Predictors of Endothelial Function in Employees With Sedentary Occupations in a Worksite Exercise Program

Article Outline

• Abstract
• Methods
• Results
• Discussion
• Acknowledgment
• References
• Copyright

A sedentary workforce may be at increased risk for future cardiovascular disease. Exercise at the work site has been advocated, but effects on endothelium as a biomarker of risk and relation to weight loss, lipid changes, or circulating endothelial progenitor cells (EPCs) have not been reported. Seventy-two office and laboratory employees (58 women; average age 45 years, range 22 to 62; 26 with body mass index values >30 kg/m²) completed 3 months of participation in the National Heart, Lung, and Blood Institute's Keep the Beat program, with the determination of vital signs, laboratory data, and peak oxygen consumption (VO₂) during treadmill exercise. Brachial artery endothelium was tested by flow-mediated dilation (FMD), which at baseline was inversely associated with Framingham risk score (r = −0.3689, p <0.0001). EPCs were quantified by colony assay. With exercise averaging 98 ± 47 minutes each workweek, there was improvement in FMD (from 7.8 ± 3.4% to 8.5 ± 3.0%, p = 0.0096) and peak VO₂ (+1.2 ± 3.1 ml O₂/kg/min, p = 0.0028), with reductions in diastolic blood pressure (−2 ± 8 mm Hg, p = 0.0478), total cholesterol (−8 ± 25 mg/dl, p = 0.0131), and low-density lipoprotein cholesterol (−7 ± 19 mg/dl, p = 0.0044) but with a marginal reduction in weight (−0.5 ± 2.1 kg, p = 0.0565). By multiple regression modeling, lower baseline FMD, greater age, reductions in total and low-density lipoprotein cholesterol and diastolic blood pressure, and increases in EPC colonies and peak VO₂ were jointly statistically significant predictors of change in FMD and accounted for 47% of the variability in FMD improvement with program participation. Results were similar when modeling was performed for women only. In contrast, neither adiposity at baseline nor change in weight was a predictor of improved endothelial function. In conclusion, daily exercise achievable at their work sites by employees with sedentary occupations improves endothelial function, even with the absence of weight loss, which may decrease cardiovascular risk, if sustained.

Exercise has been associated with multiple health benefits, including favorable effects on lipids, blood pressure, insulin sensitivity, and endothelial function,¹, ², ³, ⁴, ⁵ yet almost 2/3 of American adults do not engage in any form of routine exercise,⁶ suggesting that many individuals find the time commitment recommended by these organizations challenging or impractical, possibly because of demands of work and family. We used the National Heart, Lung, and Blood Institute's (Bethesda, Maryland) comprehensive workplace health intervention, called Keep the Beat, which includes work-site exercise facilities, to determine predictors of an important marker of cardiovascular risk (endothelial nitric oxide bioactivity⁷, ⁸) and whether individuals with sedentary occupations could improve endothelial function with relatively brief periods of daily exercise achievable during the workweek.

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Methods 

This study was conducted at the Clinical Center of the National Institutes of Health (Bethesda, Maryland) with employees enrolled in the Keep the Beat wellness program. All subjects provided informed consent to participate in this protocol, approved by the institutional review board of the National Heart, Lung, and Blood Institute. Women were not pregnant, and all subjects had no known coronary artery or other vascular disease and reported no regular daily exercise activity. No medications or hormone therapies had been initiated within 1 month of enrollment. All subjects underwent focused cardiovascular physical examinations, and venous blood samples were drawn in the fasting state for routine chemistries and blood counts, lipid profile, glucose, insulin, estradiol and follicle-stimulating hormone for women, high-sensitivity C-reactive protein (hsCRP), and assays for endothelial progenitor cells (EPCs) derived from mononuclear cells isolated from blood samples. Insulin sensitivity was estimated from fasting glucose and insulin values using homeostasis model assessment.⁹ Cardiovascular risk scores were calculated using the Framingham Heart Study prediction score sheet for men and for women (http://www.nhlbi.nih.gov/about/framingham/riskabs.htm). Study participants underwent brachial artery reactivity testing to assess endothelial function and metabolic treadmill stress testing to assess level of fitness.

