 |
|
Long-term Exercise and Atherogenic Activity of Blood Mononuclear Cells in Persons at Risk of Developing Ischemic Heart Disease
J. Kelly Smith, MD;
Rhesa Dykes, BS;
John E. Douglas, MD;
Guha Krishnaswamy, MD;
Steven Berk, MD
JAMA. 1999;281:1722-1727.
ABSTRACT
| |
Context Increasing evidence demonstrates that atherosclerosis is an immunologically mediated disease in which the secretion of atherogenic and atheroprotective cytokines, by infiltrating blood mononuclear cells, plays an important role. It is not known whether long-term exercise alters this atherogenic and atheroprotective activity directly.
Objective To determine the effect of long-term exercise on the atherogenic activity of blood mononuclear cells in persons at risk of developing ischemic heart disease.
Design Before-after trial using a 6-month individualized, supervised exercise program, with an enrollment period from December 1996 to October 1997.
Setting Hospital-based community wellness center.
Participants Of 110 persons who responded to a public request for volunteers, 52 met the inclusion criteria (risk ratio for myocardial infarction  1.7 based on serum complement and/or C-reactive protein levels, and normal exercise treadmill test results). Forty-three of the 52 enrollees (25 women [mean age, 49.7 years] and 18 men [mean age, 48.1 years]) completed the study; 9 withdrew for personal reasons. Additional risk factors for ischemic heart disease included hypercholesterolemia (65.1%), a family history of coronary heart disease (62.8%), inactivity (60.5%), hypertension (32.6%), obesity (25.6%), smoking (11.6%), and diabetes mellitus (4.7%).
Main Outcome Measures Blood levels were compared at baseline and after the exercise program had been completed for the following: spontaneous and phytohemagglutinin-induced production of interleukin 1  , tumor necrosis factor , and interferon gamma (atherogenic cytokines), and interleukin 4, interleukin 10, and transforming growth factor beta 1 (atheroprotective cytokines) by blood mononuclear cells; lymphocyte phenotypes and mitogenic responses to phytohemagglutinin; and serum C-reactive protein levels.
Results Subjects exercised for a mean of 2.5 (range, 0.3-7.4) hours per week. Mononuclear cell production of atherogenic cytokines fell by 58.3% (P<.001) following the exercise program, whereas the production of atheroprotective cytokines rose by 35.9% (P<.001). Changes in transforming growth factor beta 1 and in phytohemagglutinin-induced atherogenic cytokine production after the exercise program were proportionate to the time subjects spent performing repetitive lower-body motion exercises (P<.02), indicating a dose-response relationship. After the exercise program, changes in cellular function were reflected systemically by a 35% decrease in serum levels of C-reactive protein (P=.12).
Conclusions Our data suggest that long-term exercise decreases the atherogenic activity of blood mononuclear cells in persons at risk of developing ischemic heart disease. This may be a mechanism whereby physical activity protects against ischemic heart disease.
INTRODUCTION
Although the age-adjusted death rate due to cardiovascular disease (CVD) has declined in the past 25 years, heart disease remains the leading cause of death in the United States, accounting for 733,834 deaths, or 31.6% of total mortality, in 1996.1
A number of studies have shown that moderate-intensity physical activity reduces the incidence of all-cause mortality, particularly deaths due to CVD.2-9 The accumulated evidence on the health benefits of physical activity prompted participants in a National Institutes of Health Consensus Conference to recommend that "children and adults alike should set a goal of accumulating at least 30 minutes of moderate-intensity physical activity on most, and preferably all, days of the week."10
Despite the documented health benefits, the mechanism whereby physical activity prevents CVD is incompletely understood, although it is probably multifactoral. Risk factors such as hypertension,11 obesity,12 hyperlipidemia,13 and insulin resistance14 may respond favorably to moderate levels of physical activity, thereby protecting against CVD. However, because exercise also protects against CVD in smokers and in persons without evident risk factors,6 it appears to favorably influence the course of atherogenesis in ways yet to be discovered. Whatever the reasons, reports have documented a strong and independent association of low cardiorespiratory fitness and low levels of physical activity and the risk of death due to CVD.2-10
There is increasing evidence that atherosclerosis may be an immunologically mediated disease.15-24 Early atherosclerotic lesions contain activated immune cells, including CD4+ and CD8+ T cells, monocytes, macrophages, and endothelial cells. These cells are responsible for the local production of a variety of cytokines that have been identified in atherosclerotic lesions, including interleukin (IL) 1, IL-2, IL-4, IL-6, IL-10, tumor necrosis factor alpha (TNF-), interferon gamma (IFN- ), and transforming growth factor beta (TGF- ). There is provocative but, as yet, inconclusive evidence that this immune reaction may be in response to an infectious agent,25-27 heat shock protein (HSP) 60,19, 23 or oxidized low-density lipoprotein (LDL).28 Whatever the inciting events, in transplanted human hearts, activation of coronary endothelial cells is predictive of the subsequent development of coronary atherosclerosis,29 lending credence to the importance of the immune response in the early stages of CVD. Indirect evidence is also found in reports documenting an association between blood levels of acute-phase reactants, notably C-reactive protein (CRP),30-31 fibrinogen,31 and C332 and the future risk of heart attack. Acute phase reactants are produced by hepatocytes in response to several cytokines, notably IL-1, IL-6, and TNF-, and often serve to minimize tissue damage that follows an inflammatory response.
