44 IL‐6, pg/mL 6 130 121 −0.05 −0.27 to 0.17 0.66 IL‐18, pg/mL 2 67 56 18.3 0.10 to 36.6 0.05 TNF‐α, pg/mL 3 43 44 0.21 −0.37 to 0.79 0.48 Adiponectin, μg/mL 6 273 267 0.52 −0.20 to 1.23 0.16 Leptin, ng/mL 7 312 315 −2.72 −4.03 to −1.42 <0.001 Glucose/insulin metabolism markers Glucose, mmol/L 49 1720 1569 −0.07 −0.13 to 0.004 0.06 Insulin, μIU/mL 29 1272 1149 −1.03 −1.69 to −0.37 0.002 HOMA‐IR 14 1033 912 −0.3 −0.49 to −0.11 0.002 HbA1c, % 19 972 878 −0.28 −0.42 to −0.14 <0.001 C‐peptide, nmol/L 2 66 34 −0.08 −0.29 to 0.46 0.67 IGF‐1, ng/mL 5 230 207 3.16 −2.98 to 9.31 0.31 IGF‐BP3, μg/mL 2 170 164 −0.002 −0.23 to 0.23 0.99 Hemostatic factors Fibrinogen, g/L 2 36 39 −0.39 −0.75 to −0.03 0.04 Endothelin‐1, pg/mL 2 34 32 −0.22 −0.62 to 0.19 0.29 Angiotensin II, pg/mL 2 24 25 −1.32 −2.11 to −0.54 0.001

Lipid and Lipoprotein Markers

The number of comparisons for each lipid and lipoprotein marker is shown in Table 4. Exercise training significantly lowered the levels of triglycerides (P=0.02) and increased the levels of high‐density lipoprotein cholesterol (HDL‐C; P<0.001) and apolipoprotein A1 (P<0.001). The WMDs were −5.31 mg/dL (95% CI −10.63 to −0.89; I2=71.8%; P<0.001 for heterogeneity) for triglycerides, 2.32 mg/dL (95% CI 1.16 to 3.87; I2=87.5%; P<0.001 for heterogeneity) for HDL‐C, and 0.03 g/L (95% CI 0.02 to 0.04; I2=0.0%; P=0.81 for heterogeneity) for apolipoprotein A1. The P value of the Egger's test for HDL‐C was 0.03, suggesting possible publication bias; however, the results from the trim and fill analysis did not show substantial impact of publication bias on the estimates or the statistics (filled analysis: WMD 2.32 mg/dL, 95% CI 1.16 to 3.87, P<0.001).

Adipokine and Inflammatory Markers

Significant associations were found for interleukin‐18 (WMD 18.3 pg/mL; 95% CI 0.10 to 36.6; I2=0.0%; P=0.95 for heterogeneity) but not for C‐reactive protein, interleukin‐6, or tumor necrosis factor α in the primary analysis (Table 4). Although there was no effect on adiponectin, exercise training was significantly associated with reduced levels of leptin (WMD −2.72 ng/mL; 95% CI −4.03 to −1.42; I2=82.10%; P<0.001 for heterogeneity) (Table 4).

Markers of Glucose Intolerance and Insulin Resistance

Table 4 also shows the effects of exercise training on markers of glucose intolerance and insulin resistance. Fasting insulin levels; homeostatic model assessment–insulin resistance, or HOMA‐IR; and glycosylated hemoglobin A1c were significantly lowered in exercise groups compared with control groups (P=0.002, P=0.002, and P<0.001) (Table 4). The WMDs between exercise groups and control groups were −1.03 μIU/mL (95% CI −1.69 to −0.37; I2=79.8%; P<0.001 for heterogeneity) for fasting insulin. The WMD for HOMA‐IR was −0.30 (95% CI −0.49 to −0.11; I2=77.5%; P<0.001 for heterogeneity), whereas the WMD for hemoglobin A1c was −0.28% (95% CI −0.42 to −0.14; I2=80.1%; P<0.001 for heterogeneity). The Egger's tests for fasting glucose and insulin were not suggestive of substantial publication bias (P=0.18 and P=0.24, respectively). The results from the trim and fill analysis suggested that there was no substantial impact of publication bias on the results for HOMA‐IR or hemoglobin A1c (filled analysis for HOMA‐IR: WMD −0.30, 95% CI −0.49 to −0.11, P=0.002; filled analysis for hemoglobin A1c: WMD −0.28%, 95% CI −0.42 to −0.14, P<0.001).

