Doi:10.1016/s0889-1591(03)00054-0

Brain,Behavior,and Immunity 17 (2003) 251–259 Acute stress evokes selective mobilization of T cells that differ in chemokine receptor expression: a potential pathway linking immunologic reactivity to Jos A. Bosch,a Gary G. Berntson,b John T. Cacioppo,c Firdaus S. Dhabhar,d,e a Periodontology Section, The Ohio State University, College of Dentistry, 305 West 12th Avenue, P.O. Box 182357, b Department of Psychology, The Ohio State University, Columbus, OH, USA c Department of Psychology, University of Chicago, Chicago, IL, USA d Institute for Behavioral Medicine Research, The Ohio State University, Columbus, OH, USA e Department of Oral Biology, The Ohio State University, College of Dentistry, Columbus, OH, USA Received 31 October 2002; received in revised form 7 February 2003; accepted 19 February 2003 T lymphocytes and monocytes/macrophages are the most abundant cells found in the atherosclerotic plaque. These cells can migrate towards the activated endothelium through the local release of chemotactic cytokines,or chemokines.
Given the important role of leukocyte migration in atherosclerosis and the role of stress in mediating leukocyte traf-ficking,the present study examined the effects of an acute stressor on the redistribution of T cells (CD3+) andmonocytes that express the chemokine receptors CCR5,CCR6,CXCR1,CXCR2,CXCR3,and CXCR4. Forty-fourundergraduate students underwent a public speaking task. The acute stressor induced sympathetic cardiac activation,parasympathetic cardiac withdrawal,lymphocytosis,and monocytosis (all p < :001). Although the total number of Tlymphocytes did not change,there was a selective increase in the number of circulating T cells expressing CXCR2,CXCR3,and CCR5. The ligands of these receptors are chemokines known to be secreted by activated endothelial cells.
Analyses of individual differences in stress-induced responses demonstrated a positive relationship between sympatheticcardiac reactivity and mobilization of the various T cell subsets (:35 < r < :56; p < :05). For the monocytes,all sub-populations increased in parallel with total monocyte numbers,with no relation to changes in sympathetic cardiacdrive. These results indicate that acute stress induces a mobilization of T cells that are primed to respond to inflamedendothelium. Acute stressors may thus promote the recruitment of circulating immune cells into the sub-endothelia,andtherefore accelerate atherosclerotic plaque formation and potentially contribute to the complications that follow acutestressful events. This mechanism may help explain the link between stress,reactivity,and cardiovascular disease.
Ó 2003 Elsevier Science (USA). All rights reserved.
Keywords: Cardiovascular disease; Acute psychological stressor; Psychoneuroimmunology; Cardiovascular reactivity; Autonomicbalance; Lymphocyte redistribution; Chemokines * Corresponding author. Fax: 1-614-292-4612.
0889-1591/03/$ - see front matter Ó 2003 Elsevier Science (USA). All rights reserved.
doi:10.1016/S0889-1591(03)00054-0 J.A. Bosch et al. / Brain, Behavior, and Immunity 17 (2003) 251–259 Acute psychological stressors are known to modulate this process of leukocyte trafficking and to enhance Many lines of evidence,ranging from pathologic subsequent cellular immune responses in the local tissues analyses to epidemiological studies,show that athero- (Dhabhar & McEwen,1997,1999; Dhabhar,Miller, sclerosis is intrinsically an inflammatory disease (Libby, Stein,McEwen,& Spencer,1994; Sanders & Straub, Ridker,& Maseri,2002; Ross,1999). The initiation of 2002). If,as the exisiting evidence suggests,migratory inflammatory reactions is a complex process involving responses of leukocytes are crucial in the development of the coordinated expression of cellular adhesion mole- atherosclerotic lesions,then acute stress may influence cules and chemotactic cytokines (chemokines),which atherosclerotic plaque formation in part through its ef- recruit blood-derived leukocytes to the site of inflam- fects on leukocyte migration and recruitment.
mation. The recruitment of leukocytes by chemokines The magnitude of cardiovascular system responses to into the sub-endothelium of the vascular wall is a major acute stressors (‘‘cardiovascular reactivity’’) is consid- aspect of atherogenesis. T lymphocytes are among the ered a potential risk factor for cardiovascular disease first cells to infiltrate the sub-endothelium (Libby et al., progression and its acute clinical manifestations (Kop, 2002; Ross,1999; Song,Leung,& Schindler,2001),and 1999; Krantz,Kop,Santiago,& Gottdiener,1996; Ro- remain a major local cell population throughout the zanski,Blumenthal,& Kaplan,1999; Sheps et al.,2002).