In this study, we investigated the possibility that long-term exercise benefits persons at risk of developing ischemic heart disease by favorably altering the production of cytokines with atherogenic and atheroprotective properties. According to current evidence, the cytokines with atherogenic properties include IL-1, TNF-, and IFN-.16-24 The cytokines with atheroprotective properties include IL-4, IL-10, and TGF-.33-50 Because blood leukocytes provide the major source of immune cells in atherosclerotic lesions21 and because it is not feasible to obtain these cells from arterial biopsy specimens, we have chosen to measure the effect of exercise on the production of these cytokines by blood mononuclear cells. We have also determined the effect of exercise on serum levels of CRP, an acute-phase protein that has been speculated to serve as a marker of the severity of the immune-mediated inflammatory response in atherosclerosis.30
METHODS
Subjects
This study was approved by the institutional review board of East Tennessee State University, Johnson City. Each participant read and signed the informed consent in the presence of an investigator.
Subjects were recruited from the general public by placing an outline of the study and a request for volunteers in 3 local newspapers. A total of 110 persons responded and were screened for participation in the study. Of these, 54 had serum C3 and/or CRP levels that placed them at greater risk of future heart attack (risk ratio 1.7),30, 32 and they underwent exercise treadmill testing (ETT) using a modified Bruce protocol. Fifty-two subjects had normal ETT results and qualified for final inclusion in the study. These subjects were enrolled in a hospital-based wellness center where, after analysis of their medical history and previous levels of activity, they were assigned to supervised and individually tailored exercise programs. To minimize seasonal influences on the results, 4 to 5 subjects were enrolled each month over an 11-month period extending from December 1996 to October 1997. Subjects were not paid for participating in the study. Forty-three subjects (18 men, 25 women) successfully completed the study. Nine subjects withdrew for personal reasons. Summaries of subject demographics and risk factors for CVD are shown in Table 1.
|
|
|
|
Table 1. Risk Factors for Cardiovascular Disease*
|
|
|
Medications taken daily during the study included aspirin (30.2%), antihypertensive agents (25.6%), thyroxine (16.3%), lipid-lowering agents (14%), antidepressants (11.6%), insulin (2.3%), and an oral hypoglycemic (2.3%). Nineteen subjects (44.2%) consumed an average of 2.3 alcoholic beverages a week. Medications taken daily only by women included estrogen (64%), progesterone (28%), biophosphonates (8%), and oral contraceptives (4%).
Immunologic studies were performed at baseline and after completion of the 6-month exercise program. All blood samples were drawn in the morning at approximately the same time of day. Subjects were instructed not to exercise for at least 24 hours prior to blood drawing.
Blood CRP
C-reactive protein serum levels were assayed before and after the exercise program by radial immunodiffusion using CRP LL and CRP EL Nanorid kits (The Binding Site Ltd, Birmingham, England).
Lymphocyte Phenotyping
Immunophenotyping of blood lymphocytes was performed with lysed whole blood and a FACScan flow cytometer (Becton Dickinson, San Jose, Calif) and fluorescein- and phycoerythrin-labeled murine monoclonal IgG antibodies to measure levels of T lymphocytes (CD3+); T helper lymphocytes (CD4+); T cytotoxic lymphocytes (CD8+); T lymphocytes displaying major histocompatibility complex class II antigen (DR+), vascular adhesion molecule 4 (VLA-4) (CD49d+), Fas antigen (CD95+), or gamma-delta antigen T-cell receptor (TCR +); B lymphocytes (CD3-CD19+); and natural killer (NK) cells (CD3-CD16+CD56+).
Cytokine Production
Blood mononuclear cell preparations containing 15% to 20% monocytes and 80% to 85% lymphocytes were isolated from venous blood using Accu-Prep (Accurate Chemical & Scientific Corp, Westbury, NY), washed 3 times at 10°C with sterile phosphate-buffered saline solution (pH, 7.4; 0.1 mol/L), and suspended at a concentration of 2 x 106 cells/mL in Rosewell Park Memorial Institute Growth Medium, formula 1640 (Mediatech, Herndon, Va) containing 5% heat inactivated human AB serum (vol/vol), l-glutamine (2 mmol/L), penicillin (50 U/mL), and gentamicin and streptomycin (50 µg/mL each). Preparations were incubated under 5% carbon dioxide at 37°C for 48 hours with and without the T-cell mitogen phytohemagglutinin (PHA) (5 µg/mL). Culture supernatants were rendered cell free by centrifuging at 1000g for 10 minutes at 12°C, and stored in 1- to 2-mL aliquots at -120°C for later use. Supernatants were subsequently assayed for IL-1, IL-4, IL-10, IFN-, TNF-, and TGF-1 using solid-phase enzyme-linked immunoassay kits (Quantikine, R & D Systems, Inc, Minneapolis, Minn, for IL-1 and TGF-1; Predicta, Genzyme Corp, Cambridge, Mass, for TNF-; Cytoscreen, BioSource International, Inc, Camarillo, Calif, for IFN-; and Immunotech, Inc, Westbrook, Me, for IL-4 and IL-10).
Mitogenic Assays
Mitogenic responses were measured by adding methyl-3H-thymidine (0.74 MBq, 50 µL) to culture samples removed 6 hours prior to supernatant harvesting. Labeled samples were incubated under 5% carbon dioxide at 37°C for an additional 6 hours and the cells collected on glass fiber filter paper using a Mash II Cell Harvester (Microbiology Associates, Walkersville, Md). Samples were air dried, placed in vials containing Scinti-Verse II, and assayed with a Beckman LS 9800 liquid scintillation counter (Beckman, Fullerton, Calif). Proliferative responses are expressed as net counts per minute ( cpm), calculated as cpm in PHA-stimulated cultures minus cpm in unstimulated cultures. The mitogenic assay used in this study had been optimized in accordance with standard procedures using varying concentrations of PHA, cells per well, and incubation times.51
Statistical Analysis
Statistical analysis was performed using STATISTICA 5.1 F (Statsoft, Inc, Tulsa, Okla). The 2-sided t test for paired samples was used to determine the significance of differences between cytokine, lymphocyte phenotype, and CRP measurements in blood samples taken before and after the exercise program. A 2-sided t test for independent samples was used to determine within-group differences. A  2 analysis was used to determine the significance of differences between expected and observed frequencies. Unless stated otherwise, results are expressed as the mean (SEM).