Hemostatic Factors

The primary analysis examined 3 hemostatic factors: fibrinogen, endothelin‐1, and angiotensin II (Table 4). On average, the levels of fibrinogen and angiotensin II were 0.39 g/L (95% CI 0.03 to 0.75; I2=45.00%; P=0.18 for heterogeneity) and 1.32 pg/mL (95% CI 0.54 to 2.11; I2=0.00%; P=0.71 for heterogeneity) lower in exercise groups than in control groups. No significant association was found for endothelin‐1.

Subgroup Analyses

Our metaregression results suggest that the differences in CRF between exercise and control groups were modified by age and sex (absolute CRF: P=0.008 and P<0.001 for age and sex, respectively; relative CRF: P=0.003 and P=0.001 for age and sex, respectively) (Table 5, Figure 3). In addition, the effects of exercise on levels of total cholesterol (P=0.04), low‐density lipoprotein cholesterol (LDL‐C; P=0.06), and fasting insulin (P=0.05) were modified by the presence of at least 1 of the following comorbidities: type 2 diabetes, hypertension, hyperlipidemia, and metabolic syndrome (Tables 6 and 7, Figure 3). Sex differences in the effects of exercise were also found for fasting insulin (P=0.04).

Table 5. WMDs in Absolute and Relative Cardiorespiratory Fitness Comparing Exercise Intervention Groups to Control Groups by Specific Modifiers Modifier Absolute CRF (L/min) Relative CRF (mL/kg per minute) n WMD 95% CI I2, % P interaction a n WMD 95% CI I2, % P interaction Age, y <50 16 0.47 0.34 to 0.60 93.4 0.008 28 5.60 4.56 to 6.65 85.1 0.003 ≥50 12 0.21 0.11 to 0.32 84.0 30 3.31 2.46 to 4.15 91.0 Sex Women 25 0.19 0.13 to 0.24 92.3 <0.001 48 3.24 2.61 to 3.87 88.7 0.001 Men 27 0.42 0.32 to 0.53 90.4 37 5.43 4.32 to 6.53 90.2 Lifestyle Active 9 0.33 0.15 to 0.51 97.0 0.89 14 3.62 1.39 to 5.85 96.5 0.83 Sedentary 43 0.31 0.25 to 0.37 88.4 88 3.85 3.36 to 4.33 90.5 BMIb Obese 19 0.28 0.20 to 0.36 93.3 0.65 19 3.85 2.83 to 4.87 94.9 0.96 Nonobese 20 0.26 0.17 to 0.36 89.1 46 4.01 3.22 to 4.79 85.7 Health statusc Yes 8 0.33 0.07 to 0.60 88.2 0.84 16 3.34 2.63 to 4.04 74.8 0.46 None 53 0.27 0.22 to 0.33 94.6 94 4.10 3.51 to 4.71 92.7 Duration, wk <16 39 0.33 0.25 to 0.40 91.3 0.09 69 3.83 3.12 to 4.54 90.7 0.72 ≥16 28 0.21 0.15 to 0.28 92.3 54 3.90 3.34 to 4.35 90.4

