ORIGINAL INVESTIGATION. Exercise and Weight Loss Reduce Blood Pressure in Men and Women With Mild Hypertension

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1 ORIGINAL INVESTIGATION Exercise nd Weight Loss Reduce Blood Pressure in Men nd Women With Mild Hypertension Effects on Crdiovsculr, Metolic, nd Hemodynmic Functioning Jmes A. Blumenthl, PhD; Andrew Sherwood, PhD; Elizeth C. D. Gullette, PhD; Michel Byk, PhD; Roert Wugh, MD; Anstsi Georgides, PhD; Lind W. Crighed, PhD; Dmon Tweedy; Mrk Feinglos, MD; Mrk Appelum, PhD; Junichiro Hyno, MD; Aln Hinderliter, MD Bckground: Lifestyle modifictions hve een recommended s the initil tretment strtegy for lowering high lood pressure (BP). However, evidence for the efficcy of exercise nd weight loss in the mngement of high BP remins controversil. Methods: One hundred thirty-three sedentry, overweight men nd women with unmedicted high norml BP or stge 1 to 2 hypertension were rndomly ssigned to eroic exercise only; ehviorl weight mngement progrm, including exercise; or witing list control group. Before nd following tretment, systolic nd distolic BPs were mesured in the clinic, during dily life, nd during exercise nd mentl stress testing. Hemodynmic mesures nd metolic functioning lso were ssessed. Results: Although prticipnts in oth ctive tretment groups exhiited significnt reductions in BP reltive to controls, those in the weight mngement group generlly hd lrger reductions. Weight mngement ws ssocited with 7 mm Hg systolic nd 5 mm Hg distolic clinic BP reduction, compred with 4 mm Hg systolic nd distolic BP reduction ssocited with eroic exercise; the BP for controls did not chnge. Prticipnts in oth tretment groups lso displyed reduced peripherl resistnce nd incresed crdic output compred with controls, with the gretest reductions in peripherl resistnce in those in the weight mngement group. Weight mngement prticipnts lso exhiited significntly lower fsting nd postprndil glucose nd insulin levels thn prticipnts in the other groups. Conclusions: Although exercise lone ws effective in reducing BP, the ddition of ehviorl weight loss progrm enhnced this effect. Aeroic exercise comined with weight loss is recommended for the mngement of elevted BP in sedentry, overweight individuls. Arch Intern Med. 2000;160: From the Deprtments of Psychitry nd Behviorl Sciences (Drs Blumenthl, Sherwood, Gullette, Byk, nd Georgides) nd Medicine (Drs Wugh nd Feinglos nd Mr Tweedy), Duke University Medicl Center, Durhm, NC; the Deprtment of Psychology, University of Colordo, Boulder (Dr Crighed); the Deprtment of Psychology, University of Cliforni, Sn Diego (Dr Appelum); the Deprtment of Internl Medicine, Ngoy City University, Ngoy, Jpn (Dr Hyno); nd the Deprtment of Medicine, University of North Crolin, Chpel Hill (Dr Hinderliter). HYPERTENSION IS mjor helth prolem in this country, ffecting more thn 43 million people in the United Sttes. 1 Hypertension is mong the most common resons for outptient visits. 2 Despite this, lood pressure (BP) control is often indequte. 3 Although BP cn e lowered phrmcologiclly in hypertensive individuls, 4,5 ntihypertensive medictions re not effective for everyone, my e costly, nd my induce dverse effects 6-9 tht impir qulity of life nd reduce dherence. Moreover, normlities ssocited with hypertension, such s insulin resistnce nd lipemi, my persist or my even e excerted y some ntihypertensive medictions As result, nonphrmcologicl pproches to the tretment of hypertension hve received growing ttention. The 1997 report 5 of the Joint Ntionl Committee on Prevention, Detection, Evlution, nd Tretment of High Blood Pressure recommends tht lifestyle modifictions e the initil tretment strtegy for lowering high BP. Despite these recommendtions, however, empiricl dt supporting the efficcy of exercise nd weight loss in the mngement of hypertension re reltively limited. Numerous oservtionl studies hve demonstrted n inverse reltion etween physicl ctivity nd BP, nd interventionl studies 17,18 hve shown exercise to lower BP in normotensive individuls; however, there hve een few rndomized, controlled trils of exercise trining in hypertensive individuls, nd results hve een mixed. Moreover, virtully ll previous studies hve importnt methodologicl shortcomings s none of the studies, to our knowledge, mesured BP, physicl fitness, or such potentil confounding fctors s ge, ody weight, or ody composition in n optiml wy, nd study smples hve een smll nd lmost lwys excluded women Americn Medicl Assocition. All rights reserved.