RESULTS
Production of Atherogenic Cytokines
The production of IFN- and TNF- by blood mononuclear cells was significantly attenuated in both PHA-negative and PHA-positive cultures by exercise (Table 2). Compared with baseline values, IFN- levels fell by 44% and 71% and TNF- values by 28% and 51% in cultures with and without added PHA, respectively (P .007). In addition, IL-1 secretion fell by 13% in PHA-stimulated cultures (P=.047). Overall the production of atherogenic cytokines fell by 58.3% after the exercise program (P<.001).
|
|
|
|
Table 2. Effect of Exercise on Cytokine Production by Blood Mononuclear Cells*
|
|
|
Production of Atheroprotective Cytokines
In contrast to the effects of exercise on the production of atherogenic cytokines, the production of IL-4, IL-10, and TGF-1 by blood mononuclear cells was significantly augmented by exercise (Table 2 In PHA-negative cultures, IL-10 levels increased by 940% and TGF-1 by 43% (P.003). In PHA-positive cultures, significant changes were seen in IL-4 (94% increase) and TGF-1 (37% increase) (P.001). Overall the production of atheroprotective cytokines increased by 35.9% after the exercise program (P<.001).
Lymphocyte Phenotypes
There were no significant changes in the numbers or percentages of lymphocyte phenotypes following exercise (Table 3).
|
|
|
|
Table 3. Effect of Exercise on Blood Lymphocyte Levels*
|
|
|
Mitogenic Responses
Proliferative responses of lymphocytes to PHA decreased following exercise, from a mean (SEM) value of 9142 (760) cpm to 3155 (584) cpm (P<.001).
CRP Levels
C-reactive protein levels measured before the exercise program ranged from 0 to 0.9 mg/dL in the lower quartile to 5.8 to 37.5 mg/dL in the upper quartile, with a mean (SEM) value of 4.81 (1.09) mg/dL. Values taken after the exercise program decreased by 35% to 3.13 (0.64) mg/dL (P=.12) (2-sided t test). The frequency of values in the upper quartile dropped by 50% following exercise (P=.01) (2 analysis).
Exercise Parameters
The mean number of hours per week that subjects underwent supervised exercise was 2.5 (range, 0.3-7.4 hours per week). The mean duration of each exercise session was 70 minutes (range, 36-123 minutes), and the mean number of visits per week was 2 (range, 0.3-5.3 visits per week). The mean percentage of time spent doing different exercises was as follows: weight lifting (35%), walking or running on a treadmill (32%), cycling (16%), stretching (8%), aerobics (3%), rowing (3%), climbing (2%), and skiing (1%).
Four subjects (9.3%) changed their diet to one that was lower in energy intake and animal fat, and 2 of the 5 tobacco users discontinued smoking during the study. By completion of the study, 15 subjects (34.9%) had lost weight, with the mean weight for all subjects falling from 80.1 to 77.4 kg (P=.02). There were no changes in medications or alcohol consumption during the study.
Relationship of Exercise Parameters to Cytokine Production
The percentage decrease in atherogenic cytokine production by PHA-stimulated mononuclear cells was proportionate to the time subjects spent performing repetitive lower-body motion exercises (ie, walking, running, cycling, rowing, climbing, aerobics, and skiing) (r=-0.267, P=.002). The correlation was most significant for IFN- (P=.03) (Figure 1), followed by IL-1 (P=.05) and TNF- (P=.09).
In contrast, both the spontaneous and PHA-induced production of TGF-1 increased in proportion to the time spent doing these exercises (r0.354, P.02). No other correlations were found between exercise parameters and main outcome measures.
Within-Group Variations
Blood mononuclear cells taken from men prior to exercise produced more IFN- and TNF- in cultures without added PHA than did mononuclear cells taken from women (P.04). Following exercise, men spontaneously produced more IL-1 and TNF- than women (P.004). In contrast, men had lower circulating levels of CD4+ and VLA-4+ T cells prior to and after exercise (P.049), and lower levels of CD95+ T cells following exercise (P=.03). Mitogenic responses before the exercise program were also lower in men (P=.03), whereas there was no difference in proliferative responses to PHA in samples between men and women taken after the exercise program.
Mononuclear cells of hypertensive subjects produced significantly more IL-1 and TNF- than those of normotensive subjects following exercise (P.03). The production of IL-1 and TNF- was also higher in hypertensive subjects before the exercise program, with differences approaching statistical significance (P.13). This finding may explain in part the higher levels of IL-1a and TNF- in men, since they had a higher prevalence of hypertension than did women.
No within-group differences could be demonstrated as a result of menopause, estrogen therapy, use of aspirin or other medications, alcohol consumption, obesity, hypercholesterolemia, smoking, diabetes mellitus, dieting, weight loss, or smoking cessation during the study.
COMMENT
In our study, 6 months of moderate-intensity exercise attenuated blood mononuclear cell production of cytokines with predominantly atherogenic properties, while simultaneously augmenting the production of cytokines with predominantly atheroprotective properties.