Table 6. WMDs in Lipid Biomarkers Comparing Exercise Intervention and Control Groups by Specific Modifiers Modifier Total Cholesterol (mg/dL) Total Triglycerides (mg/dL) n WMD 95% CI I2, % P interaction a n WMD 95% CI I2, % P interaction Age, y <50 12 −4.25 −10.1 to 1.55 0.0 0.43 12 −6.20 −14.2 to 2.66 34.3 0.21 ≥50 15 0.77 −5.41 to 7.35 72.5 13 1.77 −8.86 to 13.3 75.5 Sex Women 28 1.16 −5.41 to 7.73 91.6 0.61 27 −1.77 −9.74 to 5.31 76.1 0.25 Men 15 −0.39 −5.80 to 5.03 54.3 13 −8.86 −14.2 to −4.43 12.8 Lifestyle Active 6 8.12 −7.73 to 24.0 92.5 0.71 5 −8.86 −30.1 to 12.4 61.2 0.64 Sedentary 47 1.93 −13.9 to 17.4 99.1 43 −3.54 −9.74 to 2.66 75.1 BMIb Obese 16 12.8 −22.4 to 47.6 99.7 0.20 19 −7.97 −14.2 to −1.77 53.0 0.70 Nonobese 29 −1.55 −7.73 to 4.25 83.6 28 −5.31 −14.2 to 4.43 80.7 Health statusc Yes 10 −11.2 −19.3 to −3.48 75.2 0.04 9 −9.74 −26.6 to 6.20 63.9 0.48 None 47 −1.55 −5.41 to 2.32 81.6 44 −4.43 −11.5 to 2.66 75.2 Duration, wk <16 39 3.87 −15.5 to 22.8 82.9 0.34 35 −6.20 −13.3 to 0.89 71.1 0.76 ≥16 29 −3.09 −7.73 to 1.55 99.2 31 −5.31 −11.5 to 1.77 72.7 Modifier HDL‐C (mg/dL) LDL‐C (mg/dL) N WMD 95% CI I2, % P interaction a N WMD 95% CI I2, % P interaction Age, y <50 16 4.25 2.32 to 6.19 73.9 0.94 9 −3.87 −10.8 to 3.09 49.3 0.38 ≥50 15 3.87 0.77 to 6.96 84.5 14 0.39 −5.03 to 6.19 73.0 Sex Women 28 2.32 0.08 to 4.64 84.8 0.80 24 −1.93 −9.67 to 5.80 95.0 0.93 Men 19 2.71 0.39 to 5.03 92.5 13 −2.32 −8.89 to 4.25 79.7 Lifestyle Active 5 4.25 0.39 to 8.51 86.9 0.52 2 8.12 −10.4 to 27.1 54.9 0.21 Sedentary 52 2.32 0.77 to 3.87 18.6 45 −3.87 −8.12 to 0.39 88.3 BMIb Obese 19 4.25 1.93 to 6.96 88.1 0.13 14 −0.08 −4.64 to 4.25 62.0 0.33 Nonobese 30 1.16 −1.16 to 3.87 83.0 25 −4.25 −10.4 to 2.32 91.4 Health statusc Yes 11 2.71 −2.32 to 7.73 91.2 0.89 12 −11.6 −19.7 to −3.09 80.8 0.06 None 50 2.32 0.77 to 3.87 87.3 39 −3.09 −7.73 to 1.55 89.3 Duration, wk <16 39 2.71 1.16 to 4.64 83.0 0.55 29 −3.09 −9.28 to 3.48 89.6 0.63 ≥16 35 1.93 0.15 to 0.28 90.4 30 −4.64 −10.4 to 1.16 92.2

Table 7. WMDs in Biomarkers of Glucose Intolerance and Insulin Resistance Comparing Exercise Intervention Groups to Control Groups by Specific Modifiers Modifier Fasting Glucose (mmol/L) Fasting Insulin (μIU/mL) n WMD 95% CI I2, % P interaction a n WMD 95% CI I2, % P interaction Age, y <50 5 0.09 −0.11 to 0.29 91.3 0.57 4 −1.34 −3.44 to 0.76 76.9 0.22 ≥50 7 0.01 −0.06 to 0.07 36.9 3 0.45 −1.23 to 2.13 75.6 Sex Women 16 −0.06 −0.19 to 0.08 91.4 0.93 9 −0.27 −1.12 to 0.57 68.7 0.04 Men 9 −0.07 −0.25 to 0.12 84.3 6 −2.86 −3.55 to −2.17 0.0 Lifestyle Active 2 −0.20 −0.74 to 0.34 99.0 0.63 0 NA NA NA NA Sedentary 29 −0.06 −0.16 to 0.03 80.2 17 −0.94 −1.75 to −0.13 78.5 BMIb Obese 20 −0.06 −0.20 to 0.07 90.7 0.90 13 −0.93 −2.18 to 0.32 82.0 0.88 Nonobese 18 −0.05 −0.17 to 0.07 80.7 10 −0.86 −1.52 to −0.19 32.8 Health statusc Yes 9 −0.18 −0.40 to 0.05 0.0 0.40 6 −2.68 −4.67 to −0.70 75.2 0.05 None 27 −0.03 −0.11 to 0.06 87.2 14 −0.70 −1.60 to 0.21 77.5 Duration, wk <16 30 −0.10 −0.22 to 0.03 90.0 0.70 13 −1.35 −2.50 to −0.20 79.3 0.58 ≥16 19 −0.02 −0.09 to 0.06 47.5 16 −0.83 −1.83 to 0.17 78.7