2 SUBJECTS AND METHODS SUBJECTS Prticipnts were recruited from newspper, television, nd rdio dvertisements; locl clinics; nd screenings t community helth firs nd locl shopping centers. Sujects were eligile if they were t lest 29 yers old nd hd n unmedicted high norml BP or stge 1 to 2 hypertension (men clinic systolic BP [SBP] of mm Hg nd/or men clinic DBP of mm Hg on 4 seprte occsions during 3-week period). In ddition, sujects were sedentry (not performing regulr eroic exercise) nd overweight or oese (BMI, 25-37), s defined in the Ntionl Institutes of Helth sttement on oesity tretment. 29 Prticipnts previously treted for hypertension were included if they hd een tking no more thn 1 mediction tht hd een discontinued for t lest 6 weeks. Resons for suject exclusion included history of crdic disese, secondry hypertension, renl disese, trioventriculr conduction defects or high-grde rrhythmis, vlvulr disese, severe sthm or chronic ostructive pulmonry disese, dietes requiring insulin or hypoglycemic gents, nd orthopedic prolems tht would preclude prticiption in eroic exercise; mjor psychitric disorder requiring tretment; comorid medicl condition tht could require intensive tretment, such s cncer; use of ny medictions known to ffect the crdiovsculr system (ntihistmines nd decongestnts); or history of drug use or lcoholism. In this mnner, 133 sujects, including 59 men nd 74 women, 23% of whom were Africn Americn, were enrolled initilly in the study (Figure 1). STUDY DESIGN This study ws pproved y the Institutionl Review Bord t Duke University Medicl Center, Durhm, NC, nd informed consent ws otined from ll sujects efore their prticiption. Initil screening procedures included medicl history nd physicl exmintion to rule out secondry hypertension nd contrindictions to exercise, in ddition to the seline ssessment of clinic BP. At seline, sujects lso underwent ssessment of BP on seprte dys during ABPM, physicl exercise nd mentl stress testing, hemodynmic mesurements, glucose tolernce testing, dietry ssessment, nd nthropometric mesurements. Sujects were then rndomized to 1 of 3 tretment conditions for 6 months: exercise only, weight mngement, or witing list control. All mesurements otined t seline were gin otined t the conclusion of the 6-month tretment progrm. BP MEASUREMENTS Clinic BP Blood pressure mesurements were otined y trined technicin with rndom zero sphygmomnometer nd were stndrdized for cuff size nd position. Mesurements were mde on 4 seprte visits during 3-week period. At ech visit, BP ws mesured in the nondominnt rm in the sitting position 4 successive times t 2-minute intervls fter n initil rest period of 5 minutes. The first BP mesurement of ech visit ws discrded, nd the verge of the remining 3 mesurements represented the clinic visit BP. The overll clinic BP ws then determined y verging the men BPs over the 4 visits. Mesurements were otined in this stndrdized mnner t seline nd fter 6 months. Amultory BP Monitoring The use of ABPM provides n opportunity to ssess BP during routine ctivities of dily life. Becuse dt from ABPM studies suggest tht BP is highest during working hours, 30 sujects were studied during typicl workdy. Sujects were hooked up etween 8 nd 10 AM to n multory BP monitor (Accutrcker II unit; Suntech, Rleigh, NC), nd SBP nd DBP recordings were verified y simultneous mnul redings. The multory BP monitor mesures BP noninvsively using the usculttory technique, in which microphone records nd processes Korotkoff sounds; it uses electrocrdiogrphic R-wve gting to correctly identify Korotkoff sounds originting from the rchil rtery. The multory BP monitor used hs een vlidted independently. 31 The monitor ws progrmmed to otin redings t n verge frequency of 4 times per hour until edtime. During ABPM, sujects were instructed to mintin diry, which included informtion out their posture, mood, nd ctivities. All multory BP mesurements were checked, nd redings judged invlid (due to rtifct) were excluded. The men multory SBP nd DBP redings were then computed sed on ll remining redings. BP During Mentl Stress Blood pressure ws mesured using monitor (exercise BP monitor, Accutrcker model 4240; Suntech) during mentl stress protocol consisting of 20-minute seline rest period nd 4 mentl stress tsks with 10 minutes of rest etween ech. The tsks, presented in counterlnced order, included: (1) pulic speking, in which sujects were sked to give 3-minute tlk out current events topic; (2) mirror imge trcing, in which sujects hd 3 minutes to outline str, viewed in mirror, s mny times s possile without mking ny errors; (3) nger interview, in which sujects were given 3 minutes to relte n interpersonl sitution tht mde them ngry during the previous week; nd (4) cold pressor, in which sujects plced 1 foot in ucket of ice wter for 2 minutes. BP During Exercise Stress Mximl exercise testing ws performed using the Duke Wke Forest protocol in which grded exercise egn t 3.2 kilometers per hour nd 0% grde nd worklod ws incresed t rte of 1 metolic equivlent per minute (oxygen, 3.5 ml/kg per minute). 32 To ensure comprility in BP mesurements during mentl nd exercise stress testing, the BP ws otined t ech worklod lso using monitor (exercise BP monitor, Accutrcker model 4240; Suntech). Expired gses were collected for the determintion of pek oxygen consumption using metolic crt (model 2900; Sensormedics, Yor Lind, Clif). RESTING HEMODYNAMICS The hemodynmic determinnts of BP, including hert rte (HR), CO, nd TPR, were ssessed y impednce Americn Medicl Assocition. All rights reserved.

3 crdiogrphy 33 during 20-minute rest period. An impednce crdiogrph (model H100-I; Hutcheson, Chpel Hill, NC) ws used in conjunction with the stndrd tetrpolr nd electrode configurtion for signl cquisition. Two voltge electrode nds were pplied, 1 round the se of the neck nd 1 round the thorx t the tip of the xiphoid process; the 2 current electrode nds lso were pplied round the neck nd chest, prllel to the voltge electrodes, with constnt distnce of 4 cm ove (neck) nd elow (chest) the voltge electrode nds. Impednce signls were recorded nd processed using recording progrm (Crdic Output Progrm; Bio-Impednce Technology, Chpel Hill) tht hs een empiriclly vlidted. 