The decrease in atherogenic cytokine production by PHA-stimulated mononuclear cells and the increase in mononuclear cell production of the atheroprotective cytokine TGF-1 after the exercise program were proportionate to the time subjects spent in performing repetitive lower-body motion exercises, indicating the existence of a dose-response relationship between exercise and mononuclear cell function in our subjects. The changes in immune cell function were accompanied by a reduction in serum CRP, a possible systemic reflection of decreased IL-1 and TNF- production and a favorable sign in persons at risk of developing CVD.30-31 Importantly, the changes were unrelated to the ingestion of aspirin or other medications, or to dieting, weight loss, or smoking cessation during the study. Subjects included men and women who had been selected from the general population and who had well-defined risk factors for ischemic heart disease.
We found that exercise had a particularly significant attenuating effect on the production of IFN- and TNF-. Both of these cytokines have been identified in early and advanced atherosclerotic lesions and are postulated to play preeminent roles in atherogenesis.16-24 Tumor necrosis factor alpha is produced primarily by monocytes and macrophages and is a potent proinflammatory cytokine.33 Interferon gamma is produced in T-helper type 1 (Th1) lymphocytes, NK cells, and cytotoxic T lymphocytes and is the most important cytokine regulating the activities of mononuclear phagocytes35, 52 and, therefore, cell-mediated immune responses of the type seen in atherosclerotic lesions.16-17 Both cytokines can activate endothelial cells, monocytes, macrophages, and smooth muscle cells, thereby contributing to leukocyte recruitment, endothelial cell procoagulant activity, LDL oxidation, and foam cell formation in atherosclerotic lesions.16-24 The importance of IFN- in atherogenesis has recently been demonstrated in transgenic mice with targeted disruptions of the APOE gene and the IFN- receptor gene (apoE 0/IFN-R 0 mice).53 These mice demonstrate a substantial reduction in atherosclerotic lesion size, cellularity, and lipid accumulation, and an increase in plasma concentrations of potentially atheroprotective phospholipid/apoliprotein A-IV rich particles when compared with APOE 0 mice, suggesting that IFN- promotes and modifies atherosclerosis through its local effects in the arterial wall as well as by its effects on plasma lipoproteins.
In contrast to the atherogenic cytokines, the production of cytokines that possess predominantly atheroprotective properties was augmented by exercise. In unstimulated blood mononuclear cell cultures, the cytokine most affected was IL-10, followed by TGF-1. The secretory responses of PHA-stimulated cultures were generally similar, except that IL-4 production was also up-regulated by exercise. These cytokines effectively down-regulate delayed-type hypersensitivity reactions of the type seen in atherosclerotic lesions, primarily by suppressing mononuclear phagocyte and Th1 lymphocyte function.33-50,52 They inhibit endothelial cell, monocyte, macrophage, and smooth muscle cell activation by down-regulating the production of IL-1 and TNF- by mononuclear phagocytes (IL-4, IL-10, and TGF-1), and IFN- production by Th1 lymphocytes (IL-10 and TGF-). They also reduce IL-1 activity by augmenting the production of IL-1 receptor antagonist.33 Although TGF- is thought to be primarily responsible for stimulating collagen and proteoglycan synthesis by vascular smooth muscle cells in atherosclerotic plaques, it inhibits the proliferation and migration of these cells in atherosclerotic lesions48 and is thought to function primarily as an atheroprotective cytokine.44-50 In this regard, low plasma levels of TGF- have been documented in patients with ischemic heart disease,46 possibly due to its sequestration into an inactive pool by lipoproteins.45 It is of note that, in our study, mononuclear cell production of TGF-1 increased in proportion to time spent doing exercises traditionally considered to be cardioprotective.
It is probable that the changes in blood mononuclear cell function among the subjects after undergoing the exercise program resulted, at least in part, from an augmented suppression of TNF- and IFN- production by the atheroprotective cytokines. Furthermore, because blood leukocytes are thought to provide the main source of immune cells in atherosclerosis, similar functional changes may have occurred in mononuclear cells present in atherosclerotic lesions.21 This possibility is supported indirectly by the decrease in serum levels of CRP in our subjects after the exercise program. It remains uncertain, however, what initiated these changes. Since herpes viruses and chlamydia have been isolated from atherosclerotic plaques,25-27 it is possible that physical activity stimulated the immune system to eradicate these agents. Alternatively, it may be that exercise reduced levels of oxidized LDL or HSP 60 in fatty streaks and atherosclerotic plaques in our subjects. Both of these molecules have been postulated to be the target of an autoimmune attack in atherosclerosis and are capable of independently activating endothelial cells.19, 23, 28 Whatever the explanation, our finding that moderate long-term exercise reduces blood mononuclear cell production of cytokines with predominantly atherogenic properties, while simultaneously increasing their production of cytokines with predominantly atheroprotective properties, provides an insight as to how physical activity helps protect against CVD.
AUTHOR INFORMATION
Funding/Support: This research was supported by grants from the Rondal B. Cole Foundation, Johnson City, Tenn, the Dishner Chair of Excellence in Medicine, Tennessee grant 20233, and the Cardiovascular Research Institute of the James H. Quillen College of Medicine and Johnson City Medical Center Hospital, Johnson City, Tenn.
Acknowledgment: We thank Scott Reynolds and Karen Cantor for their technical assistance, and we recognize the contributions of members of the Division of Cardiology, Jack Whitaker, MD, and Christopher Downs, MD. A special thanks to William Joyner, PhD, and Jim Gill for their support, and to Johnson City Medical Center Hospital for providing the exercise facilities and supervisory staff.
