RESEARCII PLAX AND SUPPORTL'IG DATA THZ ReseArch Plan Introduction -xni Specific Aims: Incrcased proficiency, In performance, decreased marbicu- tj from illness, lncrea-sed lonpevity and similar claims for improved bealtis status have bee.-k Dropo3ed as benefits of re;;ular physical exercise. In certain populations i reeialar jVmnastic5 are a part of daily life from childl,,ood io advanced age. In P f@--ctor-f vorkers "break" not fo2r coffee and a cigarette, but for ca2esthe;.ics. African nomadz, herders by vocation and necessi.,@,,/ of life, with a diet con- P&r-@ible to that Cound in Western societies but who walk uo to forty miles a day a.re repo.-ted to have nefpligible coronary, artery ard ischelaic hea2rt disease. A dccm-rlse in ldhysic&l exer.-ise has been related to an inerersed incidenc-3 of coronary and lschemic he&rt disease. In this setting, the sedentul lire, lospurt" activity has been i--icriminated in acute ischemic --pisoles. Wnether 2 directly reiated or whether one of several conditionino, or pr-edis-oosing factors, most investig,%tors now aeree that sedentary living is not condue-@ve, through several Dossible mechaLnisms , with good cardiov"cvlar health. P'nysica.1 exercise has been f3ur-oortA-d to be of theraoeutic benefit. It has been prescribed in the treatment of obesity. In musculstr and skeletal diso!-dt-r3, is routi.-ie in general rehabilitation from acute ard chronic disease, is en- cour-aged post--oo(-ratively to precl,.;@ pulmonary embolism and is recc=e@!sdL-4 following acute myocardial inf&rction In the hope that inter-coronary artery anastomo-,is will increase. Physical medicine is part of' the theral5y of anoolev from iti onset to recovery. Other examples could be cited and the physi4:ians re@,,@ar'@id.,uonil.ion to p;Ltient3 is to exercise refrulmrly,. The pft 'ioloo ys ,y of exercise has been the subject of intensive study, especially since the Seco@-.a ';orld War. The resuiratory and eirculatorr adaotations to exercise stres2s has been studied: ii acute mild to s4tver,- exercise stress; during supine and upright exerci:;e; in thi field and in the laboratory-, II ficonditik>ned" and "uncondilloned" subj-!cts; in viriou3 occupatio.-lal i,,rou'05. 4 2 In age groups from childhood to old *,_,; during and sometime after acute circulatory di!se5tler- and In velrious dl,.epse state%. including clironic ltn,4 dir,o-:a-te, di,,.tbet#-s mellitus and situatioiis of chronic ry,.tolle 2 and di=tolic left ventricul;tr ovorl.oaa. Despite thi3 tremendour. i%ffort, there is much tlirlt rem,-iins obsetire iibout the rc3pon:@e to physical work. t4'nile what hmopens in variow, situations, in x--spon-7@c to this stress. ir2, known, ho,6r nnii ±@L it h-tppor,-, is lt-rs -clear. In -nany of. there cl.udies , the resul t-- -ire not consistent, the n,=nles are ;mill, the strfss Is v-.%riable and the results are of questiontloIF-, statistical sippnific.3-Lnce in extr.,spolation to Do-,)ulations or pen-!r3l rroups, "hys i-,'Ll lae ha3 bet---i e.,tnloyed as a diagnostic tool: to rI.r.oir,"tory and eircu-tttorl adequacy; to detem-ine and to Iuantite@e fitness; to est,%bliah functional or aerobic capaci-y and Nnc+.io.-ial re.,ie:-rieb for p.-iysical work in(i to diagnose or detect lsitert ischenic heti&. disease in ag(- eroups -it high risk from covert coronary hcp--t disen-se. The st:tndard exercise toler-Lnet% test (-.%Insters) has bee2n clarifiL4d ar. to tritorca tn Iorns of der,-.%-a oC positivlt_v ('Llobb and ','iarkz) 41.4rou,%h 'U@(i eL.Inical ccrrr%lations. While this test detectr, advinced coronart lse6trt disc,L:-,e, it is insensitive to mild or moderate degrees that r-ay be equally hkzrlriour, by locatioft or other me-ins to overt lsc-he.,nic heart disease. The stuflies emolovino, graded and maximal exercise str--ss (Bruce, I!elle.-Stein) ho-vc- 2 nrrl,md a mori! sensitive method of detecting si@nificant coronax-f artery -iisea,se at an early stage. Such sensitivity is essential if methods availablc or rte-.reloped, tim to be at)plied to p-ovent the overt expression of' t:-iis prG2eesT .-w clinical ischeue he-irt disease. Fror-. the atudies avrtil.%ble ,then, it is clear that no one para.-.ieter ch.-tracl.or,'.ze in indiv-Ldu.-tll.,i -ohysiolof;ic or cardiovascular healt'.11 status at a 2,,iv@-,n point in ti,,ic. The b3tly milieu is d,,In=ic and therefo--e. dynamic te3l@ing Vill best, tictseribt% its resp..)nso charzteteristic-3 ard health ste@u3. Throug7n 6.1.@e 'licatio.i of physical exerci2se as a stressor, eipecially if suf,i,@ient stre-qs app 4. is applied, and through the measurement of multiple reszonse character stics or pa.-amcters, a phystologi: portrayal of an lndi,,idual can be described. 2 '.Io.-e o, -rer, siich a portrayal -,rill remain relativv constant unless improved by physical tr,%Lning or deteri.:orelted by intercurrent illness or dit;ease. Health 3t,itus cm therefore be des,:ribe4 and follcved in terms of functional 2 canacity and reserve. Throup,b the application of these methods to nomp-I subjects, in quantity and thrc4n longitudinal as well as verlticgll observations in differert ame -.rou-vs; through identical observations in subjects at high risk for circulator.