34 The Kuicek eqution 35 ws used to compute stroke volume, nd CO ws computed s the product of HR nd stroke volume. All impednce dt were sed on three 30-second smples of continuous dt, which were recorded to correspond temporlly to the 30-second periods of cuff defltions ssocited with BP mesurements. Simultneous mesurement of CO nd rteril BP llowed for the derivtion of the TPR: TPR (mesured s dynes times seconds per centimeters to the fifth power)=[men rteril pressure (MAP)/CO] 80, where MAP=DBP+[(SBP DBP)/3]. GLUCOSE TOLERANCE TESTING An orl glucose tolernce test ws performed on ech ptient efore nd fter the 6-month intervention. Prticipnts fsted overnight, following which heprin lock ws inserted nd lood drwn for fsting plsm glucose nd insulin testing. Dextrose, 75 g, ws dministered orlly, nd smples for plsm glucose nd insulin testing were otined t 30-minute intervls for 3 hours. The glucose level ws nlyzed y hexokinse (model 800; Olympus, Melville, NJ) nd y oxidse reduction (Ektchem/Vitros, Rritn, NJ). The plsm insulin level ws nlyzed y n insulin-specific rdioimmunossy (Linco Reserch, Inc, St Chrles, Mo); the men coefficients of vrition for within- nd etweenssy vrition were 3.2% nd 3.9%, respectively. DIETARY, WEIGHT, AND BODY COMPOSITION ASSESSMENT To ssess the reltive contriutions of exercise, dietry hits, nd weight loss, n independent ssessment of dietry content ws otined t seline nd t the conclusion of the intervention. Sujects recorded ll food intke over 4 consecutive dys in diet diry tht ws nlyzed for energy nd nutritionl content using computer softwre (Nutritionist IV softwre; N-Squred Computing, Slem, Ore). Weight ws mesured y stndrd lnce scle. Body ft mesurements were performed using ioelectricl impednce nlyzer (BIA-101Q; Quntum, Highlnd Heights, Ohio) in conjunction with ioelectricl impednce nlyzer interprettion softwre (RJL Systems, Inc, Clinton Township, Mich). Mesurements were done using stndrd right-sided, tetrpolr electrode plcement with ech suject in supine position. Studies were conducted etween 3 nd 5 PM t mient temperture following stndrd protocol in which sujects hd refrined from eting or drinking for t lest 3 hours efore testing. 36 INTERVENTIONS Aeroic Exercise Only Sujects exercised 3 to 4 times per week t level of 70% to 85% of their initil HR reserve 37 determined t the time of the seline tredmill test. The exercise routine consisted of 10 minutes of wrm-up exercises, 35 minutes of cycle ergometry nd wlking (nd eventully jogging), nd 10 minutes of cool-down exercises. Sujects were instructed in how to monitor their rdil pulses, nd mintined their HRs t, or ove, their trget HRs for t lest 30 minutes. A trined exercise physiologist supervised ll exercise sessions, nd performed 2 to 3 rndom checks of HRs per session to ensure tht sujects were exercising t sufficient intensity. Sujects were instructed to mintin their usul diets. Weight Mngement Sujects exercised 3 to 4 times per week using the identicl protocol s previously descried. In ddition, sujects prticipted in weight mngement progrm in smll groups of 3 to 4 memers. The weight mngement progrm ws ehviorl intervention sed on the LEARN mnul, 38 which focuses on 5 elements: lifestyle, exercise, ttitudes, reltionships, nd nutrition. The primry gol of the intervention ws weight loss of 0.5 to 1.0 kg/wk, chieved grdully y decresing energy nd ft intke through permnent lifestyle chnges. Initil dietry gols were set t pproximtely 5021 J for women nd 6276 J for men, with out 15% to 20% of this energy coming from ft. These vlues were flexile, however, nd could e djusted sed on the rte of weight loss for ech individul. The progrm formt consisted of pproximtely 26 weekly group sessions. At the strt of ech session, prticipnts recorded their weight. Record keeping ws key component of the intervention, nd ll meetings egn with review of ech memer s food diry nd homework (ie, ehvior modifiction trgets) from the previous week. prticiption ws encourged during this process in supporting fellow group memers nd in prolem solving round ostcles nd lpses tht they my hve encountered. After this review, new mteril from the mnul, focusing primrily on ehvior chnge strtegies, ws then introduced. This mteril included such topics s distinguishing crvings from hunger, plnning helthy mels, shopping for food, deling with pressures to et, eting wy from home, nd coping with relpse. During the lst prt of ech session, gols for the coming week were developed for ech memer nd homework to help chieve these gols ws ssigned. During the lst 6 weeks of the progrm, sessions focused incresingly on weight mintennce, nd group memers worked on individulized plns for mintining the chnges they hd mde during the pst 6 months. Witing List Control Sujects were sked to mintin their usul dietry nd exercise hits for 6 months until they were reexmined. Witing list sujects then selected either of the 2 ctive tretments on completion of their posttretment ssessment. Continued on next pge Americn Medicl Assocition. All rights reserved.

4 DATA ANALYSIS Bseline differences mong tretment groups were ssessed using 1-wy nlysis of vrince for continuous vriles nd 2 tests for ctegoricl vriles. Tretment effects were evluted using multivrite nlysis of vrince, with posttretment DBP nd SBP serving s the dependent vriles nd tretment group s the fctor. To exmine potentil differences etween men nd women in response to tretment, sex ws lso entered s etween-sujects fctor. Seprte multivrite nlysis of vrince models were estimted for clinic, multory, mentl stress, nd exercise BPs nd for ech dditionl set of conceptully relted vriles (eg, glucoserelted vriles). Before ech nlysis, outcome mesures were residulized on their respective pretretment levels to djust for seline differences nd to increse the precision of estimtes. Within ech model, plnned contrsts were used to compre (1) the 2 tretment groups with controls nd (2) weight mngement with exercise only. Following the intentionto-tret principle, posttretment BP vlues were nlyzed irrespective of ptient dherence. In the event tht some ptients filed to return to the lortory for their 6-month BP mesurement, missing dt were replced with the corresponding pretretment vlues. Epidemiologicl studies hve shown BP to e positively correlted with ody mss index (BMI) (clculted s weight in kilogrms divided y the squre of height in meters), weight, nd percentge ody ft. Weight loss lso hs een shown to lower BP levels. 23 In recent review, Jeffery 24 noted tht there hve een only 5 rndomized, controlled trils of weight reduction for hypertension nd tht there is no reserch literture on weight loss tretments specificlly for ptients with hypertension. Furthermore, methodologicl limittions hve proved to e significnt. The uncontrolled use of ntihypertensive medictions, determintion of BP from single clinic visit, nd filure to consider potentilly importnt confounders, including mesurement of exercise nd dietry hits, hve een especilly prolemtic. Surprisingly, there hve een only 2 studies of weight loss in unmedicted ptients with mild hypertension, nd results hve een inconsistent. One study 25 showed no effect of weight loss on BP, while the other 26 demonstrted tht sujects in weight reduction group chieved greter declines in distolic BP (DBP) thn sujects receiving either plceo or metoprolol fter 21 weeks of tretment. However, BP ws determined on only 1 clinic visit, nd neither exercise hits nor fitness levels were documented. The present study exmines the effects of exercise, lone nd in comintion with ehviorl weight loss progrm, on BP in reltively lrge smple of unmedicted men nd women with high BP. Becuse BP mesured during routine ctivities of dily living my e more representtive of n individul s BP level thn clinic redings, ptients lso underwent multory BP monitoring (ABPM) during wking hours. Blood pressure lso Weight Mngement (n = 55) Did Not Complete the Intervention (n = 9 [16%]) Study Conflicted With Fmily or Work Responsiilities (n = 2) Elevted BP With Exercise (n = 2) Unknown Resons (n = 5) Completed the Intervention (n = 46 [84%]) Preliminry Telephone Screening (N = 2399) Medicl Evlutions (N = 320) Rndomized After Bseline Assessments (N = 133) Exercise Trining (n = 54) Did Not Complete the Intervention (n = 10 [19%]) Study Conflicted With Fmily or Work Responsiilities (n = 7) Elevted BP With Exercise (n = 1) Unknown Resons (n = 2) Completed the Intervention (n = 44 [81%]) ws mesured in more controlled lortory setting, during exercise, nd during mentl stress testing. Heightened mentl stress induced BP responses hve een shown to e ssocited with myocrdil ischemi 27 nd future development of hypertension. 