atherosclerotic process. These T cells subsequently se- Likewise,immune reactivity (the response of immune crete cytokines (e.g.,interferon-c,TNF-a,and interleu- parameters during acute stress) has been proposed as a potential predictor for vulnerability to immune medi- atherosclerotic response. Monocytes are another critical ated disease (Cacioppo et al.,1998; Cohen et al.,2002; constituent of the atherosclerotic response. Once resi- Sanders & Straub,2002). Cardiovascular and immune dent in the vessel wall,monocytes develop into macro- reactivity are correlated phenomena that are both de- phages as they take up oxidized low-density lipoprotein termined by sympathetic nervous system activation and differentiate into so-called foam cells. Macrophages (Cacioppo et al.,1995; Sgoutas-Emch et al.,1994; and lipid-laden foam cells are implicated as prime cul- Uchino,Cacioppo,Malarkey,& Glaser,1995). Thus,it prits in the events that ultimately complicate athero- is possible that the observed link between sympathetic sclerosis (Libby et al.,2002; Ross,1999).
cardiac reactivity and cardiovascular disease manifesta- It is likely that the endothelium itself initiates this tions is mediated in part through immunological path- process of leukocyte recruitment (Libby et al.,2002; ways. The present study examined the effects of an acute Reape & Groot,1999; Shin,Szuba,& Rockson,2002).
stressor on the redistribution of T cells (CD3+) and Endothelial cells can secrete numerous chemokines monocytes that express the chemokine receptors CCR5, upon activation by molecules derived from the circula- tion and adjacent cells (e.g.,Burke-Gaffney,Brooks,& findings suggest that immune reactivity,or at least some Bogle,2002; Kotani,Hori,Matsumura,& Uchiyama, aspects of this phenomenon,may also be relevant to the 2002; Mach et al.,1999; Qi & Kreutzer,1995; Seeger development of cardiovascular disease.
et al.,2002). In fact,virtually all cardiovascular riskfactors (e.g.,increased LDL levels,hypertension,dia-betes,obesity,and infection) are capable of promoting an inflammatory response in endothelial cells with theconcomitant secretion of inflammatory mediators (Lib- by et al.,2002). Chemokines secreted by endothelialcells include Growth Regulated Oncogene (GRO,which Forty-four university undergraduates (mean age 20, has an a; b,and c sub-type),Epithelial Neutrophil Ac- range 18–27 years,22 male) volunteered to participate in tivating peptide-78 (ENA-78),Neutrophil Activating this study as part of a longitudinal study on psychoso- Protein-2 (NAP-2),and Interleukin 8 (IL-8). These cial factors and wound healing. Participants gave writ- chemokines are all ligands for the pleiotrophic chemo- kine receptor CXCR2,whereas IL-8 can also stimulate compensation for their participation. Participants were the chemokine receptor CXCR1. Other examples of ineligible if they were using medication,or reported chemokines secreted by endothelial cells are Interferon- health problems indicative of cardiovascular,inflam- c Inducible Protein-10 (IP-10),which binds to the chemokine receptor CXCR3,and Regulated on Acti-vation Normal T cell Expressed and Secreted (RAN- TES),which is a ligand for several chemokine receptorsincluding CCR5 (Burke-Gaffney et al.,2002; Oppen- In preparation for the study,participants were in- heim,Zachariae,& Goetzl,2000; Wang,Su,Gong,& structed not to engage in strenuous physical exercise, and to refrain from using alcohol or non-prescription J.A. Bosch et al. / Brain, Behavior, and Immunity 17 (2003) 251–259 drugs 24 h before the experimental sessions. In addition, ECG R-wave across 1-min periods. From these 1-min participants were instructed to abstain from smoking ensembles,average levels were computed for heart rate and caffeine the day of the experiment,to eat breakfast (HR) and preejection period (PEP). These minute-by- before 10 a.m. and stay null per os (except for water) minute means were averaged over a 6-min pretask from 10 a.m. onwards. Women were scheduled in the baseline and over each 6-min stressor.