After baseline data were obtained, all subjects received a Keep the Beat binder, which provided them with 15-minute exercise programs for the fitness centers equipped with endurance-training (stationary bicycles and elliptical trainers) and muscle-strengthening devices and information about additional exercise during the workday (stairs at work, walking maps for the National Institutes of Health campus). Study participants were requested to record total exercise time per week on diary sheets. At the end of 3 months, subjects returned to the Clinical Center for repeat of all testing performed at baseline, 48 to 72 hours after the last exercise session. All subjects continued taking their current medications throughout the study as prescribed by their health care providers, without changes in dosages or the initiation of new medications. Participants were in contact with the protocol coordinator on a weekly basis, with the submission of exercise diaries.

Brachial artery flow-mediated dilation (FMD) as an index of endothelial function was performed by a single experienced technician, who also performed this testing in a study reported previously from our center.¹⁰ Imaging of the left brachial artery proximal to the antecubital fossa was performed using high-resolution ultrasound (with a 12.5-MHz linear-array transducer) after 10 minutes of rest. FMD was determined as the maximum increase in the diameter of the brachial artery during reactive hyperemia created by an inflated cuff (200 mm Hg for 5 minutes) on the forearm, distal to the measurement site. Arterial diameter was measured in millimeters from the leading edge of the intima-lumen interface of the near wall (echo zone 3) to the leading edge of the lumen-intima interface of the far wall (echo zone 5), coincident with the R wave on the electrocardiogram (i.e., end-diastole). FMD was calculated as percentage vasodilation = [(postischemia − baseline diameter) × 100]/baseline diameter. The intraobserver variability of this analysis (measured twice in blinded fashion by a single operator) was assessed in 15 subjects by this technician, with a correlation coefficient of 0.885.

Symptom-limited cardiopulmonary treadmill exercise testing was performed using the standard Bruce protocol. Respiratory gas analysis was performed using a breath-by-breath analysis of O₂ and CO₂ on a SensorMedics VMAX 229c instrument (SensorMedics, Yorba Linda, California). Peak oxygen consumption relative to body weight (peak VO₂) as a measure of exercise fitness, peak respiratory exchange ratio (VCO₂/VO₂) as a measure of exercise effort, and the ventilatory response to peak exercise (VE/VO₂) were expressed as the highest 20-second averaged samples during the last stage of the exercise test. Anaerobic threshold was determined by the ventilatory equivalents method.¹¹

Blood was collected into tubes with Ficoll (GE Healthcare, Milwaukee, Wisconsin) and sodium heparin for the isolation of mononuclear cells, washed twice in phosphate-buffered saline with 5% fetal bovine serum, and resuspended in media (EndoCult basal media with supplements; StemCell Technologies, Vancouver, British Columbia, Canada) for EPC colony–forming assay. Cells were plated on dishes coated with human fibronectin (BIOCOAT; Becton Dickinson Labware, Bedford, Massachusetts) at a density of 5 × 10⁶ cells/well and incubated at 37°C in humidified 5% CO₂. After 48 hours, the nonadherent cells suspended in the growth media were replated onto fibronectin-coated 24-well plates at a density of 10⁶ cells/well. After 5 days, colony-forming units, defined as a central core of rounded cells surrounded by elongated and spindle-shaped cells, were counted manually in 4 to 8 wells of a 24-well plate. Interobserver variability of colony determination was assessed by 2 investigators who independently counted colonies in wells from 7 participants; agreement was excellent, with a correlation coefficient of 0.998.