Corresponding Author and Reprints: J. Kelly Smith, MD, Department of Internal Medicine, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614 (e-mail: smithj{at}access.etsu.edu).
Author Affiliations: Divisions of Immunology (Drs Smith, Krishnaswamy, and Berk, and Ms Dykes) and Cardiology (Dr Douglas), Department of Internal Medicine, James H. Quillen College of Medicine, East Tennessee State University, Johnson City.
REFERENCES
| |
1. Centers for Disease Control and Prevention. Mortality patterns: preliminary data, United States, 1996. MMWR Morb Mortal Wkly Rep. 1997;46:941-944.
PUBMED
2. Paffenbarger RS Jr, Wing AL, Hyder T. Physical activity as an index of heart attack risk in college alumni. Am J Epidemiol. 1978;108:161-175.
FREE FULL TEXT
3. Blair SN, Kohl III HW, Paffenbarger RS Jr, Clark DG, Cooper KG, Gibbons LW. Physical fitness and all-cause mortality: a prospective study of healthy men and women. JAMA. 1989;262:2395-2401.
FREE FULL TEXT
4. Lee IM, Hsieh CC, Paffenbarger RS Jr. Exercise intensity and longevity in men: the Harvard Alumni Study. JAMA. 1995;273:1179-1184.
FREE FULL TEXT
5. Blair SN, Kohl III HW, Barlow CE, Paffenbarger RS Jr, Gibbons LW, Macera CA. Changes in physical fitness and all-cause mortality. JAMA. 1995;273:1093-1098.
FREE FULL TEXT
6. Blair SN, Kampert JB, Kohl III HW, et al. Influences of cardiorespiratory fitness and other precursors on cardiovascular disease and all-cause mortality in men and women. JAMA. 1996;276:205-210.
FREE FULL TEXT
7. Kushi LH, Fee RM, Folsom AR, Mink PJ, Anderson KE, Sellers TA. Physical activity and mortality in postmenopausal women. JAMA. 1997;277:1287-1292.
FREE FULL TEXT
8. Kujala UM, Kaprio J, Sarna S, Koskenvuo M. Relationship of leisure-time physical activity and mortality: the Finnish twin cohort. JAMA. 1998;279:440-444.
FREE FULL TEXT
9. Hakim AA, Petrovitch H, Burchfiel CM, et al. Effects of walking on mortality among nonsmoking retired men. N Engl J Med. 1998;338:93-94.
10. National Institutes of Health Consensus Development Panel on Physical Activity and Cardiovascular Health. Physical activity and cardiovascular health. JAMA. 1996;276:241-246.
FREE FULL TEXT
11. American College of Sports Medicine. Physical activity, physical fitness, and hypertension: position stand. Med Sci Sports Exerc. 1993;25:1-10.
12. Blair SN. Evidence for success of exercise in weight loss and control. Ann Intern Med. 1993;119:702-706.
FREE FULL TEXT
13. Stefanick ML, Wood PD. Physical activity, lipid and lipoprotein metabolism, and lipid transport. In: Bouchard C, Shephard RJ, Stephens T, eds. Physical Activity, Fitness, and Health: International Proceedings and Consensus StatementChampaign, Ill: Human Kinetics Publishers Inc; 1994:417-431.
14. Mayer-Davis EJ, D'Agostino R Jr, Kerter AJ, et al. Intensity and amount of physical activity in relation to insulin sensitivity: the insulin resistance atherosclerosis study. JAMA. 1998;279:669-674.
FREE FULL TEXT
15. Van Der Wal AC, Das PK, Van De Berg DB, Van Der Loos CM, Becker AE. Atherosclerotic lesions in humans: in situ immunophenotypic analysis suggesting an immune mediated response. Lab Invest. 1989;61:166-170.
ISI
| PUBMED
16. Munro JM, Cotran RS. Biology of disease: the pathogenesis of atherosclerosis, atherogenesis and inflammation. Lab Invest. 1988;58:249-261.
ISI
| PUBMED
17. Libby P, Hansson GK. Biology of disease involvements of the immune system in human atherogenesis: current knowledge and unanswered questions. Lab Invest. 1991;64:5-15.
ISI
| PUBMED
18. Ross R. The pathogenesis of atherosclerosis: a perspective for the 1990s. Nature. 1993;362:801-809.
FULL TEXT
| PUBMED
19. Wick G, Schett G, Amberger A, Kleindienst R, Xu Q. Is atherosclerosis an immunologically mediated disease? Immunol Today. 1995;16:27-33.
FULL TEXT
|
ISI
| PUBMED
20. Yokota T, Hansson GK. Immunological mechanisms in atherosclerosis. J Intern Med. 1995;238:479-489.
ISI
| PUBMED
21. Watanabe T, Haraoka S, Shimokama T. Inflammatory and immunological nature of atherosclerosis. Int J Cardiol. 1996;54(suppl):S51-S60.
22. Selwyn AP, Kinlay S, Ganz P. Atherogenesis and ischemic heart disease. Am J Cardiol. 1997;80:3H-7H.
23. Wick G, Romen M, Amberger A, et al. Atherosclerosis, autoimmunity, and vascular-associated lymphoid tissue. FASEB J. 1997;11:1199-1207.
ISI
| PUBMED
24. Campbell JH, Campbell GR. The cell biology of atherosclerosis: new developments. Aust N Z J Med. 1997;27:497-500.
ISI
| PUBMED
25. Adam E, Melnick JL, Probtsfield JL, et al. High levels of cytomegalovirus antibody in patients requiring vascular surgery for atherosclerosis. Lancet. 1987;2:291-293.