28 To gin insight into potentil mechnisms y which BP ws ltered, prticipnts lso underwent glucose tolernce testing to ssess insulin nd glucose responses, ody composition evlutions to determine ody weight nd ft distriution, ssessment of dietry content, nd noninvsive mesurements of crdic output (CO) nd totl peripherl resistnce (TPR) to ssess chnges in hemodynmic profile. RESULTS BACKGROUND CHARACTERISTICS Of the 133 sujects rndomized, 112 prticipnts (84%) completed the study, nd n dditionl 9 of the 21 prticipnts who dropped out of the tretment groups returned for follow-up ssessment (Figure 1). There were no sttisticl differences cross study groups on ny seline fetures, with the exception tht prticipnts in the exercise only group tended to hve lower clinic SBP t study enrollment compred with ptients in the control group (Tle 1). In ddition, there were no sex-ytretment interctions for ny BP nlysis. ADHERENCE Witing List Control (n = 24) Did Not Complete the Intervention (n = 2 [8%]) Disstisfied With Assignment (n = 1) Unknown Resons (n = 1) Completed the Intervention (n = 22 [92%]) Figure 1. Ptient flow from initil contct through completion of the intervention. BP indictes lood pressure. Of the 54 prticipnts in the exercise only group, 44 (81%) completed the full 26-week progrm, while 46 (84%) of the 55 prticipnts in the weight mngement progrm completed the full progrm. Among the 24 control group prticipnts, 22 (92%) were ville for follow-up t the Americn Medicl Assocition. All rights reserved.

5 Tle 1. Bckground Chrcteristics* Vrile Weight Mngement (n = 55) Tretment Exercise Only (n = 54) Control (n = 24) Entire Cohort (N = 133) Mles 21 (38) 25 (46) 13 (54) 59 (44) Whites 44 (80) 41 (76) 15 (63) 100 (75) Age, men (SD), y 48.5 (1.2) 46.6 (1.2) 47.2 (1.8) 47.5 (0.77) College degree 34 (62) 38 (70) 15 (63) 87 (65) History of ntihypertensive medicine use 17 (31) 12 (22) 4 (17) 33 (26) Fmily history of hypertension 41 (75) 32 (59) 15 (63) 88 (68) Clinic SBP, men (SD), mm Hg (1.4) (2.1) (1.4) (0.9) Clinic DBP, men (SD), mm Hg 93.2 (0.7) 93.6 (1.0) 94.4 (0.7) 93.6 (0.4) Crdic output, men (SD), L/min 5.03 (1.6) 5.44 (1.8) 4.62 (1.1) 5.10 (1.6) Totl peripherl resistnce, men (SD), dyne s cm (771) 1649 (671) 1889 (554) 1754 (696) Fsting glucose level, men (SD), mmol/l 4.82 (0.70) 4.80 (0.68) 4.76 (0.61) 4.80 (0.67) Working outside of the home 50 (91) 51 (94) 21 (88) 122 (92) Current smokers 2 (4) 5 (9) 2 (8) 9 (7) Alcohol use, 1 serving/d 49 (89) 48 (89) 20 (83) 117 (91) *Dt re given s numer (percentge) of sujects unless otherwise indicted. SBP indictes systolic lood pressure; DBP, distolic lood pressure. Significntly ( P.05) different from the control group. To convert fsting glucose from millimoles per liter to milligrms per deciliter, divide millimoles per liter y end of the 26-week study period. Including dropouts, prticipnts in the weight mngement group ttended n verge of 73 (70%) of the 104 exercise trining sessions; ptients in the exercise only group ttended n verge of 80 (77%) of the exercise sessions (P=.18). Prticipnts in the exercise only group exercised t or ove their trget HR trining rnge 81% of the time, compred with 85% of the time for those in the weight mngement group (P=.60). Three prticipnts in the exercise only group, nd 4 in the weight mngement group, spent most of their exercise trining using cycle ergometry rther thn wlking. When compred with prticipnts who wlked, the 7 who used the icycle showed similr chnges in oxygen consumption (wlk, +11%; icycle, +13%; P=.48) nd tredmill time (wlk, +12%; icycle, +14%; P=.61). CHANGES IN AEROBIC FITNESS The groups differed significntly in posttretment eroic cpcity nd tredmill time (multivrite F 4,194 =6.57, P.001). Prticipnts in oth ctive tretment groups were sttisticlly different from controls on posttretment pek oxygen consumption nd tredmill time (P.001 for oth). The tretment groups lso differed sttisticlly from ech other on tredmill time (P=.04), nd there ws trend for greter pek oxygen consumption in the weight mngement group (P=.07) (Figure 2). CHANGES IN BODY WEIGHT, BODY COMPOSITION, AND DIET There were significnt differences etween the 3 groups in weight loss nd postintervention BMI, percentge ody ft, len ody mss, nd len-ft rtio (multivrite F 10,222 =7.15, P.001). Prticipnts in the weight mngement group exhiited n verge weight loss of 7.8 kg, compred with men loss of 1.8 kg for those in the exercise only group nd men gin of 0.7 kg for those in the control group. A similr pttern emerged Pek Oxygen Consumption, ml/kg (Ft-Free Mss) per Minute A for BMI, percentge ody ft, len ody mss, nd lenft rtio, with prticipnts in the weight mngement group showing lrger chnges thn those in the exercise only group nd controls showing virtully no chnge on these vriles. Contrsts showed tht the posttretment weight, BMI, nd percentge ody ft were lower in the tretment groups compred with the control group. The len ody mss nd len-ft rtio were higher in the tretment groups compred with controls; the weight mngement group lso exhiited lower weight nd BMI compred with the exercise only group (Tle 2). In ddition, multivrite nlysis of vrince reveled significnt tretment group effects for dietry vriles (multivrite F 8,200 =8.15, P.001). Figure 3 shows tht following tretment, those in the weight mngement group consumed less energy, less ft, nd less protein thn either those in the exercise only group or controls. There were no group differences for crohydrte intke. In ddition, those in the weight mngement group consumed less sodium fter Tredmill Time, min B Figure 2. Aeroic fitness (A) nd exercise tolernce (B) fter tretment, djusting for pretretment levels. indictes tht weight mngement (WM) nd exercise only (EX) prticipnts differed from control sujects for pek oxygen consumption nd tredmill time (P.001 for oth);, WM prticipnts differed from EX prticipnts for tredmill time (P=.04); nd CT, witing list control Americn Medicl Assocition. All rights reserved.