Figure 3. Forest plot of effects of exercise interventions on cardiorespiratory fitness, TC, TG, HDL ‐C, LDL ‐C, Fasting glucose, and fasting insulin within subgroups. The WMD s (diamonds) and corresponding CI s (extended line) between exercise groups and control groups are shown for each subgroup. Abs. CRF indicates absolute cardiorespiratory fitness; BMI, body mass index; HDL ‐C, high‐density lipoprotein cholesterol; LDL ‐C, low‐density lipoprotein cholesterol; Rel. CRF , relative cardiorespiratory fitness; TC , total cholesterol; TG , triglycerides; WMDs, weighted mean differences.

After conducting metaregressions, analyses within subgroups were performed. Compared with older people, those aged <50 years appeared to have larger changes in CRF. Consistent with the metaregression results, men seemed to have greater exercise‐related improvement in CRF, LDL‐C, and fasting insulin than women did (Figure 3). Exercise interventions appreciably improved the levels of total cholesterol, LDL‐C, and fasting insulin (P=0.004, P=0.01, and P=0.01, respectively) in people having at least 1 of type 2 diabetes, hypertension, hyperlipidemia, and metabolic syndrome (Tables 6 and 7, Figure 3); no such improvements were observed among people without any of those health conditions (P=0.44, P=0.19, and P=0.13, respectively) (Tables 6 and 7, Figure 3).

Sensitivity Analyses

In light of the potential impact of exercise intensity, we conducted separate analyses of all eligible comparisons for moderate and vigorous exercise interventions, respectively. The 95% CIs for moderate and vigorous interventions overlapped for both CRF measures and for all biomarkers (Table 8).

Table 8. WMDs in Cardiorespiratory Fitness and Circulating Concentrations of Biomarkers Comparing Moderate and Vigorous Exercise Intervention Groups to Control Groups Outcome Moderate Vigorous No.a WMD 95% CI No.* WMD 95% CI Cardiorespiratory fitness Absolute, L/min 39 0.22 0.16 to 0.29 33 0.31 0.22 to 0.40 Relative, mL/kg per minute 64 3.22 2.61 to 4.18 68 3.26 2.63 to 3.89 Lipids markers TC, mg/dL 41 4.25 −7.73 to 16.6 28 3.87 −31.7 to 39.8 TG, mg/dL 37 −5.31 −12.4 to 1.77 32 −5.31 −11.5 to 0.09 HDL‐C, mg/dL 44 1.16 −0.39 to 2.71 33 2.71 0.39 to 5.03 HDL 2 ‐C, mg/dL 2 1.16 −0.77 to 3.48 2 1.55 −1.16 to 4.25 HDL 3 ‐C, mg/dL 1 −1.16 −5.80 to 3.87 2 0.04 −1.55 to 1.55 LDL‐C, mg/dL 35 −3.09 −8.12 to 2.32 26 −4.64 −12.0 to 2.32 VLDL‐C, mg/dL 5 −1.93 −5.41 to 1.93 2 −7.35 −22.9 to 6.19 Apo AI, g/L 4 0.03 0.02 to 0.04 1 0.00 −0.12 to 0.12 Apo AII, g/L 1 −0.001 −0.24 to 0.24 1 0.01 −0.01 to 0.03 Apo B, g/L 3 0.01 −0.01 to 0.03 2 −0.02 −0.21 to 0.18 FFA, mmol/L 5 −0.06 −0.16 to 0.03 3 −0.04 −0.17 to 0.10 Inflammatory markers CRP, mg/L 9 −0.23 −1.01 to 0.55 4 0.04 −0.24 to 0.31 IL‐6, pg/mL 5 0.02 −0.22 to 0.25 2 −0.39 −0.83 to 0.06 IL‐18, pg/mL 1 14.0 −128 to 156 1 18.4 0.02 to 36.8 TNF‐α, pg/mL 3 0.06 −0.48 to 0.60 1 −0.01 −0.93 to 0.91 Adiponectin, μg/mL 1 3.52 1.17 to 5.87 6 0.52 −0.20 to 1.23 Leptin, ng/mL 1 −0.70 −1.19 to −0.21 6 −2.56 −4.04 to −1.08 Insulin resistance markers Glucose, mmol/L 31 −0.04 −0.24 to 0.17 22 0.03 −0.08 to 0.12 Insulin, μIU/mL 17 −0.91 −2.08 to 0.26 17 −1.32 −2.15 to −0.50 HOMA‐IR 7 −0.30 −0.66 to 0.06 7 −0.47 −0.82 to −0.12 HbA1c, % 11 −0.28 −0.46 to −0.11 7 −2.71 −0.54 to −0.002 C‐peptide, nmol/L 1 0.22 0.19 to 0.25 1 −0.18 −0.62 to 0.26 IGF‐1, ng/mL 2 −4.64 −29.58 to 20.30 3 3.91 −2.87 to 10.69 IGF‐BP3, μg/mL 0 NA NA 2 −0.002 −0.23 to 0.23 Hemostatic factors Fibrinogen, g/L 0 NA NA 2 −0.39 −0.75 to −0.03 Endothelin‐1, pg/mL 2 −0.22 −0.62 to 0.19 0 NA NA Angiotensin II, pg/mL 2 −1.32 −2.11 to −0.54 0 NA NA