first week after their menses. Upon arriving at the Interbeat intervals (IBI) were checked and edited for General Clinical Research Center at 12:00 p.m.; (a) in- artifacts by a detection algorithm developed by Berntson, formed consent was obtained; (b) a 19-G indwelling Quigley,Jang,and Boysen,1990. Respiratory sinus ar- catheter was placed into the antecubital vein of the non- rhythmia (RSA) was derived by the method of Porges dominant arm; (c) participants were served a standard- (Porges & Bohrer,1990),using the MXedit program ized lunch (300 kcal,containing 10 g of protein,12 g of (Delta Biometrics,Bethesda MD). This program converts carbohydrate,and 16 g of fat) and water ad libitum; and, the heart period series into a time series,applies a moving (d) electrodes for electrocardiography (ECG) and im- polynomial filter (polynomial ¼ 3,coefficients ¼ 21) to pedance cardiography (ICG) were attached. Subse- remove slow non-stationarities in the data,applies a quently,while seated in supine position,participants band-pass filter (.12–.40 Hz) to the residual series,and filled out questionnaires and engaged in leisure reading.
then derives the natural log of the band variance. This At 1:30 p.m.,a baseline blood sample was obtained and corresponds to the statistical variance of the time sampled the procedure for the laboratory stressor was initiated.
heart period data within the respiratory frequency band.
Changes in PEP were used to index changes in car- diac sympathetic drive,whereas RSA was used to indexchanges in cardiac vagal tone.
The stress task consisted of two back-to-back spee- ches,each with 2 min of preparation and 4 min of speech delivery. To enhance social stress,the speeches werevideotaped and attended by a small audience consisting Whole blood was collected into sodium heparin of a female nurse,a female research assistant,and a male tubes,and maintained at room temperature. Samples psychologist. For the first speech,the participant had to were prepared within 2 h after collection. White blood defend him/herself after being falsely accused of shop- cell counts were obtained on a hematology analyzer lifting (Saab,Matthews,Stoney,& McDonald,1989), (F800,Sysmex,McGraw Park,IL). Specific leukocyte and for the second speech the participant gave a pre- sub-types were identified by immunofluorescent anti- sentation about his or her best and worst personal body staining using flow cytometry (FACSCalibur, characteristics (van Eck,Nicolson,Berkhof,& Sulon, Becton–Dickinson,San Jose,CA). Whole blood was 1996). In order to standardize timing and instructions stained using phycoerythrin (PE) and FITC conjugated for the task,the instructions were presented on a video monoclonal antibodies for chemokine receptors,and screen. Including instructions,the task took 15 min. A cychrome (CyChr) for CD3 (Pharmingen,San Diego, second blood sample was obtained during second min- CA). Briefly,cell suspensions were incubated with anti- ute of the second presentation (13 min after initiation of body for 20 min at room temperature,lysed with FACS the task). Cardiac activity was recorded continuously.
Brand Lysing Solution (Becton–Dickinson,San Jose,CA),which results in a simultaneous lysis of red blood cells and partial fixation of leukocytes,washed withPBS,and read on the FACSCalibur with 3000–5000 Assessment of cardiovascular responses focused on events being acquired from each preparation. Matched cardiac sympathetic and vagal control (Berntson,Caci- antibody isotype controls were used to set negative oppo,& Quigley,1993). Indices of sympathetic and staining criteria. Data were analyzed using Cell Quest- parasympathetic drive were obtained by analysis of pro software (Becton–Dickinson,San Jose,CA).