6 Tle 2. Chnges in Weight nd Body Composition Vrile Tretment Time* Tretment Contrst P Weight Mngement Exercise Only Control All Tretments vs Control Weight Mngement Exercise Only Weight, kg Before 93.3 (17.7) 95.4 (14.5) 94.0 (17.3) After 85.4 (17.1) 93.6 (14.2) 94.7 (17.9) Chnge 7.9 (6.0) 1.8 (2.8) 0.7 (3.3) BMI Before 32.1 (4.0) 32.8 (4.0) 32.6 (5.1) After 29.4 (4.5) 32.1 (4.0) 32.9 (5.4) Chnge 2.7 (1.9) 0.6 (0.9) 0.3 (1.1) % Body ft Before 34.3 (8.3) 35.1 (8.4) 34.0 (8.2) After 31.2 (8.8) 33.5 (9.7) 34.7 (8.5) Chnge 3.2 (4.0) 1.6 (4.7) 0.7 (2.0) Len ody mss Before 65.8 (8.3) 65.1 (8.4) 66.0 (8.2) After 68.9 (8.9) 66.7 (9.8) 65.3 (8.6) Chnge 3.2 (4.0) 1.6 (4.7) 0.7 (2.0) Len-ft rtio Before 2.1 (1.0) 2.1 (1.1) 2.1 (0.7) After 2.5 (1.1) 2.3 (0.6) 2.1 (0.8) Chnge 0.4 (0.7) 0.3 (0.6) 0.1 (0.2) *Differences etween Before nd After Vlues nd Chnge scores re due to rounding. Dt re given s men (SD). Contrsts for pretretment mens compre rw group mens. Posttretment mens were compred fter djusting for pretretment levels. Ellipses indicte dt not pplicle. BMI indictes ody mss index, which is clculted s weight in kilogrms divided y the squre of height in meters. 6 months (3411 vs 2259 mg; P.005), while consumption for those in the exercise only (3520 vs 3109 mg) nd control (3116 vs 3039 mg) groups did not chnge. There lso were no significnt differences in the consumption of clcium (P=.32), potssium (P=.93), or mgnesium (P=.95) mong the groups. CHANGES IN BP Clinic BP Comprison of posttretment mens reveled significnt difference mong the groups (multivrite F 4,258 =6.76, P.001). Plnned contrsts reveled tht oth tretment groups hd significntly lower SBPs nd DBPs compred with the controls, while the 2 tretment groups did not differ significntly (Figure 4). Prticipnts in the weight mngement group exhiited n verge 7.4/5.6 mm Hg reduction in clinic SBP/DBP compred with 4.4/ 4.3 mm Hg reduction for prticipnts in the exercise only group nd 0.9/1.4 mm Hg chnge for controls. Amultory BP Posttretment multory BPs lso were significntly different for the groups (multivrite F 4,256 =5.45, P.001). The SBPs nd DBPs were significntly lower in the ctive tretment groups compred with controls (P=.02 nd P=.002, respectively) (Figure 5). In ddition, compred with ptients in the exercise only group, ptients in the weight mngement group hd lower DBP (P=.008) nd tended to hve lower SBP (P=.11). Mentl Stress BP The groups differed significntly fter tretment on BP t rest nd during mentl stress testing (multivrite F 8,248 =2.84, P=.005). At rest, prticipnts in oth tretment groups hd significntly lower SBPs nd DBPs compred with controls (P.001 for oth); those in the weight mngement group lso hd lower DBPs thn those in the exercise only group t rest (P=.05). During mentl stress, those in the 2 tretment groups hd significntly lower SBPs (P.001) nd DBPs (P=.003) thn controls. Prticipnts in the weight mngement group tended to hve lower SBPs (P=.15) nd DBPs (P=.07) compred with prticipnts who only exercised (Figure 6). Exercise Stress Testing BP In multivrite nlysis, there were no group differences in pek BP or BP t sumximl (4 metolic equivlents) worklod (multivrite F 8,204 =1.36, P=.21) (Tle 3). Similrly, contrsts t the univrite level showed tht for pek exercise, there were no differences etween the tretment groups nd controls on SBP nd DBP, nd there were no differences etween those in the weight mngement group nd those in the exercise only group on SBP or DBP. At sumximl worklods, however, contrsts t the univrite level reveled tht BPs were lower for those in the ctive tretment groups compred with controls for SBP. Prticipnts in the weight mngement nd exercise only groups did not differ on SBP (P=.48), ut DBP tended to e lower for those in the weight mngement group thn for those in the exercise only group. GLUCOSE TOLERANCE TESTING At seline, the men fsting glucose level for this smple ws in the norml rnge, lthough 5% of sujects met the Americn Dietes Assocition dignostic criteri 39 for dietes nd 20% met criteri for glucose intolernce. There were no seline group differences in glu Americn Medicl Assocition. All rights reserved.

