beta-blockers, exercise, and the immune system in men with coronary artery disease

7/30/2019 Beta-Blockers, Exercise, And the Immune System in Men With Coronary Artery Disease

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Beta-blockers, exercise, and the immunesystem in men with coronary artery diseaseMICHAEL SAGIV, DAVID BEN-SIRA, and EHUD GOLDHAMMERThe Sports Medicine and RehabilitationDivision, The Zinman College at Wingate, ISRAEL; and Heart Institute Bnai-ZionHaifa Medical Center, ISRAEL

ABSTRACTSAGIV, M., D. BEN-SIRA, and E. GOLDHAMMER. Beta-blockers, exercise, and the immune system in me n with coronary arterydisease. Med. Sci. Sports Exerc., Vol. 34, No. 4, pp. 587-591, 2002. Purpose: Th e purpose of the present study was to examine theeffect of aerobic exercise training on the immune system in coronary artery disease patients treated with ,-blockers. Methods:Twenty-five patients (46.1 2 yr) treated with atenolol, a ,-blocker agent, for 3 months before exercising were divided randomly intotwo groups: 15 underwent an aerobic exercise training program for 12 wk at 65-70% of their work capacity, whereas the other 10patients served as controls, Results: After training, levels ofCD 4 and CD S cells were significantly (P < 0.05) higher and concomitantlythe CD4/CD8 ratio decreased significantly (P < 0.05) in the exercising group compared with the control group. Conclusions: Datasuggest that coronary artery disease patients exercising aerobically at 65-70% of their work capacity gain a statistically significanthigher lymphocyte T cell function as compared with their untrained counterparts. Ke y Words: T CELLS, LYMPHOCYTES, HUMAN,AEROBIC TRAINING.

D rugs that selectively block adrenergic activity oncardiac and vascular smooth-muscle cells play animportant role in the treatment of patients withcoronary artery disease and/or in essential hypertension( 1). These drugs regulate heart rate, myocardial contractionforce, vascular resistance, (3,7) and thus myocardial oxygendemand.

In normal subjects aerobic exercise-training programswith intensities of 60-70% VO 2,,,x, lasting at least 6 wk,have been shown to increase lymphocyte subsets. Th e moststriking increase was found in natural killer cells followedby CD4+ and CD8+, T cells, and B cells, respectively ( 6).However, as with many potent drugs, n-blockers possesssome effects on the immune system, such as attenuation ofhuman lymphocytic 8-adrenergic receptors (4,12), and inmice might possess some in vivo effect on the immunesystem (5).Catecholamines appear to play an important role in theactivation of the cardiovascular system and in the regulationof energy metabolism mediated through ,-adrenoceptorslocated in cell membranes. It seems that the changes inlymphocyte levels are dependent on f0-adrenergic receptorexpressio-n on the respective cell types and also on cyclicadenosine monophosphate which activates protein kinase A0 1 5-913 1/02/3404-0587/$3.00/)MEDICINE & SCIFNCE IN SPORTS &EXERCISE,Copyright C) 002 by the American College of Sports MedicineSubmitted for publication Septermber 2000.Accepted for publication August 2001.

(9,10,12,18). We hypothesized that aerobic training mightfacilitate the interaction between T cells and adrenoceptors,because aerobic training has the effect of lowering catechol-amine levels while increasing adrenoreceptors sensitivity(2). Therefore, the purpose of the present study was first toexamine the effect of an aerobic exercise-training programon the immune system, more specifically lymphocyte sub-populations, in coronary artery disease patients treated with0-blockers. Secondly, we assessed whether continuation ofmedication intervention without exercise supplementationwould further adversely affect the function of the immunesystem.

METHODSExperimental approach. After baseline measure-ments, in the first stage of the study (onset of medicationintervention), all 25 coronary artery disease patients partic-ipating in the study were treated with atenolol f3-adrenergicblocking agent. This stage was designed to assess the effectof f-adrenergic blocking agents on the immune system. Th efollowing stage, which included 12 wk of exercise trainingduring drug intervention, was designed to address two is-sues. The first one was to evaluate the effect of aerobictraining on the immune system in patients treated with,-adrenergic blocking agents. Th e second was to assesswhether continuation of medication intervention withoutexercise supplementation further adversely affects the func-tion of the immune system. Accordingly, two experimentalgroups were established randomly, an exercising group and


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a control group. Because of the limited availability of qtal-ified subjects, the exercising group was deliberately set toinclude a large sample size to secure a relatively greaterstatistical power with regard to the first issue.Variables chosen (T cells) for this study are distingushedby their functions and by cell surface antigen, notably CDSon cytotoxic T cells and CD 4 on helper and inflammatory Tcells. Natural killer cells may represent a third population oflymphocyte arising from the common bone marrow progen-itor cell. These cells conistitute about 15% of circulatinglymphocytes. Therefore, blood analyses were performed inthe present study because the chosein immune cells circulatecontinuously between tissues and blood. It has been esti-mated that 1-2% of all lymphocytes circulate through theblood every hour and, thus, m-iay represent changes in theimmune system brought about by fl-blockers or by exercise.