Flow cytometric analysis was used to quantify potential EPCs (cluster of differentiation [CD] 133 or vascular endothelial growth factor receptor–2 [VEGFR-2]) using fluorochrome-conjugated antibodies (CD133 APC; Miltenyi Biotec, Auburn, California; VEGFR-2 PE; R&D Systems, Minneapolis, Minnesota). Lymphocytes of B and T lineages were excluded from analysis using fluorochrome-conjugated antibodies with appropriate isotype controls (CD3, CD19, CD33 FITC; BD Biosciences, San Jose, California). All cells were stained with either 7AAD (BD Biosciences) or Live/Dead (BD Biosciences) to allow the exclusion of dead cells. A subset of samples was stained with Hoescht (Invitrogen, Carlsbad, California) to ensure that the flow cytometer was counting nucleated cells (<1% of cells were non-nucleated). The Cyan flow cytometer was used with Summit Software (Dako, Fort Collins, Colorado) for data acquisition, and FCSExpress (De Novo Software, Thornhill, Ontario, Canada) was used for analysis.

Laboratory, exercise fitness, and brachial artery endothelial testing were performed and interpreted by separate investigators without knowledge of one another's findings. Data are reported as mean ± SD unless otherwise indicated. As prespecified in the protocol, FMD of the brachial artery, a bioassay for endothelial nitric oxide bioactivity, was chosen as the primary measure of vascular health in our cohort of sedentary subjects. The study was designed to detect a 1% absolute improvement in FMD on the basis of a sample size of 88 subjects (β = 0.80, α = 0.05). Covariates of interest as predictors of change in FMD were age, baseline FMD, and baseline and 3-month changes in exercise fitness (peak VO₂), body mass index (BMI), systolic blood pressure, diastolic blood pressure, total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides, insulin, fasting glucose, c-reactive protein (high sensitivity assay [hsCRP]), and EPC colony–forming units. The covariates were first investigated as univariate predictors of change in brachial artery FMD using simple linear regression and correlation analysis. Multiple regression models for explaining changes in FMD during program participation were then constructed using the forward, backward, and stepwise model-building approaches. Covariates found significant in the stepwise model with type II sums of squares were rerun using the general linear model with type III sums of squares. Therefore, the p value for each covariate reflects adjustment for all other model covariates. The models were rerun on the a priori specified subgroup of women only. All analyses were performed using SAS version 9, using the STEPWISE, GLM, and MEANS procedures (SAS Institute Inc., Cary, North Carolina). All reported p values are based on 2-sided Student's t tests for continuous data (hsCRP data were log transformed) or Fisher's exact test for comparison of proportions.

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Results 

Characteristics of the 72 study participants are listed in Table 1. BMI was directly associated with Framingham risk score (r = 0.2263, p = 0.0180) and inversely associated with exercise fitness (r = −0.6425, p <0.0001). Participants averaged 98 ± 47 minutes of exercise each workweek and showed statistically significant improvements in level of exercise fitness (peak VO₂) and exercise duration on the standard Bruce protocol (Table 2). Improvement in level of fitness was inversely associated with age (r = −0.3283, p = 0.0075) but was not related to level of fitness at baseline (r = −0.1031, p = 0.4137), BMI at baseline (r = −0.1868, p = 0.1368), or weight loss during program participation (r = −0.1761, p = 0.1745). Study participants also experienced statistically significant reductions in diastolic blood pressure, total cholesterol, and LDL cholesterol, with similar improvement for men and for women (all p values >0.1999 for comparisons). Reductions in diastolic blood pressure and total cholesterol were inversely related to baseline values (r = −0.4806, p <0.0001, and r = −0.2860, p = 0.0149, respectively), with a trend toward a similar relation between baseline values and reduction in LDL cholesterol levels (r = −0.2199, p = 0.0635). HDL cholesterol levels decreased slightly but significantly for the cohort, with greater decreases in men than in women (−6 ± 8 vs −1 ± 8 mg/dl, p = 0.03). Weight loss was minimal for the cohort (−0.5 ± 2.1 kg, p = 0.0565), and similar for men and women (p = 0.4230) but proportionate to the length of time devoted to exercise on a weekly basis (r = −0.3425, p = 0.0042). Insulin sensitivity did not change for the cohort as a whole, although it tended to improve proportionate to weight loss (r = 0.221, p = 0.0511). Changes in blood pressure and lipoprotein values were not associated with baseline BMI or change in weight during the program (all p values >0.50). Nineteen subjects took medications for hypertension or hypercholesterolemia or were receiving hormone therapy for contraception or menopause. A trend toward a reduction in systolic blood pressure (−3 ± 13 mm Hg, p = 0.066) was noted in this group; otherwise, changes in diastolic blood pressure and lipid values were no different for these 19 participants than changes in the 53 subjects not receiving these treatments (all p values >0.40).