7 A 85 B Energy, J Ft, g C 300 D Protein, g Crohydrte, g Figure 3. Dietry vriles fter tretment, djusting for pretretment levels. Energy consumption (A), ft intke (B), protein intke (C), nd crohydrte intke (D) re plotted seprtely. indictes tht weight mngement (WM) nd exercise only (EX) prticipnts differed from control sujects on ft intke (P=.009);, WM prticipnts differed from EX prticipnts on energy intke (P.001), ft intke (P.001), nd protein intke (P=.01); nd CT, witing list control. Blood Pressure, mm Hg Before Tretment After Tretment Figure 4. Oserved clinic lood pressure efore nd fter tretment. s were compred on lood pressure following tretment fter djusting for pretretment levels. indictes tht weight mngement (WM) nd exercise only (EX) prticipnts differed from control sujects for systolic (P=.001) nd distolic (P.001) lood pressure; CT, witing list control. Amultory Systolic Blood Pressure, mm Hg A Amultory Distolic Blood Pressure, mm Hg B Figure 5. Amultory systolic (A) nd distolic (B) lood pressure fter tretment, djusting for pretretment levels. Blood pressure ws determined during wking hours. indictes tht weight mngement (WM) nd exercise only (EX) prticipnts differed from control sujects on multory systolic (P=.02) nd distolic (P=.002) lood pressure;, WM prticipnts differed from EX prticipnts on distolic lood pressure (P=.008); nd CT, witing list control. cose or insulin levels in the fsting stte or in response to n orl dextrose lod, represented y the incrementl glucose nd insulin res mesured over time. This re under the curve ove the fsting glucose or insulin level provides single numer tht illustrtes the plsm glucose nd insulin secretory response to nutrient lod. As shown in Tle 4, there were significnt group differences in fsting glucose nd insulin levels, nd in the re under the curve for glucose nd insulin (multivrite F 8,206 =2.86, P=.005), fter tretment. Sujects in the weight mngement group hd significntly lower fsting glucose levels fter tretment thn sujects in the exercise only group. Sujects in the weight mngement group lso hd mrginlly significntly lower posttretment fsting insulin levels thn those in the exercise only group Americn Medicl Assocition. All rights reserved.

8 For the posttretment glucose re under the curve, contrsts reveled tht sujects in the ctive tretment groups tended to hve lower glucose res thn controls; however, sujects in the weight mngement group hd prticulrly lower glucose res compred with those in the exercise only group. Similrly, for the insulin re under the curve, those in the ctive tretment groups tended to hve lower res thn controls, nd the vlue for those in the weight mngement group ws lower thn for those in the exercise only group (Tle 4). Figure 7 shows tht the chnges in glucose nd insulin levels were lrger for those in the weight mngement group thn for those in the exercise only nd control groups. RESTING HEMODYNAMIC MEASURES SBP, mm Hg A Rest PS AI MT CP Tsk WM EX CT Rest PS AI MT CP Tsk Figure 6. Systolic lood pressure (SBP) (A) nd distolic lood pressure (DBP) (B) t rest nd during mentl stress tsks following tretment, djusting for pretretment levels. indictes tht weight mngement (WM) nd exercise only (EX) prticipnts differed from control sujects for SBP nd DBP t rest nd during ll stress (P.05 for ll);, WM prticipnts differed from EX prticipnts for DBP t rest (P=.05); PS, pulic speking; AI, nger interview; MT, mirror trce; CP, cold pressor; nd CT, witing list control. DBP, mm Hg B The groups lso differed significntly fter tretment on resting MAP, HR, CO, nd TPR (multivrite F 8,196 =4.96, P.001). Figure 8 shows tht prticipnts in oth ctive tretment groups were different from controls on MAP (P.001), HR (P=.003), CO (P=.01), nd TPR (P=.004). The MAP ws lower for those in the weight mngement group thn for those in the exercise only group (P=.05); those in the weight mngement group lso hd lower TPR compred with those in the exercise only group (P=.04). Those in the weight mngement nd exercise only groups did not differ significntly from ech other on HR (P=.50) or CO (P=.28). COMMENT The results of this clinicl tril of exercise nd weight loss mong men nd women with n elevted BP indicte tht while exercise lone is effective in reducing SBP nd DBP, the ddition of ehviorl weight loss progrm significntly ugments the efficcy of eroic trining. The reduction in resting clinic BP ws pproximtely 4 mm Hg for SBP nd DBP in prticipnts in the exercise only group compred with 7 mm Hg for SBP nd 5 mm Hg for DBP in prticipnts in the weight mngement group. Lrger BP reductions lso were oserved for those in the weight mngement group reltive to those in the exercise only group with ABPM during routine ctivities of dily living, prticulrly for DBP. In ddition, BP levels were lower for those in the exercise only nd weight mngement groups reltive to controls during mentl stress nd sumximl exercise. Those in the weight mngement group lso tended to hve lrger DBP reductions thn those in the exercise only group during mentl stress nd sumximl exercise. These results contrst with those of previous study 20 in which exercise lone ws not ssocited with significnt BP reductions fter 4 months of exercise trining. The resons for this discrepncy cn e ttriuted to importnt methodologicl differences etween the 2 studies, including different ptient chrcteristics ( 20% vs 10%-50% ove idel ody weight) nd more ex- Tle 3. Chnges in Blood Pressure During Exercise* Vrile Tretment Time Tretment Weight Mngement Exercise Only Control All Tretments vs Control Contrst P Weight Mngement vs Exercise Only Pek BP, mm Hg Systolic Before (20.8) (25.0) (22.5) After (20.5) (23.3) (18.8) Chnge 4.1 (23.6) 2.8 (23.2) 3.8 (22.1) Distolic Before 95.3 (14.7) 94.1 (13.2) 94.6 (11.2) After 94.3 (16.2) 93.3 (11.7) 92.8 (9.0) Chnge 1.0 (13.9) 0.7 (12.1) 1.8 (11.2) BP t 4 METs, mm Hg Systolic Before (22.4) (24.2) (16.2) After (27.1) (21.0) (19.8) Chnge 9.7 (18.7) 8.2 (17.3) 1.0 (20.1) Distolic Before 96.2 (11.5) 93.4 (10.5) 93.3 (10.0) After 90.8 (10.9) 92.6 (10.2) 94.9 (10.7) Chnge 5.4 (11.0) 0.8 (11.3) 1.6 (9.7) *BP indictes lood pressure; MET, metolic equivlent; nd ellipses, dt not pplicle. Differences etween Before nd After vlues nd Chnge scores re due to rounding. Dt re given s men (SD) Americn Medicl Assocition. All rights reserved.