FULL TEXT
|
ISI
| PUBMED
26. Yamashiroya HM, Ghosh L, Yang R, Robertson AL Jr. Herpesviridae in the coronary arteries and aorta of young trauma victims. Am J Pathol. 1988;130:71-79.
ABSTRACT
27. Kuo CC, Grayston JT, Campbell LA, Goo YA, Wissler RW, Benditt EP. Chlamydia pneumoniae (TWAR) in coronary arteries of young adults (15-34 years old). Proc Natl Acad Sci U S A. 1995;92:6911-6914.
FREE FULL TEXT
28. Witztum JL. Immunological responses to oxidized LDL. Atherosclerosis. 1997;131:S9-S11.
29. Labarrere CA, Nelson DR, Faulk WP. Endothelial activation and development of coronary artery disease in transplanted human hearts. JAMA. 1997;278:1169-1175.
FREE FULL TEXT
30. Ridker PM, Cushman M, Stampfer MJ, Tracy RP, Hennekens CH. Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men. N Engl J Med. 1997;336:973-979.
FREE FULL TEXT
31. Danesh J, Collins R, Appleby P, Petro R. Association of fibrinogen, C-reactive protein, albumin, or leukocyte count with coronary artery disease: meta-analyses of prospective studies. JAMA. 1998;279:1477-1482.
FREE FULL TEXT
32. Muscari A, Bozzoli C, Puddu GM, et al. Association of serum C3 levels with the risk of myocardial infarction. Am J Med. 1995;98:357-364.
FULL TEXT
|
ISI
| PUBMED
33. Borish L, Rosenwasser LJ. Update on cytokines. J Allergy Clin Immunol. 1996;97:719-733.
FULL TEXT
|
ISI
| PUBMED
34. Te Velde AA, Huijbens RJF, Heije K, de Vries JE, Fidgor CG. Interleukin-4 (IL-4) inhibits secretion of IL-1, tumor necrosis factor , and IL-6 by human monocytes. Blood. 1990;76:1392-1397.
FREE FULL TEXT
35. Elliot MJ, Gamble JR, Park LS, Vadas MA, Lopez AE. Inhibition of human monocyte adhesion by interleukin-4. Blood. 1991;12:2739-2745.
36. Fenton MJ, Buras JA, Donnelly RP. IL-4 reciprocally regulates IL-1 and IL-1 receptor antagonist expression in human monocytes. J Immunol. 1992;149:1283-1288.
ABSTRACT
37. Vasse M, Paysant J, Soria J, Mirshahi S, Vannier JP, Soria C. Down-regulation of fibrinogen biosynthesis by IL-4, IL-10 and IL-13. Br J Haematol. 1996;93:955-961.
FULL TEXT
|
ISI
| PUBMED
38. Krakauer T. IL-10 inhibits the adhesion of leukocyte cells to IL-1 activated human endothelial cells. Immunol Lett. 1995;45:61-65.
FULL TEXT
|
ISI
| PUBMED
39. Fiorentino DF, Zlotnik A, Mosmann TR, Howard M, O'Garra A. IL-10 inhibits cytokine production by activated macrophages. J Immunol. 1991;147:3815-3822.
ABSTRACT
40. Bogdan C, Vodovotz Y, Nathan C. Macrophage deactivation by interleukin 10. J Exp Med. 1991;174:1549-1555.
FREE FULL TEXT
41. Grazinelli TT, Oswald IP, James SL, Sher A. IL-10 inhibits parasite killing and nitrogen production by IFN-activated macrophages. J Immunol. 1992;148:1792-1799.
ABSTRACT
42. D'Andrea A, Aste-Amezaga M, Vaiante NM, Ma X, Kubin M, Trinchieri G. Interleukin 10 (IL-10) inhibits human lymphocyte interferon- production by suppressing natural killer cell stimulatory factor/IL-12 synthesis in accessory cells. J Exp Med. 1993;178:1041-1048.
FREE FULL TEXT
43. Uyemura K, Demer LL, Castle SC, et al. Cross-regulatory roles of interleukin (IL)-12 and IL-10 in atherosclerosis. J Clin Invest. 1996;97:2130-2138.
ISI
| PUBMED
44. Vadas MA, Gamble JR, Rye K, Barter P. Regulation of leucocyte-endothelial interactions of special relevance to atherogenesis. Clin Exp Pharmacol Physiol. 1997;24:A33-A35.
45. Grainger DJ, Byrne CD, Witchell CM, Metcalfe JC. Transforming growth factor beta is sequestered into an inactive pool by lipoproteins. J Lipid Res. 1997;38:2344-2352.
ABSTRACT
46. Tashiro H, Shimokawa H, Yamamoto K, Momohara M, Tada H, Takeshita A. Altered plasma levels of cytokines in patients with ischemic heart disease. Coron Artery Dis. 1997;8:143-147.
ISI
| PUBMED
47. Reckless J, Metcalfe JC, Granger DJ. Tamoxifen decreases cholesterol sevenfold and abolishes lipid lesion development in apolipoprotein E knockout mice. Circulation. 1997;95:1542-1548.
FREE FULL TEXT
48. Angles-Cano E. Structural basis for the pathophysiology of lipoprotein (a) in the athero-thrombotic process. Braz J Med Biol Res. 1997;30:1271-1280.
ISI
| PUBMED
49. Di Febbo C, Baccante G, Reale M, et al. Transforming growth factor beta induces IL-1 receptor antagonist production and gene expression in rat vascular smooth muscle cells. Atherosclerosis. 1998;136:377-382.
FULL TEXT
|
ISI
| PUBMED
50. Takami S, Yamashita S, Kihara S, et al. Lipoprotein (a) enhances the expression of intercellular adhesion molecule-1 in cultured human umbilical vein endothelial cells. Circulation. 1998;97:721-728.