Table 1. Baseline characteristics and testing data for 72 subjects who completed Keep the Beat program participation

Parameter	Value
Age (yrs)	45(22–62)
Women	58(81%)
Caucasians	45(62%)
African Americans	17(24%)
Asians	10(14%)
Hypertension (blood pressure >160/90 mm Hg) by history or exam	14(19%)
Treated with medications	14(100%)
Hypercholesterolemia (LDL cholesterol >160 mg/dl) by history or exam	18(25%)
Treated with medications	10(56%)
Diabetes mellitus (fasting glucose >125 mg/dl) by history or exam	6(8%)
Treated with medications	5(83%)
Cigarette smoking (current)	5(7%)

Data are expressed as average (range) or number (percentage).

Table 2. Baseline and 3-month data for 72 subjects who completed Keep the Beat program participation

Parameter	Baseline	3 Months	p Value
Vital signs
BMI (kg/m2)	28.8±7.0	28.5±6.9	0.0565
Systolic blood pressure (mm Hg)	117±14	118±13	0.4825
Diastolic blood pressure (mm Hg)	73±9	71±9	0.0478
Heart rate at rest (beats/min)	70±10	69±11	0.7814
Laboratory values
Total cholesterol (mg/dl)	189±35	181±36	0.0131
LDL cholesterol (mg/dl)	122±31	116±32	0.0044
HDL cholesterol (mg/dl)	60±14	58±17	0.0277
Triglycerides (mg/dl)	109±74	106±69	0.5159
C-reactive protein (mg/L)	3.5±4.4	4.2±6.9	0.4788
Glucose (mg/dl)	94±23	95±17	0.0435
Insulin (μU/ml)	11±8	12±8	0.0687
Homeostasis model assessment of insulin sensitivity	2.67±2.15	3.01±2.63	0.1901
Estradiol⁎ (pg/ml)	77±76	72±65	0.7567
Follicle-stimulating hormone⁎ (IU/L)	28±32	27±30	0.7323
EPC testing
FMD (% change)	7.8±3.4	8.5±3.0	0.0096
EPC colonies/well	37±47	54±55	0.0003
CD133 or VEGFR-2† (cells/ml)	3±4	19±13	<0.0001
Treadmill exercise data (Bruce protocol)
Exercise duration (s)	544±137	599±143	0.0001
Peak heart rate (beats/min)	172±13	174±13	0.1672
Respiratory exchange ratio	1.2±0.1	1.2±0.1	0.9886
Peak oxygen consumption (ml O2/kg/min)	28.7±6.9	30.1±7.0	0.0028
Ventilatory threshold	28.7±3.3	29.7±3.6	<0.0001
Anaerobic threshold	19.9±3.9	19.7±3.9	0.3068

Data are expressed as mean ± SD.

VEGFR-2 = vascular endothelial growth factor receptor–2.

At baseline, FMD was inversely associated with Framingham risk score (r = −0.3689, p <0.0001). FMD improved significantly for study participants (Table 2) and was similar for the 19 subjects taking medications compared with the 53 subjects not taking medications (p = 0.9185). Participants also showed increases in the number of EPC colonies (from 37 ± 47 to 54 ± 55 colonies per well, p = 0.0003) and, in the subset who underwent this measure, increases in cells positive for CD133 or vascular endothelial growth factor receptor–2 cells by flow cytometry, from 3 ± 4 to 19 ± 3 cells/ml blood (p = 0.0001).