Subjects. Twenty-five men (46.1 2 yr) with coronaryartery disease volunteered to participate in this study. Awritten consent form was obtained from all subjects afterbeing fully informited of the details and possible discomfortsassociated with the experimental protocol, which was ap-proved by the Clinical Science Center Committee on Hu-man Subjects. The patients with coronarry artery disease hadprior myocardial infarction or coronary artery disease, doc-umented within 1 yr of the study by clinical and electrocar-diographic criteria, and cardiac catheterization that revealedsingle-vessel disease in 14 patients, doutble-vessel disease in9, and three-vessel disease in 2.Inferior wall motion abnormalities were noted in 15 pa-tients, posterior in five and anterior in five. All patients tookonly atenolol fl-adrenergic blocking agent (20 patients hadbeen taking 50 mg-d-'; 4 patients took 25 mg'd:; and onepatient took 100 mg'd -) for 3 nmonths before training.Three patients took AC E inhibitors and four took diuretics.They were asked to withdraw from these medications duringthe week before blood sampling, in ore to enable suffi-cient washout period for these drugs. Patients were notincluded in the present study if they had mitral regurgitation,rhythm abnormalities, systemic hypertension or left ventric-ular hypertrophy, history of autoimmunity, cancer, diabetesand other endocrinopathy, renal failure, recent infection, orrecent hospitalization. All patients were not active partici-pants in supervised aerobic cardiac rehabilitation programsand had attained a power capacity of 10.4 1 0 kcal -mill - .Procedures. There were three testing sessions for all

subjects. Th e first session was devoted to acclimating thesubjects to the treadmill and to explaining the niature of thestudy. In addition, before taking the atenootol l-adrenergicblocking agent, 2.5 mL of peripheral venous blood samiplewas taken from each subject for analysis. During the secondmeeting, after 3 months of taking the atenolol f-adrenergicblocking agent, and without exercisin:g, 2.:5 L of peripheralvenous blood sample was taken from each subject for anal-ysis. In addition, after warm-up, all patients underwent asubmaximal exercise- stress test on a treadmill utilizing theBalke protocol. The stress test was terminated according tothe guidelines of the American College of Sports Medicine

Medicine

(1), Based on the stress test performance, training workloadwas calculated for each patient according to Karvonen et al.(6). At the third session after 12 wk of training, 2.5 mL ofperipheral venous blood samnple was taken for analysis, anda stress test was given to all the participants in the sttudy.

Training program. Twenty-five coronar} artery dis-ease patients volunteered to participate in the present study.After 3 months of medicatioon intervention, tl-ey were di-vided randomly into two groups: 15 patients were in theexercising group and 10 served as controls. F or the exer-cising group closely supervised training sessions were held3-4 times per week for 12 wk. Subjects ranhAalked for 45min at a mean heart rate of 124 + 10 beat nwin-, whichcorresponded to 65% of the maximal work capacity of eachsubject. Training loads were adjusted for the exercisinggroup as work capacity at the prescribed heart rate increasedas a result of training.

Blood sampling. Peripheral venous blood samples (2.5mL) were collected by sterile antecubital -venipuncture tech-niques into ethyl.enediam-inotetra-acetate-containing tubes,an-d the samples were analyzed within 6 h. Tii-ae of day forblood sampling was kept consistent to control for problemsassociated with diurnal variation. Blood colle tion was ob-tained: 1) before onset of drug intervention, 2i after 12 wkof drug intervention, and 3) after 12 wk of exercise training,during drug intervention.

Analysis. Methods used were utilized previously else-where (13,14). Routine total blood counts were performedand differential counts were obtained using standard proce-dures (Coulter STKS Instrument Coulter Electronics, Inc.,Hialeah, FL). Heparinized peripheral blood, diluted withDulbec o's phosphate buffered saline at pH of 7.4 (phos-phatebufred saline (PBS); Ca 2 , Mg2+ frac), was usedfor immune cell phenotyping for analysis o< lymphocytesubset profile. Lymphocyte phenotyping was acconplishedby direct immunofluorescence labeling of eel. surface anti-gens with mouse antihuman monoclonal antibodies con'.ju-gated to FITC or PE from AMAC, Inc. (Westbrook, ME).The immunophenotyping was performed on i heparinizedwhole blood and, after lysis of the red cells, wv s analyzed ona Becton Dickinson FACScan flow cytonmeter (BectonDickinson, Franklin Lakes, NJ).