9 Tle 4. Chnges in Glucose nd Insulin Levels Vrile Tretment Time* Tretment Weight Mngement Exercise Only Control All Tretments vs Control Contrst P Weight Mngement vs Exercise Only Fsting level, µu/ml Glucose Before 86.9 (12.6) 86.5 (12.2) 85.8 (11.0) After 82.8 (9.0) 88.8 (18.3) 90.3 (11.4) Chnge 4.0 (10.3) 2.2 (13.5) 4.5 (6.7) Insulin Before 17.1 (8.5) 19.3 (11.6) 21.3 (12.8) After 13.5 (5.7) 19.3 (16.5) 21.6 (11.2) Chnge 3.5 (6.0) 1.0 (14.1) 0.3 (7.0) Are under the curve, mg min/dl Glucose Before 7297 (3943) 6441 (3921) 6021 (3861) After 5392 (3133) 6080 (3459) 6708 (3862) Chnge 1904 (3218) 361 (2770) 687 (2630) Insulin Before (7035) 9839 (6587) (8265) After 6948 (4700) 9075 (6996) (9715) Chnge 4239 (6549) 765 (5246) 248 (5629) *Differences etween Before nd After vlues nd Chnge scores re due to rounding. Dt re given s men (SD). Vlues re undjusted. Contrsts for pretretment mens compre undjusted group mens; posttretment mens were compred fter djusting for pretretment levels. Ellipses indicte dt not pplicle. tended exercise progrm (4 vs 6 months). Most significntly, while the within-group BP chnges were comprle mong the exercisers in the 2 studies, the witing list control group in the previous study exhiited significnt BP reduction fter 4 months, while the BP for the witing list control group in the present study remined unchnged. This difference could e ttriuted to greter stility in BP s result of the dded numer of qulifying BP mesurements. The results of the present study re comprle generlly with findings from 5 other rndomized clinicl trils. In Finnish study 40 of 34 normotensive men nd 25 hypertensive men rndomized to 4 months of either exercise or oservtion, the exercise nd control groups hd similr 8 mm Hg reductions in DBP, ut exercise ws ssocited with lrger decreses in SBP (9 vs 0 mm Hg). However, the exercisers lso lost significnt weight, which ws not controlled for in the nlysis. In study of 20 Jpnese men with hypertension, 41 sujects who exercised for 10 weeks exhiited 12/5 mm Hg BP reduction, wheres control sujects showed no chnge in BP. In third study 42 of 56 hypertensive men, BP decresed 12/7 mm Hg mong exercisers compred with decrese of 6 mm Hg in SBP nd n increse of 3 mm Hg in DBP mong controls. In fourth study 43 of 27 hypertensive men, exercisers exhiited BP reduction from 137/95 to 130/85 mm Hg fter 10 weeks, while the control group showed no chnge (135/94 to 136/94 mm Hg). The chnges in DBP, ut not SBP, were significntly different. However, oth groups showed comprle chnges in ody weight nd eroic fitness. Finlly, Gordon nd collegues 44 rndomized 55 sedentry, overweight ptients with high norml BP or stge 1 or 2 hypertension to exercise only, diet (reduced energy), or exercise nd diet for 12 weeks. Clinic BP reductions in the comintion group (12.5/7.9 mm Hg) were lrger thn those in the diet only (11.3/7.5 mm Hg) nd exercise lone % Chnge WM EX CT Fsting Glucose Level 2-h Glucose Level Fsting Insulin Level 2-h Insulin Level Figure 7. Percentge chnge in fsting nd 2-hour glucose nd insulin levels. WM indictes weight mngement; EX, exercise only; nd CT, witing list control. (9.9/5.9 mm Hg) groups. However, ecuse results filed to rech sttisticl significnce, the reserchers concluded tht the BP-lowering effects of exercise nd weight loss were not dditive. Tken together, these previous studies present mixed picture. One study 20 showed comprle BP reductions in exercisers nd controls; 2 studies found BP reductions in oth groups, ut one 40 found lrger SBP, ut not DBP, chnges in the exercise group, wheres the other 43 found lrger DBP, ut not SBP, chnges in the exercise group; nd 2 other studies 41,42 found lrger BP reductions in the exercise group reltive to controls. The finl study 44 lcked control group, nd did not hve sufficient sttisticl power to detect group differences. In ddition, ll of the studies were limited ecuse of high dropout rtes, unplnned crossover, imprecise mesurement Americn Medicl Assocition. All rights reserved.