ECG and thoracic impedance (ICG) signals (Berntson etal.,1997; Sherwood et al.,1990). The thoracic imped- ance and ECG signals were recorded from six Ag/AgClspot-electrodes (AMI type 1650-005,Medtronic) using the Vrije Universiteit Ambulatory Monitoring System ducted to examine the effects of the laboratory stressor (VU-AMS) device. Reliability and validity of the VU- on mood,cardiovascular parameters,and cellular dis- AMS device have been reported elsewhere (de Geus, tribution. The ECG recording of one subject could not Willemsen,Klaver,& van Doornen,1995; de Geus & be completed due to a technical problem. For two sub- van Doornen,1996; Willemsen,De Geus,Klaver,Van jects,flow cytometry data was incomplete due to in- Doornen,& Carroll,1996). The ECG and ICG com- complete lysis of a blood sample. Degrees of freedom plexes were ensemble averaged with reference to the J.A. Bosch et al. / Brain, Behavior, and Immunity 17 (2003) 251–259 numbers of CD3+CXCR2+,CD3+CXCR3+,andCD3+CCR5+ lymphocytes (see Table 2). Analyses of 3.1. Psychological and cardiovascular reactions these sub-populations expressed as% of total T cellnumbers yielded a similar pattern of results,showing a Analysis of POMS subscales indicated that the selective increase of CXCR2+,CXCR3+,and CCR5+ speech tasks were perceived as stressful,as evidenced by T-cells within the total circulating T-cell pool (all increases in tension-anxiety (Mbaseline 3.1 (SEM 0.5), Mtask Fð43Þ > 6:5; p < :01). This analysis further revealed a 9.3 (SEM 0.8), Fð43Þ ¼ 21:34; p < :001) and anger-hos- small decrease in CCR6+ T-cells relative to the total tility (Mbaseline 0.18 (SEM 0.3), Mtask 2.3 (SEM 0.6), number of T cells (Fð43Þ ¼ 6:18; p < :05).
Fð43Þ ¼ 10:73; p < :01). Replicating prior research,anal- Data and statistical analyses for monocytes are pre- yses confirmed that the acute psychosocial stressor ele- sented in Table 3. The speaking stressor increased total vated HR,increased cardiac sympathetic activation,and monocyte numbers. A general increase was also seen for produced vagal withdrawal (see Table 1). Because gen- the various monocyte sub-populations,which paralleled der and body composition (i.e.,BMI) have been re- the increase in total monocyte numbers (see Table 3).
ported to moderate the autonomic responses to acute That all monocyte subsets (as defined by chemokine stressors (as well as being independent predictors of receptor expression) changed to the same degree was cardiovascular disease occurrence),we included these further corroborated by non-significant changes in potential modifiers in our statistical model. As shown in monocyte subsets expressed as percentage of total Table 1,controlling for these variables yielded compa- rable results. Further analyses did neither reveal modi- We again performed analyses controlling for possible fying effects of age or smoking on cardiac responses.
moderating effects of gender and BMI. As shown inTables 2 and 3,these analyses yielded a similar pattern of results. Subsequent exploratory analyses neither in-dicated moderating effects of smoking status or age.
Data and statistical analyses for the lymphocytes are presented in Table 2. The acute stressor induced signif- 3.3. Associations between cellular and cardiac autonomic icant lymphocytosis,whereas the total number of cir- culating T lymphocytes did not increase. Furtheranalysis of T cell sub-population on basis of chemokine To confirm the assumption that cardiac sympathetic receptor expression,revealed significant increases in the reactivity and immune reactivity are related phenomena, Table 1Mean values (with SEM in parentheses) and results of statistical analyses (repeated measures ANOVA/ANCOVA) for cardiacautonomic measures during baseline and speech tasks Table 2Mean values (with SEM in parentheses) and results of statistical analyses (repeated measures ANOVA/ANCOVA) for lymphocyte cellnumbers during baseline and speech tasks J.A. Bosch et al. / Brain, Behavior, and Immunity 17 (2003) 251–259 Table 3Mean values (with SEM in parentheses) and results of statistical analyses (repeated measures ANOVA/ANCOVA) for monocyte cellnumbers during baseline and speech tasks we compared cellular mobilization responses in subjects low reactors exhibited no change or a decrease (see Fig.
that exhibited a high versus a low cardiac sympathetic 1). Independent t tests yielded significant differences for reactivity. The cardiac PEP was utilized as a measure of cardiac sympathetic drive. Reactivity was calculated as (tð40Þ ¼ 3:62; p < :005),CD3+CXCR1+ ðPEPtask 1 þ PEPtask 2Þ=2 À PEPbaseline,and grouping into p < :05),CD3+CXCR2+ (tð40Þ ¼ 3:72; p < :005),CD3+ high and low PEP reactors was based on a median split CXCR3+ (tð40Þ ¼ 3:44; p < :005),and CD3+CXCR4+ of these reactivity scores. The average Dms for the high (tð39Þ ¼ 3:47; p < :005) (see Fig. 1). Inspection of the PEP reactors was )17.2 (SEM 1.8),and )1.5 (SEM 0.6) scatter plots and computation of bivariate correlations for the low PEP reactors (tð41Þ8:29; p < :001). High and indicated that the associations between sympathetic low PEP reactors also differed in HR reactivity cardiac drive and cellular mobilization showed a near (tð41Þ2:47; p < :05; Dbpm 21.9 (SEM 2.9) vs. 13.3 (SEM linear relationship (see Table 4 and Fig. 2).