Discussion

This systematic review and meta‐analysis of 160 RCTs involving 7487 participants indicates that exercise training may significantly improve CRF and CVD biomarkers of lipid and lipoprotein metabolism, glucose intolerance and insulin resistance, systemic inflammation, and hemostasis (Figure 4). In addition, we identified several important modifiers, including age, sex, and health status, that may partially modify the exercise effects on cardiovascular health.

Figure 4. Mechanisms by which exercise training may improve cardiovascular health.

The current meta‐analysis shows that exercise, with relatively low risk of side effects compared with medications, may be an effective way to prevent CVD through impact on various biomarkers. Our results from the meta‐analysis showed that exercise training significantly raised CRF, which has been demonstrated to be an independent predictor of CVD risk, CVD mortality, and total mortality.200, 201 Lower levels of triglycerides and higher levels of HDL‐C were observed in exercise groups. Aside from conventional CVD biomarkers, our meta‐analysis also examined the effects on biomarkers that have not been well studied in previous studies, including biomarkers of insulin resistance and hemostasis, adipokines, and novel lipid and inflammatory biomarkers. We found evidence supporting the favorable effects of exercise on apolipoprotein A1, interleukin‐18, fasting insulin, HOMA‐IR, and hemoglobin A1c. Although the exact biological mechanisms are not clear, our findings indicate that exercise may exert cardioprotective effects by altering dyslipidemia, inflammation, insulin resistance, and hemostasis.19

As a major component of HDL, apolipoprotein A1 plays an important role in the cardioprotective effects of HDL‐C.202, 203, 204 Our findings on apolipoprotein A1 strengthen the hypothesis that exercise may accelerate reverse cholesterol transport. Another plausible mechanism by which exercise improves the lipid profile is by regulation of lipoprotein lipase. Various studies have suggested that exercise may decrease the levels of triglycerides and increase the levels of HDL‐C through its impact on lipoprotein lipase expression and activity, which were consistent with the results from our meta‐analysis.205, 206, 207 In addition, our analysis also confirmed that the proportion of CVD risk that could have been reduced by exercise via effects on total cholesterol and LDL‐C is much lower than what has been observed previously.208, 209 Consequently, the results from our meta‐analysis provide additional evidence in support of the notion that, in addition to modifying total cholesterol and LDL‐C, exercise training may also affect cardiovascular health through other pathways. We found that people in exercise groups also had significantly lower levels of IL‐18 and several biomarkers of insulin resistance and hemostatic factors, indicating that exercise may exert its effects via pathways of inflammation‐characterized atherothrombosis and insulin resistance. A recent review suggested that exercise training may regulate white adipose tissue mass and the expression of adipokines.210 Obesity has become widely regarded as a chronic proinflammatory state, and substantial evidence indicates that chronic inflammation in adipose tissues, especially in white adipose tissue, could lead to insulin resistance.211, 212 Consequently, it is biologically plausible that by reducing the white adipose tissue mass and regulating the expression of adipokines, exercise could mitigate the chronic inflammation in adipose tissues, resulting in improved insulin sensitivity. Nevertheless, the exact mechanism remains to be elucidated.