FREE FULL TEXT
51. Maluish AE, Strong DM. Lymphocyte proliferation. In: Rose NR, Friedman H, Fahey JL, eds. Manual of Clinical ImmunologyWashington, DC: American Society for Microbiology; 1986:274-281.
52. Farrar MA, Schreiber RD. The molecular cell biology of interferon- and its receptor. Annu Rev Immunol. 1993;11:571-611.
FULL TEXT
|
ISI
| PUBMED
53. Gupta S, Pablo AM, Jiang XC, Wang N, Tall AR, Schindler C. IFN-gamma potentiates atherosclerosis in ApoE knock-out mice. J Clin Invest. 1997;99:2752-2761.
ISI
| PUBMED
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati  Twitter
What's this?
THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES
|
Active middle-aged men have lower fasting inflammatory markers but the postprandial inflammatory response is minimal and unaffected by physical activity status
Dixon et al.
J. Appl. Physiol. 2009;107:63-68.
ABSTRACT
| FULL TEXT
Internet-delivered lifestyle physical activity intervention: limited inflammation and antioxidant capacity efficacy in overweight adults
Smith et al.
J. Appl. Physiol. 2009;106:49-56.
ABSTRACT
| FULL TEXT
Exercise training-induced lowering of inflammatory (CD14+CD16+) monocytes: a role in the anti-inflammatory influence of exercise?
Timmerman et al.
J. Leukoc. Biol. 2008;84:1271-1278.
ABSTRACT
| FULL TEXT
Comparison of Different Regression Analyses for Identifying Risk Factors in Obese and Nonobese Patients With Coronary Artery Disease
Yologlu et al.
ANGIOLOGY 2007;58:543-549.
ABSTRACT
State of the Art Reviews: Health Benefits Related to Exercise in Patients With Chronic Low-Grade Systemic Inflammation
Pedersen
AMERICAN JOURNAL OF LIFESTYLE MEDICINE 2007;1:289-298.
ABSTRACT
State of the Art Reviews: The Anti-Inflammatory Actions of Exercise Training
Flynn et al.
AMERICAN JOURNAL OF LIFESTYLE MEDICINE 2007;1:220-235.
ABSTRACT
The Effect of Weight Loss on C-Reactive Protein: A Systematic Review
Selvin et al.
Arch Intern Med 2007;167:31-39.
ABSTRACT
| FULL TEXT
Diet and exercise reduce low-grade inflammation and macrophage infiltration in adipose tissue but not in skeletal muscle in severely obese subjects
Bruun et al.
Am. J. Physiol. Endocrinol. Metab. 2006;290:E961-E967.
ABSTRACT
| FULL TEXT
Physical activity status, but not age, influences inflammatory biomarkers and toll-like receptor 4.
McFarlin et al.
Journals of Gerontology Series A: Biological Sciences and Medical Sciences 2006;61:388-393.
ABSTRACT
| FULL TEXT
Effect of exercise training on plasma levels of C-reactive protein in healthy adults: the HERITAGE Family Study
Lakka et al.
Eur Heart J 2005;26:2018-2025.
ABSTRACT
| FULL TEXT
Exercise training: only if needed?
Perk
Eur Heart J 2005;26:1939-1941.
FULL TEXT
Epidemiological evidence for the role of physical activity in reducing risk of type 2 diabetes and cardiovascular disease
Bassuk and Manson
J. Appl. Physiol. 2005;99:1193-1204.
ABSTRACT
| FULL TEXT
Association Between Physical Activity, Physical Performance, and Inflammatory Biomarkers in an Elderly Population: The InCHIANTI Study
Elosua et al.
Journals of Gerontology Series A: Biological Sciences and Medical Sciences 2005;60:760-767.
ABSTRACT
| FULL TEXT
The Effects of Physical Activity on Serum C-Reactive Protein and Inflammatory Markers: A Systematic Review
Kasapis and Thompson
J Am Coll Cardiol 2005;45:1563-1569.
ABSTRACT
| FULL TEXT
Behavioural treatments for chronic systemic inflammation: effects of dietary weight loss and exercise training
Nicklas et al.
CMAJ 2005;172:1199-1209.
ABSTRACT
| FULL TEXT
The anti-inflammatory effect of exercise
Petersen and Pedersen
J. Appl. Physiol. 2005;98:1154-1162.
ABSTRACT
| FULL TEXT
Effects of exercise and diet on chronic disease
Roberts and Barnard
J. Appl. Physiol. 2005;98:3-30.
ABSTRACT
| FULL TEXT
Effect of six months' exercise training on C-reactive protein levels in healthy elderly subjects
Hammett et al.
J Am Coll Cardiol 2004;44:2411-2413.
FULL TEXT
Elevated circulating levels of thioredoxin and stress in chronic heart failure
Jekell et al.
Eur J Heart Fail 2004;6:883-890.
ABSTRACT
| FULL TEXT
Effect of exercise training on endothelium-derived nitric oxide function in humans
Green et al.
J. Physiol. 2004;561:1-25.
ABSTRACT
| FULL TEXT
Can Exercise Training With Weight Loss Lower Serum C-Reactive Protein Levels?
Okita et al.
Arterioscler. Thromb. Vasc. Bio. 2004;24:1868-1873.
ABSTRACT
| FULL TEXT
Physical activity and risk of coronary heart disease in India
Rastogi et al.
Int J Epidemiol 2004;33:759-767.