Because of the association between endothelial function and cardiovascular risk reported in previous studies,⁷, ⁸ change in FMD after 3 months of program participation was prespecified as the primary end point in our study. No statistically significant univariate predictors of change in FMD were found over the range of covariates examined. By multiple stepwise procedure, lower baseline FMD, reduction in total cholesterol, reduction in LDL cholesterol, reduction in diastolic blood pressure, older age, and increase in EPC colonies were jointly significant predictors at the p ≤0.05 level, with improvement in peak oxygen consumption during exercise of borderline significance (Table 3). The combination of these covariates in this model provided a cumulative coefficient of determination (model R²) of 0.4676, indicating that almost half of the variation in improvement in FMD as a result of program participation was accounted for by these covariates. The results remained essentially unchanged when the models were rerun separately on the subset of 58 women, representing 81% of study finishers. In contrast, neither adiposity at baseline nor change in weight during program participation was a predictor of improved endothelial function.

Table 3. Covariates as predictors of change in brachial artery flow-mediated dilation after 3 months of program participation

Covariates initially found significant in the stepwise model, then rerun using the general linear model with type III sums of squares so that the p value of each covariate reflects adjustment for all other covariates. All reported p values are based on 2-sided Student's t tests.

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Discussion 

The most recently revised diet and lifestyle recommendations from the American Heart Association encourage a balance of caloric intake and physical activity to achieve and maintain a healthy body weight (BMI 18.5 to 24.9 kg/m²).¹² Reports that most Americans do not exercise regularly, coupled with the increasing prevalence of obesity, indicate that many find these recommendations impractical or challenging, possibly because of time demands of work and family responsibilities. We determined that level of fitness and brachial artery endothelial function were inversely associated with Framingham risk score in our cohort of largely overweight or obese employees with sedentary occupations. We found that 15 to 20 minutes of exercise daily, using facilities provided at the work site, can improve endothelial function in a relatively brief period of 3 months. Although obesity at baseline was associated with diminished exercise fitness and higher Framingham risk score, benefits of program participation to exercise fitness, lipids, blood pressure, and endothelial function were independent of body mass at baseline as well as weight loss during program participation, which was minimal for the entire group. In general, weight loss was achieved by those participants who devoted more time to exercise, with weekend activity in addition to exercise during the workweek, which in turn was weakly associated with improved insulin sensitivity.

Other groups have examined the health benefits of work-site physical activity programs, with reviews of such programs reporting limited or inconclusive benefits.¹³, ¹⁴, ¹⁵, ¹⁶ Improvements in exercise fitness and reductions in blood pressure and total and LDL cholesterol observed in our cohort not seen in other studies may be due to a more overweight or obese cohort in our study and the provision of exercise facilities with endurance and muscle-strengthening equipment at 3 locations to facilitate easy access to employees. Of interest, improvement in these parameters was seen in subjects taking medications or hormone therapy (treatments for ≥1 month before enrollment, with no changes during participation in the study) as well as in the larger cohort taking no medications that could affect study end points.

Our study provides insight into the potential health benefits of work-site exercise with respect to endothelial function, a biomarker of cardiovascular risk.⁷, ⁸ Improvement in endothelial function as a result of exercise training may be caused by repetitive shear stress effects on endothelium, with increased transcription or phosphorylation of the primary enzyme for nitric oxide synthesis, endothelial nitric oxide synthase.¹⁷ In our cohort, significant improvements in exercise duration and brachial artery reactivity were determined after 3 months of program participation. By multiple regression modeling, lower baseline FMD, older age, reductions in total and LDL cholesterol, reduction in diastolic blood pressure, increases in EPC colonies, and improvement in exercise fitness accounted for nearly half of the variability in improved brachial artery FMD with program participation, suggesting multifactorial contribution to improvement in endothelial function. In contrast, neither BMI at baseline nor change in weight during program participation was a predictor of improved endothelial function.