The results from the subgroup analyses also may have important clinical implications. Consistent with previous evidence,213 both moderate and vigorous exercise training appeared to have favorable effects on cardiorespiratory fitness and cardiometabolic health. We found that the differences in CVD risk between exercise groups and control groups were not significantly modified by lifestyle, body mass index, or intervention duration. These findings suggest that exercise interventions may have similar effects on cardiovascular health in populations regardless of these factors. Alternatively, the effectiveness of exercise training appeared to be different across strata of age, sex, and health status. The effects of exercise interventions on CRF measures were modified by age, sex, and health status such that people aged <50 years, men, and people with type 2 diabetes, hypertension, hyperlipidemia, or metabolic syndrome appeared to benefit more from exercise interventions. We also observed significant modification of the effects on total cholesterol and LDL‐C by preexisting medical conditions (type 2 diabetes, hypertension, hyperlipidemia, or metabolic syndromes), and that may explain why we did not find significant effects of exercise on total cholesterol and LDL‐C. This finding also suggests that exercise interventions may provide significant benefits for people with those preexisting conditions by lowering total cholesterol and LDL‐C.

Strengths of this meta‐analysis include the comprehensive and systematic review of both conventional and novel CVD biomarkers, detailed subgroup analyses for potential effect modifiers that have not been conducted previously, assessment of robustness with regard to exercise intensity, and evaluation of the risk of different bias. The 2008 Physical Activity Guidelines Advisory Committee Report included a number of comprehensively systematic reviews and meta‐analyses based mostly on observational studies.214 The evidence from RCTs has been relatively scarce, especially for novel cardiometabolic biomarkers. Our study is the first that synthesized evidence from the RCT setting and covered a comprehensive set of both traditional and novel biomarkers. Our findings are corroborated by several previous meta‐analyses of RCTs,20, 215 but the inclusion of both sexes, more studies, subgroup analyses, and sensitivity analyses allowed us to achieve higher precision in the estimates and to determine the effect modification in subgroups.

This meta‐analysis had some limitations. First, the evidence for hemostatic factors is based on a limited number of available trials, and we were not able to synthesize evidence for some novel biomarkers, such as plasminogen activator inhibitor 1, lipoprotein(a), and homocysteine due to sparse available data. Second, subgroup analyses were restricted to outcomes with >20 studies included, and cutoff points used for categorizing modifiers were arbitrarily selected. Third, due to the heterogeneity of exercise training programs and the limited number of RCTs that provided separate data, this meta‐analysis can neither perform a dose‐response analysis nor distinguish exercise types. We maximized the utility of data regarding exercise duration and intensity available from original RCTs and found that exercise effects were not significantly different across subgroups defined by duration and intensity. Our findings are consistent with previous evidence showing that both moderate and vigorous exercise training has similarly favorable effects on cardiometabolic health.213 The duration threshold at which exercise exerts its effects needs further investigation. Fourth, to maintain independence, we selected 1 comparison from each trial with exercise groups of different intensities compared with 1 single control group. The results may potentially be subject to bias by excluding several eligible intervention groups with moderate intensity; however, we found that the direction and magnitude of the effects on most of the outcome measures were quite similar between moderate and vigorous interventions (Table 8). Finally, like any meta‐analysis, our results may be prone to publication bias and inherent weaknesses of individual studies.

In conclusion, this large meta‐analysis of RCTs clearly shows that exercise training significantly improved CRF and some traditional and novel CVD biomarkers in adults without CVD, indicating the causal role of exercise in the primary prevention of CVD morbidity and mortality.

Acknowledgments Author contributions: Lin, Liu, and Song designed research; Lin and Zhang were involved in data collection; Lin analyzed data; Guo, Roberts, McKenzie, Wu, and Liu participated in interpretation of findings; Lin and Song wrote the first draft. All authors read, edited, and approved the final manuscript.

Sources of Funding

The study was supported by the Indiana University Health–Indiana University School of Medicine Strategic Research Initiative Grant (Zhang and Song), R01DK09406 (Roberts) and P50HL105188 (Roberts) from the National Institutes of Health (NIH), and Brown University. The NIH, Brown University, or Indiana University had no role in the design and conduct of the study; the collection, management, analysis, and interpretation of the data; or the preparation, review, or approval of the manuscript.

Disclosures

None.

Footnotes