ABSTRACT
| FULL TEXT
Effects of Aerobic Physical Exercise on Inflammation and Atherosclerosis in Men: The DNASCO Study: A Six-Year Randomized, Controlled Trial
Rauramaa et al.
ANN INTERN MED 2004;140:1007-1014.
ABSTRACT
| FULL TEXT
Inflammatory markers, D-dimer, pro-thrombotic factors, and physical activity levels in patients with peripheral arterial disease
McDermott et al.
Vasc Med 2004;9:103-105.
ABSTRACT
Diet-induced weight loss, exercise, and chronic inflammation in older, obese adults: a randomized controlled clinical trial
Nicklas et al.
Am. J. Clin. Nutr. 2004;79:544-551.
ABSTRACT
| FULL TEXT
Effects of Hypocaloric Diet and Exercise Training on Inflammation and Adipocyte Lipolysis in Obese Postmenopausal Women
You et al.
J. Clin. Endocrinol. Metab. 2004;89:1739-1746.
ABSTRACT
| FULL TEXT
Toll-like receptor 4 and CD14 mRNA expression are lower in resistive exercise-trained elderly women
Flynn et al.
J. Appl. Physiol. 2003;95:1833-1842.
ABSTRACT
| FULL TEXT
Effects of high-cholesterol diet and parallel exercise training on the vascular function of rabbit aortas: a time course study
Yang et al.
J. Appl. Physiol. 2003;95:1194-1200.
ABSTRACT
| FULL TEXT
Analytical Performance of a Highly Sensitive C-Reactive Protein-Based Immunoassay and the Effects of Laboratory Variables on Levels of Protein in Blood
Aziz et al.
CVI 2003;10:652-657.
ABSTRACT
| FULL TEXT
Physical Activity, Coronary Heart Disease, and Inflammatory Response
Rothenbacher et al.
Arch Intern Med 2003;163:1200-1205.
ABSTRACT
| FULL TEXT
C-Reactive Protein in the Prediction of Cardiovascular Events
Lloyd-Jones et al.
NEJM 2003;348:1059-1061.
FULL TEXT
Identifying Risk Factors in a Mostly Overweight Patient Population with Coronary Artery Disease
Yologlu et al.
ANGIOLOGY 2003;54:181-186.
ABSTRACT
Physical Fitness and C-Reactive Protein Level in Children and Young Adults: The Columbia University BioMarkers Study
Isasi et al.
Pediatrics 2003;111:332-338.
ABSTRACT
| FULL TEXT
Is Metabolic Syndrome X an Inflammatory Condition?
Das
Exp. Biol. Med. 2002;227:989-997.
ABSTRACT
| FULL TEXT
Prospective Study of C-Reactive Protein in Relation to the Development of Diabetes and Metabolic Syndrome in the Mexico City Diabetes Study
Han et al.
Diabetes Care 2002;25:2016-2021.
ABSTRACT
| FULL TEXT
Associations Between Cardiorespiratory Fitness and C-Reactive Protein in Men
Church et al.
Arterioscler. Thromb. Vasc. Bio. 2002;22:1869-1876.
ABSTRACT
| FULL TEXT
Exercise-Induced Suppression of Postprandial Lipemia: A Possible Mechanism of Endothelial Protection?
Chandrruangphen and Collins
Arterioscler. Thromb. Vasc. Bio. 2002;22:1239-1239.
FULL TEXT
Chronic Exercise Improves Endothelial Calcium Signaling and Vasodilatation in Hypercholesterolemic Rabbit Femoral Artery
Jen et al.
Arterioscler. Thromb. Vasc. Bio. 2002;22:1219-1224.
ABSTRACT
| FULL TEXT
Relationship Between Physical Activity and Inflammation Among Apparently Healthy Middle-aged and Older US Adults
Abramson and Vaccarino
Arch Intern Med 2002;162:1286-1292.
ABSTRACT
| FULL TEXT
Extrapolation of Correlation Between 2 Variables in 4 General Medical Journals
Kuo
JAMA 2002;287:2815-2817.
ABSTRACT
| FULL TEXT
Survival of the Fittest -- More Evidence
Balady
NEJM 2002;346:852-854.
FULL TEXT
High-Sensitivity C-Reactive Protein : Potential Adjunct for Global Risk Assessment in the Primary Prevention of Cardiovascular Disease
Ridker
Circulation 2001;103:1813-1818.
ABSTRACT
| FULL TEXT
High-Sensitivity C-Reactive Protein: A Novel and Promising Marker of Coronary Heart Disease
Rifai and Ridker
Clin. Chem. 2001;47:403-411.
ABSTRACT
| FULL TEXT
Cardiorespiratory Fitness and the Progression of Carotid Atherosclerosis in Middle-Aged Men
Lakka et al.
ANN INTERN MED 2001;134:12-20.
ABSTRACT
| FULL TEXT
Editorial: In Search of the Underlying Mechanisms of Frailty
Cohen
Journals of Gerontology Series A: Biological Sciences and Medical Sciences 2000;55:706M-708.
FULL TEXT
Cross-sectional and Prospective Relationships of Interleukin-6 and C-Reactive Protein With Physical Performance in Elderly Persons: MacArthur Studies of Successful Aging
Taaffe et al.
Journals of Gerontology Series A: Biological Sciences and Medical Sciences 2000;55:709M-715.
ABSTRACT
| FULL TEXT
A Prospective Study of Walking as Compared with Vigorous Exercise in the Prevention of Coronary Heart Disease in Women
Manson et al.
NEJM 1999;341:650-658.
ABSTRACT
| FULL TEXT
Long-Term Exercise and Atherogenic Activity
Journal Watch Cardiology 1999;1999:9-9.
FULL TEXT
|