10 110 A 2.5 B Men Arteril Pressure, mm Hg Totl Peripherl Resistnce, (dyn s cm 5) C 6.0 D Hert Rte, Bets/min Crdic Output, L/min Figure 8. Resting hemodynmic mesures fter tretment, djusting for pretretment levels. Men rteril pressure (A), totl peripherl resistnce (B), hert rte (C), nd crdic output (D) re plotted seprtely. indictes tht weight mngement (WM) nd exercise only (EX) prticipnts differed from control sujects on men rteril pressure (P.001), hert rte (P=.003), crdic output (P=.01), nd totl peripherl resistnce (P.001);, WM prticipnts differed from EX prticipnts on men rteril pressure (P=.05) nd totl peripherl resistnce (P=.04); nd CT, witing list control. of BP or eroic fitness, or filure to precisely mesure other potentil confounders. Moreover, only 2 studies 20,44 included women. The present study suggests tht exercise is ssocited with modest BP reductions, independent of weight loss, nd, in the sence of sex-ytretment interctions, tht women nd men chieve significnt exercise-relted BP reductions. Furthermore, findings indicte tht moderte exercise y itself is generlly not ssocited with significnt weight loss, nd tht dding ehviorl weight loss progrm to n exercise intervention results in even greter BP reductions thn the reductions oserved with exercise lone. Indeed, while chnges in eroic fitness were correlted with chnges in SBP (r= 0.21, P=.04) nd DBP (r= 0.27, P=.007), weight loss ws even more highly correlted with SBP nd DBP chnges (r=0.38 nd 0.44, respectively; P.001 for oth). These BP reductions re not only sttisticlly significnt ut re cliniclly meningful: 22 (67%) of the 33 prticipnts engging in exercise nd weight loss who met criteri 5 for stge 1 hypertension (SBP, mm Hg, or DBP, mm Hg) t seline were no longer hypertensive (SBP, 140 mm Hg, nd DBP, 90 mm Hg) fter tretment compred with 13 (43%) of the 30 who only exercised nd 2 (12%) of the 17 controls. When prticipnts with stge 2 hypertension were included (SBP, mm Hg, or DBP, mm Hg), 23 (55%) of 42 prticipnts in the weight mngement group, 13 (37%) of 35 prticipnts in the exercise only group, nd 2 (11%) of 19 prticipnts in the control group were no longer hypertensive. The exercise nd weight loss interventions resulted in lowering of BP tht ws due to reduction in TPR. Before rndomiztion to the intervention groups, hypertension in our study smple ws chrcterized hemodynmiclly y n elevted TPR. This hemodynmic profile is typicl of ptients with estlished hypertension, lthough some studies 45 hve shown tht oese ptients with hypertension my hve less elevted TPR thn len ptients with hypertension. Nevertheless, the exercise nd weight loss interventions resulted in reduced BPs secondry to lowered TPRs, which is consistent with the trget hemodynmic response for ntihypertensive therpy, nd the intervention is, therefore, considered to hve hd therpeutic hemodynmic effect. The intervention lso improved the metolic profile of sujects, ut primrily those in the weight mngement group. After tretment, weight mngement prticipnts exhiited significntly lower fsting nd postprndil glucose nd insulin levels, indicting improved insulin sensitivity. In contrst, exercise only prticipnts nd witing list controls did not develop improved insulin sensitivity, showing virtully no chnge from seline on either insulin or glucose vriles. The filure of eroic exercise lone to ffect glucose levels is consistent with other dt showing no enduring effect of such trining on glucose metolism, despite the positive effects on glucose ssocited with cute eroic exercise nd resistnce trining. 46,47 Moreover, the few studies 48 tht hve shown improvements in glucose control fter exercise trining hve not clerly demonstrted whether these effects re due to exercise independent of weight loss. For the effects of exercise trining on insulin sensitivity, independent of weight loss, the picture is even less cler. Although the present study found little effect of exercise lone on insulin sensitivity, previous reports hve shown tht eroic exercise im Americn Medicl Assocition. All rights reserved.

11 proves insulin sensitivity in certin ptient popultions, such s in individuls with type 2 dietes mellitus. However, the eneficil effects of exercise on insulin sensitivity pper to e short lived, 46,49 nd hve een found to hve no independent effect fter controlling for the effects of recency of exercise nd chnges in ody composition. 50,51 These fctors lso my explin the lck of ny sustntil effect of exercise trining lone on insulin sensitivity in the present study. Our smple of individuls with n elevted BP ws reltively young (men ge, 47 yers), educted (65% otined college degree), employed (92% were working), nd receptive to nonphrmcologicl pproches to reduce BP. The extent to which less motivted persons with fewer socioeconomic resources would dhere to diet nd exercise progrm is unknown, prticulrly if the progrm ws not delivered in highly structured nd supervised setting. Moreover, ecuse oth ctive tretment groups engged in exercise, we could not determine the effects of weight loss lone. In summry, the present findings suggest tht while exercise trining lone is effective in reducing BP, the ddition of ehviorl weight loss progrm significntly enhnces this effect. Moreover, comined progrm of exercise nd weight loss contriutes to dditionl enefits, such s lrger BP reductions during mentl stress nd sumximl exercise nd improved insulin sensitivity, tht re cliniclly meningful. Comining progrm of exercise nd weight loss is recommended for the mngement of overweight individuls with n elevted BP. Accepted for puliction Decemer 8, This study ws supported y grnts HL nd HL from the Ntionl Institutes of Helth, Bethesd, Md; nd grnt M01-RR-30 from the Generl Clinicl Reserch Center Progrm, Ntionl Center for Reserch Resources, Ntionl Institutes of Helth. We thnk Mohn Chilukuri, MD, for performing physicl exmintions; Julie Opitek, PhD, Kren Mllow, MS, nd Kelli Dominick, MS, for performing exercise testing nd trining; Jennifer Norten, PhD, for ssisting with the weight mngement progrm; Connie Bles, PhD, for nutrition consulttion; Richrd Bloomer, MS, for ssistnce with mnuscript preprtion; Leonrd Epstein, PhD, for his review of previous version of the mnuscript; nd the stff of the Generl Clinicl Reserch Center for their support of this reserch progrm. Reprints: Jmes A. Blumenthl, PhD, Deprtment of Psychitry nd Behviorl Sciences, PO Box 3119, Duke University Medicl Center, Durhm, NC (e-mil: lume003@mc.duke.edu). REFERENCES 1. Burt VL, Cutler JA, Higgins M, et l. Trends in the prevlence, wreness, tretment, nd control of hypertension in the dult US popultion: dt from the helth exmintion surveys, 1960 to Hypertension. 1995;26: Rosenltt RA, Cherkin DC, Schneeweiss R, Hrt LG. 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