Data acquisition and analysis were performed with FAC-Scan research software Lysis II, 1, 1, (Becten Dickinson),using gates in the forwvard light scatter versis right anglelight scatter dot plot for lymphocyte separation. Tein thou-sand events were analyzed. Photomultiplier measurementsutilized 600 V and linear amplification for FLI, whereas581 V were used with spectral compenisatior for FL2.Lymphocyte subsets were analyzed to determine percentof CD4, CD8, and natural killer cell subsets. Absolutenumiibers were calculated using complete blond count data.Direct im-imunofluorescence technique was ut lized to deter-mine lymphocyte subpopulations. Th e ethylenediam-in-otetra-acetate treated samples were incubated (20 min, 4 C,darkness) with 15 xL of fluorescin isothiocyanate and phy-coerythrin conjugated monoclonal antibody. Then erythro-

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TABLE 1. Descriptive data of trained and untrained patients (values are mean SD).Variable Trained Untrained

No. of cases 15 10Age (yr) 46.7 t 2.0 45.2 t 2.0Weight (kg) 76.0 3.0 77.1 4.0Height (cm) 178.0 + .0 177.4 t 3.0Fat (%) 15.2 + .0 14.7 3.0Ejection fraction (%) 43.1 6.0 43.3 5.0End diastolic volume (mL) 102.0 + 2.0 104.0 11.0End systolic volume (nL) 58.0 + 9 59.0 10

cytes were lysed for 20 min with 2 mL of FACS lysingsolution. (Becton Dickinson).To confirm the population analyzed, the percentage oflymphocytes obtained as compared with differential valuesof the three subpopulations and with the results obtained inthe first plot-FL I versus SSC using CD45/CD14 (Leuco-gate; Becton Dickson). Cells showing a double fluorescenceaverage intensity when compared with the negative controlwere considered positives.Natural killer cell cytotoxic activity was assessed bychromium release assay (13). Mononucleated cells (effectorcells) were separated from heparinized whole blood bydensity gradient centrifugation. Chromium-labeled K562target cells were added (1 10-.4) to each of the wells con-taining effector cells to yield 40:1, 20:1, 10:1, and 5:1effector to target ratios. The assay was performed in tripli-cate in "V" bottom microtiter plates (Costar, Cambridge,MA). The microtiter plates were then incubated for 3 h at37C in a 5% CO2 incubator. At the end of the incubation,supernatants were harvested onto Skatron harvesting frames(Skatron, Sterling, VA), and the level of radioactivity wa smeasured by Berthod multi-crystal gamma counter LB 2103 (EG&G Berthod, Nashua, NH).Statistical methods. Each variable was analyzed by atwo-way ANOVA (treatment X stage of the experiment)with repeated: measures on the stage factor. The criterion forrejection of the null hypothesis was set at alpha = 0.05.

Tukey's HS D procedure was utilized for specific post hoccomparisons.

RESULTSMean descriptive data for the two experimental groupsare presented in Table 1. Means of immune cell subsets arepresented in Table 2. In Figures 1and 2, after 12 wk of drugintervention, levels of CD 4 and CD 8 were significantly

decreased (P < 0.001), whereas the CD4/CD8 ratio wassignificantly increased, compared with the values measuredbefore the onset of drug intervention. After 12 wk of exercise training in conjunction with drug intervention, a significant group by stage interaction effect (P < 0.05) wasfound in CD4, CD8, and CD4/CD8 ratios. At the end of theexercise intervention stage, the mean levels of CD 4 cellsand of CD 8 cells significantly (P < 0.05) increased in theexercising group as compared with minor and no significantchanges in the control group. Concomitantly, the meanCD4/CD8 ratio decreased significantly (P < 0.05) in theexperimental group during the exercise intervention period,whereas the mean of the control group was not statisticallydifferent from that measured at the end of the first 12 wk ofdrug intervention.Figure I describes the effects of exercise training andatenolol on CD4, CD8, and the CD4/CD8 ratio (mean SD) in coronary artery disease patients at baseline (stage 1)preexercising (stage 2), and posttreatment (stage 3). Theindividtual data for CD 4 and CD8 in stages 1, 2, and 3 intrained and untrained coronary artery disease patients aredepicted in Table 2.All subjects of the control and the treatment groups ex-hibited response patterns that are similar to those of theirgroup means except for a single subject in the control group,whose CD4 responses resemble those of the exercise treat-ment group. As a result, his CD4/CD8 ratio is also similarto that of the exercise treatment group.No significant main effects or interaction effects wereobserved for leukocytes, lymphocytes, eosinophils. neutro-phils, and natural killer cells with values being fairly con-sistent across the experimental stages and treatment groups.