A mechanism proposed previously for improvement in endothelial function is that exercise may mobilize bone marrow–derived EPCs into the circulation, with attachment to arteries in the circulation and the replacement of dysfunctional endothelium.¹⁸, ¹⁹, ²⁰ We demonstrated increases in the number of EPCs measured by colony assay and, in a subset, by flow cytometry. By multiple stepwise procedure, the increase in EPC colonies made a small but statistically significant contribution to improvement in endothelial function in our study participants.

An unanticipated finding in our study was that HDL cholesterol levels actually decreased during program participation, especially in men. Previous studies have shown that exercise may increase HDL cholesterol levels, but a recent meta-analysis of 25 randomized clinical trials concluded that there may be critical determinants for significant increase in HDL cholesterol, including minimum exercise volume (>120 minutes of weekly exercise).²¹ Longer durations of daily exercise may also be required for weight loss (which was minimal in our cohort), improvement in insulin sensitivity, and reduction in levels of hsCRP. Reduction in hsCRP was reported for 199 healthy women participating in a 2-month exercise program in which average weight loss was 3 kg.²²

Limitations of our study include the nonrandomized design, although testing was performed by different investigators without knowledge of one another's results. Exercise time per week was self-reported, and not all subjects used the exercise equipment provided in the rooms for the same duration of time or intensity of exercise. Nonetheless, participants showed significant improvement in exercise fitness, by increased duration of exercise during treadmill stress testing and measurement of peak oxygen consumption. Reproductive-age women were not tested during the same phase of the menstrual cycle, for practical considerations. The baseline and 3-month estradiol and follicle-stimulating hormone levels were similar, however, and any effects of testing during differing phases of the cycle during would be expected to diminish our ability to determine exercise effects on study parameters, including FMD. We did not measure endothelium-independent vasodilation, which has been shown previously not to change with exercise training.²³ Finally, a subset of subjects were taking medications (previously prescribed for ≥1 month, with no changes during the program) that might have affected study parameters. Subgroup analyses, however, showed that the benefits of exercise were apparent in these subjects, as was determined for most of the participants not receiving these therapies.

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Acknowledgment 

This research was funded by the intramural research programs of the National Heart, Lung, and Blood Institute and the Clinical Center, NIH.