1.8)),whereas the two groups did not differ in vagal Previous studies have reported that individual dif- ferences in HR reactivity,instead of PEP,may predict Ideographic analyses showed a general increase in immune reactions e.g. (Benschop et al.,1998; Larson, circulating T cell subsets for high PEP reactors,whereas Ader,& Moynihan,2001; Sgoutas-Emch et al.,1994), Fig. 1. Change in T cell sub-set numbers for subjects that exhibited a high versus a low cardiac sympathetic response (indexed aschanges in PEP) during the speech stressors. Bars indicate mean,lines indicate standard error of mean.
J.A. Bosch et al. / Brain, Behavior, and Immunity 17 (2003) 251–259 Table 4Pearson correlation coefficients and SpearmanÕs rank-order correlation coefficients (between brackets) of the association between PEPreactivity and changes in T cell numbers Fig. 2. Scatter plots showing the relation between PEP reactivity and mobilization of CCR5+ and CXCR2+ T cells.
although the sympathetic component of cardiac reac- towards the activated endothelium by chemokines that tivity appears to be superior to overall reactivity (Caci- are initially secreted by the local endothelial cells. The oppo,1994; Cacioppo et al.,1995). This is consistent present study investigated the effects of an acute stressor with the present analyses. HR reactivity yielded a com- (public speaking) on the mobilization of T cells and parable pattern of results as presented in Fig. 1,albeit monocytes that express receptors for these chemotactic showing less pronounced differences. Indeed,comparing factors. Whereas the total number of circulating CD3+ the high and low HR reactivity groups yielded signifi- lymphocytes did not change,the speaking stressor in- cant group differences only for CD3+CCR5+ (tð40Þ ¼ duced an increase in CD3+ cells expressing receptors for chemokines that are known to be secreted by activated endothelium (GRO,NAP-2,ENA-78,IL-8,IP-10 for comparisons of high and low vagal/parasympathetic cardiac reactors (indexed by changes in RSA) yielded no Gaffney et al.,2002; Kotani et al.,2002; Qi & Kreutzer, statistical differences in regard to T cell responses (for all 1995; Seeger et al.,2002; Wang et al.,1998). No change was seen in the number of T cells carrying receptors for Similar analyses as described above (i.e.,dividing our chemokines that are not secreted by inflamed endothe- sample in high vs low reactors based on median differ- lial cells (SDF-1 for CXCR4,LARC/MIP-3a for ence scores of PEP,HR,or RSA) were performed to CCR6).1 The various monocyte subsets (as defined by explore monocyte responses in relation to cardiac and chemokine receptor expression),on the other hand,did autonomic reactions. In contrast to the T lymphocytes, not show such specificity: all subsets increased in monocyte responses showed no significant associations parallel with total monocyte numbers. Thus,the re- with PEP reactivity,heart rate reactivity or vagal reac- sults indicate a selective mobilization of T cells that tivity: for all t tests, t < 1:5 and p > :2.
are sensitive to the chemotactic signals of an inflamedendothelium.
1 Chemokine receptors are know to exhibit a remarkable T lymphocytes and monocytes/macrophages are the pleiotrophism,and therefore it cannot be excluded that CXCR4 most abundant cells found in the atherosclerotic plaque and CCR6 may show some responsivity to chemokines that are (Libby et al.,2002; Ross,1999). These cells are attracted secreted by inflamed endothelial cells.