DISCUSSIONFirst, the remarkable improvement in the immune param-eters after the 12 wk of exercise training among those beingtreated with atenolol ,-blocker agent clearly illustrates thebenefits of an aerobic exercise program for coronary arterydisease patients. Second, continuation of medication inter-vention in the untrained group did not further reduce thefunction of the immune system.The peripheral blood lymphocytes obtained froIn the ex-ercising coronary artery disease patients using atenolol:-blocker agent possess a statistically significant highernumber of CD4 and CD8 cells as compared with the

TABLE 2. Counts of immune cells subsets in hree periods of evaluation (mean + SD).Control (N= 10 )

Variables Base Pre Post BaseLeukocytes (n.mm 3)-102 61 11 60 10 61 10 60 12Lymphocytes (n-mm-3)-102 23 5 24 4 24 4 24 5Eosinophils (n.mm- 3).10 13 3 14 3 12 3 31 36Neutrophils (n.mm 3).102 30 37 29 40 29 38 31 36C0 4 (celis-,eL-1) 992 35 941 36t 939+ 30 98 0 34CD8 (cells-.L 1) 572 38 53 7 +28t 53 3 - 25 57 3 33CD4/CD8 (ratio) 57 2 38 53 7 +28t 1.77 0.12 1.71 .12NK (PBNK-10 9) 0.51 0.1 0.52 _ 0.1 0.53_ 0,2 0.52 _ .2

t Significant difference (P< 0.05) between base and preintervention inall subjects.4Significant interaction (P< 0.05) betweeen groups an d pre/post intervention.IMMUNE SYSTEM, EXERCISE,

Exercise (N = 15)Pre

60 + 1124 +430 3630 36948 31t53 4 -31t1.78 + .11t0.53 +0.1

Post59 + 923 +430 3530 +351041 504:674 90+:1.56 0.199t0.53 0.2


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physically inactive control group anid compared with theirown pretest values. The significant decrease in mean valuesof CD4, CD 8 cells, and the CD4/CD8 ratio froem baseline. topreexercise training indicates that the duration of medica-tion (12vk) and the type of medication used (atenolol) arefactors affecting the inimune function. Therefore, exerciseincreased the CD 4 and CD8 levels between pre- and post-exercise training period.

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The CD 4 antd CD8 cells represent the lymplhocyte subsetsand play a key role in inducing an adequate immune re-sponse to an abnormal stimulation of antigen. Thus, theyincrease the binding of antibodies to antigen and, hence,improved the ability to combat foreigni agents carrying theantigen (17). In epidemiological studies. CD4/CD8 ratiopredicts morbidity and mortality in the elderly (8). How-ever, because the present study is not epidertiological innature, the changes in CD4/CD8 ratio may suggest that CD8cells are preferentially recruited into circul.tion duringexercise.

Exercise-induced mobilization of these cells seems todepend on fi-adrenergic receptor expression oca the respec-tive cell types and also on cAMP second messelnger system.which works less well in B cells (9,10,1 8). Becausel-blockers iniduce a marked and lastiing dec rease in thefl-adrenergic receptor number (10), they caa potentiallyattenuate the human lymphocytic response (I ).

Work capacity rose in the exercising gro lp comparedwith the untrained patients (from 10.2 71.1 o 12.0 1.2and 10.4 1.1 to 10.2 1.0 kcal-min- , respectively).These results after 12 wk of moderate exercise training weresimlar to those seen previously in young adul 8s and elderly(13,14,16). It was demonstrated that the nun ber of circu-lating T cells was higher in the trained subjects than in theuLntrainied ones. Furthermore, Nieman et al. ( 13), studyingthe impact of aerobic training on elderly wo -nen, found amarked increase in lymphocyte proliferative response.

The results of the pres-ent study suggest that regularhabitlual mi:oderate exercise may help to encounter thef-blocker related decline in the potential tf T cells toproliferate, at least in part by increasing production of IL-2(8,15). We assume that atenolol administration may reduceIL-2 production by changing the initrinsic properties of thesecells (8).The nuLmber of natural killer cells anid their activity areusually described as importanit health protectib e agents (14).It appears that the immnunological pathway by which exer-cise training influences health status, especilh Jly infectiousdiseases, may involve innate mechanisms.