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References 

1. DeSouza CA, Shapiro LF, Clevenger CM, Dinenno FA, Monahan KD, Tanaka H, et al. Regular aerobic exercise prevents and restores age-related declines in endothelium-dependent vasodilation in healthy men. Circulation. 2000;102:1351–1357
   • View In Article
2. Green DJ, Walsh JH, Maiorana A, Best MJ, Taylor RR, O'Driscoll JG. Exercise-induced improvement in endothelial dysfunction is not mediated by changes in CV risk factors: pooled analysis of diverse patient populations. Am J Physiol Heart Circ Physiol. 2003;285:H2679–H2687
   • View In Article
   • MEDLINE
3. Harvey PJ, Picton PE, Su WS, Morris BL, Notarius CF, Floras JS. Exercise as an alternative to oral estrogen for amelioration of endothelial dysfunction in postmenopausal women. Am Heart J. 2005;149:291–297
   • View In Article
   • Abstract
   • Full Text
   • Full-Text PDF (152 KB)
   • CrossRef
4. Krause WE, Houmard JA, Duscha BD, Knetzger KJ, Wharton MB, McCartney JS, et al Effects of the amount and intensity of exercise on plasma lipoproteins. N Engl J Med. 2002;347:1483–1492
   • View In Article
   • CrossRef
5. Duncan GE, Perri MG, Theriaque DW, Hutson AD, Eckel RH, Stacpoole PW. Exercise training, without weight loss, increases insulin sensitivity and postheparin plasma lipase activity in previously sedentary adults. Diabetes Care. 2003;26:537–562
   • View In Article
6. American Heart Association. Heart Disease and Stroke Statistics—2005 Update. Dallas, Texas: American Heart Association; 2005;
   • View In Article
7. Verma S, Buchanan MR, Anderson TJ. Endothelial function testing as a biomarker of vascular disease. Circulation. 2003;108:2054–2059
   • View In Article
   • CrossRef
8. Lerman A, Zeiher AM. Endothelial function (Cardiac events). Circulation. 2005;111:363–368
   • View In Article
   • CrossRef
9. Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia. 1985;28:412–419
   • View In Article
   • MEDLINE
   • CrossRef
10. Hill JM, Zalos G, Halcox JPJ, Schenke WH, Waclawiw MA, Quyyumi AA, et al. Circulating endothelial progenitor cells, vascular function, and cardiovascular risk. N Engl J Med. 2003;348:593–600
    • View In Article
    • CrossRef
11. Wasserman K. Breathing during exercise. N Engl J Med. 1978;298:780–785
    • View In Article
    • MEDLINE
    • CrossRef
12. Lichtenstein AH, Appel LJ, Brands M, Carnethon M, Daniels S, Franch HA, et al Diet and lifestyle recommendations revision 2006 (A scientific statement from the American Heart Association Nutrition Committee). Circulation. 2006;114:82–96
    • View In Article
    • CrossRef
13. Blair SN, Piserchia PV, Wilbur CS, Crowder JH. A public health intervention model for work-site health promotion (Impact on exercise and physical fitness in a health promotion plan after 24 months). JAMA. 1986;255:921–926
    • View In Article
    • MEDLINE
14. Shephard RJ. Worksite fitness and exercise programs: a review of methodology and health impact. Am J Health Promot. 1996;10:436–452
    • View In Article
    • MEDLINE
15. Dishman RK, Oldenburg B, O'Neal H, Shephard RJ. Worksite physical activity interventions. Am J Prev Med. 1998;15:344–361
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (171 KB)
    • CrossRef
16. Proper KI, Koning M, van der Beek AJ, Hildebrant VH, Bosscher RJ, van Mechelen W. The effectiveness of worksite physical activity programs on physical activity, physical fitness, and health. Clin J Sport Med. 2003;13:106–117
    • View In Article
    • MEDLINE
    • CrossRef
17. Hambrecht R, Adams V, Erbs S, Linke A, Krankel N, Shu Y, et al Regular physical activity improves endothelial function in patients with coronary artery disease by increasing phosphorylation of endothelial nitric oxide synthase. Circulation. 2003;107:3152–3158
    • View In Article
    • CrossRef
18. Laufs U, Werner N, Link A, Endres M, Wassmann S, Jurgens K, et al. Physical training increases endothelial progenitor cells, inhibits neointima formation, and enhances angiogenesis. Circulation. 2004;109:220–226
    • View In Article
    • CrossRef
19. Rehman J, Li J, Parvathaneni L, Karlsson G, Panchal VR, Temm CJ, et al. Exercise acutely increases circulating endothelial progenitor cells and monocyte-/macrophage-derived angiogenic cells. J Am Coll Cardiol. 2004;43:2314–2318
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (164 KB)
    • CrossRef
20. Steiner S, Niessner A, Ziegler S, Richter B, Seidinger D, Pleiner J, et al Endurance training increases the number of endothelial progenitor cells in patients with cardiovascular risk and coronary artery disease. Atherosclerosis. 2005;181:305–310
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (108 KB)
    • CrossRef
21. Kodoma S, Tanaka S, Saito K, Shu M, Sone Y, Onitake F, et al Effect of aerobic exercise training on serum levels of high-density lipoprotein cholesterol. Arch Intern Med. 2007;167:999–1008
    • View In Article
    • MEDLINE
    • CrossRef
22. Okita K, Nishijima H, Murakami T, Nagai T, Morita N, Yonezawa K, et al. Can exercise training with weight loss lower serum C-reactive protein levels?. Arterioscler Thromb Vasc Biol. 2004;24:1868–1873
    • View In Article
    • CrossRef
23. Goto C, Higashi Y, Kimura M, Noma K, Hara K, Nakagawa K, et al. Effect of different intensities of exercise on endothelium-dependent vasodilation in humans (Role of endothelium-dependent nitric oxide and oxidative stress). Circulation. 2003;108:530–535
    • View In Article
    • CrossRef