J.A. Bosch et al. / Brain, Behavior, and Immunity 17 (2003) 251–259 Ideographic analysis,comparing mobilization re- vided by research on the role of stress-induced migratory sponses in subjects exhibiting high versus low sympa- responses in acute cardiovascular complications such as thetic cardiac reactivity,confirmed and extended the results of nomothetic analyses. In line with previous T cells constitute a heterogeneous population,and it research (Cacioppo et al.,1995; Uchino et al.,1995),it is well established that the CD8+ T cells in particular are confirmed our assumption that sympathetic cardiac re- mobilized during acute stress in humans (Benschop et activity and immune reactivity are closely related phe- al.,1996; Sanders & Straub,2002). Hence,the selective nomena. In particular,increases in T cell subsets were increases observed in our study might reflect changes in prominent in the high PEP reactors but were absent or this CD8+ sub-population. Examination of the litera- even reversed for the low PEP reactors. For example, ture suggests that this may only provide a partial ex- whereas the CD3+CCR6+ subset showed a trend to- planation. For example,we found an increase in T cells wards increased cell numbers in high PEP reactors that are positive for the receptors CXCR3 and CCR5, (p ¼ :08),a significant decrease (p < :01) was observed which are both highly expressed on CD4+ T cells (the in low PEP reactors (auxiliary analyses).
Th1 subset in particular) (Qin et al.,1998). However, Ideographic analyses also indicated that the rapidly most studies find no change,or even a slight decrease,in induced monocytosis is probably mediated by different CD4+ T cells in response to acute stress (Sanders & mechanisms than the observed lymphocytosis. In con- Straub,2002). Conversely,CXCR4 is expressed on a trast to the T lymphocytes,there were no significant large proportion of CD8+ T cells (Bleul et al.,1996; associations between PEP reactivity and increases in Oberlin et al.,1996),whereas CD3+CXCR4+ cell monocyte numbers. The reasons for these disparate ef- numbers were unaltered during the speaking stressor.
fects are unclear. Thus far,human studies have mainly Also,both the pleiotrophic IL-8 receptor CXCR2 and focused on the effects of acute stress on lymphocyte the more specific IL-8 receptor CXCR1 are expressed on subsets (Benschop,Rodriguez-Feuerhahn,& Schedlow- CD8+ cells,but not on CD4+ cells (Chuntharapai,Lee, ski,1996; Sanders & Straub,2002),and further research Hebert,& Kim,1994). Thus,if the observed increases in into the acute redeployment of other major leukocyte T cell sub-populations were simply to reflect increases in populations (e.g.,monocytes,neutrophils) seems war- CD8+ T cells,then increases should have occurred in both CXCR1+ and CXCR2+ sub-population. To- A long standing hypothesis in cardiovascular re- gether these observations are in line with other reports search,the so-called reactivity hypothesis,postulates showing a remarkable heterogeneity in chemokine re- that individuals who show exaggerated cardiovascular ceptor expression within various lymphocyte sub-popu- responses to mild acute stressors (like those encountered lations,e.g.,(Campbell et al.,1999; Campbell et al., in everyday life) may be prone to the development of 2001a,2001b; Chuntharapai et al.,1994; Kunkel et al., cardiovascular disease and acute cardiovascular syn- 2002; Qin et al.,1998). It would therefore be interesting dromes (Kop,1999; Krantz et al.,1996; Rozanski et al., to investigate whether chemokine receptor expression 1999). The underlying assumption is that such everyday might further differentiate CD4+ and CD8+ T cell challenges cause wear and tear to the cardiovascular subsets in regard to their response to acute stress (for system due to a mobilization of resources (i.e.,hemo- complementary approaches see also; Mills,Goebel, dynamic,endocrine,metabolic,and hemostatic) beyond Rehman,Irwin,& Maisel,2000; Redwine,Snow,Mills, metabolic demands (Cacioppo et al.,1998). Further- & Irwin,in press; Sanders & Straub,2002).
more,as observed in the present study,acute stressors We conclude that stress-induced cardiac sympathetic enhance immunosurveillance by lymphocytes that are activation is associated with an environment of in- primed to respond to activated endothelium. Consistent creased chemokine receptor-positive T cells,which, with the basic premise of the reactivity hypothesis,these when coupled with endothelial activation,could support responses appear to be particularly prominent in indi- the basic atherosclerotic process of recruitment and in- viduals that exhibited strong sympathetic cardiac reac- tions to stress. Acute psychological stressors may thuspromote the migration of inflammatory cells to the sub-endothelia,hereby accelerating the atherosclerotic pro- cess and potentially contributing to the acute compli-cations that follow stressful events. This presents a novel This study would have been impossible without the pathway,linking cardiac reactivity and immune reac- dedicated efforts of April C. Logue,BS,Janet Schulte, tivity with the development of cardiovascular disease.
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