In the present study, natural killer cell aclivity did notdiffer significantly between the two groups ti king l-block-ers anid across all conditions. These results are in line withprevious studies that have showni improvement in VO2,axby 12.6%. without any improvement in natural killer cellactivity (16). However, they are different from tthose sug-

1.3 IBase (1) Pre (2) Post (3)

StageFIGURE I-Effects of exercise training and atenolot on CD4. CD8,and the ratio CD4/CD8 (mean SI)) in coronary artery diseasepatients before onset of drug intervention (stage 1), after 12 wk of drugintervention (stage 2), and after 12 wk of exercise training during druginterventioni (stage 3). *Significant (P < 0.05) differences from 12 wkof drug intervention (pretesting) to after 12 wk of exercise trainingduring drug intervention (posttesting).590 Official Journal of the American College of Sports Medicine

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FIGURE 2-Individual data for CD 4 and CD8 bhefre onset of drugintervention (stage 1), after 12 wk of drug intervention (stage 2), andafter 12 wk of exercise training during drug intervention (stage 3) intrained and untrained coronary artery disease patieats.

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gested by Nieman et al. (13), in which highly conditionedwomen had superior natural kill and T cell function whencompared with their sedentary counterparts. We assume thatthe absence of training effect on natural killer cells in thepresent study is related to the fact that the immune systemis controlled by 3-adrenergic mechanisms and is only partlydependent on the spleen. In addition, the differential effectsof exercise on the immune system may be related to inten-sity and length of training (19).

CONCLUSIONAlthough our exercising coronary artery disease patients

were taking Atenolol ,B-blocker agent, the present studysuggests that those participating in twelve weeks of aerobicexercise training at a level of 65-70% of their work capac-ity, in conjunction with drug intervention, possess statisti-cally significant higher CD 4 and CD8 T cell function thantheir untrained counterparts.

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3. DALY, P. A., and M . J. SotE. Myocardial catecholamines and the patho-physiology of heart failure. Circulation82(Suppl. I):I-35-I43, 1 9).4. DE BLASI, A., M. LIPARTITi, and S. GARATrINI. Beta-adrenergic

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5. DUEmI4ES, M., G. J. FOURNIE, J. P. BASILE, M. MIGNON-CONTE, an dJ. J. CONTE. Polyclonal activation of lymphocytes induced inmouse by acebutolol, a beta blocking agent. Int. J. In munophar-macol. 8:911-917, 1986.6. KARVONEN, M., K. KENTALA, and 0. MUSTA. The effects of trainingheart rate: a longitudinal study. Ann. Med. Exp. Biol. Fenn. 35:307-315, 1975.

7. KATZ, A. M. Interplay between inotropic and lusitropic effects ofcyclic adenosine monophosphate on myocardial cell. Circulation82(Suppl. l):1-7-I-11, 1990.

8. KUBO, M., and B. CINADER. Polymor-phism of age-related changesin interleukin (IL) production: differential changes of T helpersubpopulations, synthesizing IL-2, IL-3 a, IL-3 and IL-4. Eur.J. Inununol. 20:1289-1296, 1990.9. LANDMANN, R. Beta-adrenergic receptors in human leukocyte sub-populations. F,ur. J. Clint. Invest. 22(Suppl. 1).30-36, 1992.

10. MAISEL, A. S., T. HARRIS, C. A. REARDEN, and M. C. MICHEL.Beta-adrenergic receptors in lymphocyte subsets after exercise:

Th e importance of the current results is based on theapproach that lymphocytes may be activated by exercisetraining. It is no t currently known whether this occurs be-cause activated cells are selectively recruited into the cir-culation or because cells are activated during exercise; it islikely that both occur simultaneously during exercise.We cannot comment on the likelihood of our patientsbecoming ill (cold and respiratory infections etc.) following

12 wk of drug intervention. However, previous studies havesuggested that when the immune system is suppressed,viruses and bacteria ma y increase the risk of subclinical andclinical infection (13). The current design does not us enableto comment on how long the effects of exercise will last inpatients taking a-blockers. However, we recommend thatpatients - keep exercising moderately and under propersupervision, as long as they are being treated with ,-block-ers, since the benefits of exercise are clear.

Address for correspondence: Prof. Michael Sagiv, Head of Col-lege, The Zinman College of Physical Education, The Wingate Insti-tute, Netanya 42902, Israel; E-mail: [email protected].

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beta-blockers, exercise, and the immune system in men with coronary artery disease

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