-f d2is- orders; and In patholoilical groups suitably matched vith the nor-.als, the - natural bistory of' both normal and disease-affected circulations c3i be evolvc-d in f@mctional temi. Thin Approftch to eirculatocy study of fwction 2 and health also Drovides an 0-p- portunity to test methods and techniques and to evalaate inscrunentation for the optimum Pipplication of the stress. In a rimilar way, the off(-ctz of exercise str-as, beneficial or detrimental, of varied types and mode of anplic.-ition can bob evaL2lu.L-tted to do-termine vhich will provicle 'the m:%ximurn therar>eutic effect in diseased states. 1-i simnary. the plan of investipa@.ion is ba-scd ii;kork the hy-pothesis that dyn.tmte tcstinr, yields much more mePningru.1 inf-or-n2ation about health status than.Gt.-itit teatink ind that physical exercise can be used as a research tool to dqtcrrine and quantitate cardiovo-,.cu-lar health statu3-, to detect latent 13chcmic h@-,%rt digea!,el %nd, @%-. a ther-%pautle ar-w-nt, be used to reverse the decrements in circulatory function produced by 4iseise. Methods of Procedure: Ceneral Method: rach subject will serve as his own control for I*ngitudinal study. In addition, each subjezt will be paired with another normal subi-ect in a different age group and with a pathological control with a specific abnormality of the circulation. This pairing or2 matching will be by background. amount of training or ptiysical exercise, body surface area, lean body mas and similar parar.*ters. Subject Selection: Norm;il subjects will be accepted as volunteem for this program from the commlinlty available for study. 'Nor.-.ality" will be determined by the screening eval2uation described below. The study group, at high risk from coronary artery and ischemic heart disease, will.also be determined by the screening procedure. Allocation to this grouo will. be according to such indicators'of coronary artery disease as, suggestive histor-y or physical findings, asymptomatic positive Double Masters test lschemic St 2segments I on Screening Procedure, LAD or RVI patterns on ECC, asymptomatic aqu-ired @undle branch block or other conduction disturbance* suspect of heart disease, elevated serum cholesterol, serum triglycerides, seriim uric acid or clinical &out, a strong family history of heam disease or other circulatory disorders, diastolic hypertension, Diabetes Hellitus2 (clinical or latent) and obesity. Groups of pathological controls for the above two eroups will be accepted by referral from the,out-p@tient services of and from physicians within the Coma-unity. .rn addition, pathological study groups will be established in the follcwing disease categories: 2 1. Chronfc Lung Disease 2. Chronic Systolic Load, Left Ventricle 3. Chronic Diastolic Load, Left Ventricle 4. Cardiorryopathy: a. Ischemic Heart Disease b.. Primarl Myocardial Disease ;@ruqv uroup Size; The nomal study proup should ultimately comprise 100 subjects in each decade ,from the second through the seventh. Each sub-group siou'@d consist of thirty subjects, as a minimum number for statistical sienificance. -3. Proccdure- 7'hree basic procedures will be followed in this study, according to the qrou-* as follOW3: Proced.tre A: This is ;L scret-ning technique, adapted to the study of a laree n%Lnber of test subjec-i2s. It is intended ta Provide a baseline ca-rdiovascular evaluation ol,' both static and dynami.c nature; to detect latent or potential circulatory dizorders ir@. "normal" volunteers; to provide subjects for the group, at hL.Si@. e, L- k fro.m ischerue heart disease and i3 the basic evaluation for &11 2subjects. Procedure 3: T'.@iS DrOCedure will be a more extensive evaluat@ion of eirculatorj functio-ial capacity and reserve. This procedure is an out-patient evaluation thit c= be acconiolis@ied In onz-half' day. It Is intended to provide more dctalled in2formation tli.-t can be extrapolated to the group studied only by Proced--.,,-c A. Information obtained in this Procedure will be useful in determinin& any modifications to-.fard a more meaningful screening technique. Procedure C: ThLs procedure is an exhau3t2ive study of cardiovAscu-IFtr health status. It *,nploys all av,%[IaLble facilities and techniques &vrilable within the i4edical center, Co-iventie)ral catheterization techniques ani ancillazr radiogrgkd-hic, radioisotoce and other pertinent mo.-tho2d.- of eirculatoz-f stue,,( will be emoloyed as they are pertinent to achieving the goals of this study. @Lhis nrocedure is in-',iouse, in-p,-Ltiont ev&luation requiring three 1.@ospital dpys. Fxcilities for this e--riluatlan am available through the 2 PqO'.rc)Clr.: ProcL-dur--A 1. EAch sub.lect will sign an informal consent aitho.-iz,-tion for study. rtch subject will be interviewed by a social worker Lin(I basel4Ane socio- environmental data obtained. 2 14 3. In the post-absorptive rtate, blood will be obt,,Int%d for bae-eline he.,natolo,-.y vd blood chcmistry (FBS, 2 fir. post-prindlat sui,,ir, cholesterol, uric acid, tot,i'L lipids, phospliolipid-- and triglycerides). 2 lo. Cayplete history and physical examination will be recort4ord. M-iseline mcor-t-. of the f'ollowinp, will be recort4.ed: a. Electroc,-tr,liorr,%,% 0 b. -7honocardiorrFim c. Vectorcardiogr= d. Ballistocardiogram Standard exercise tolerance test (Double Masters) post-standard exercise (Double -4asters) vectorcardiog',,am To2,4aL body water (tritium) and c&lcu-lated lean body m*@3s vill be dete.-mined. t;ce:cise Screening: ,%. Restinig control determinations -111 be m&.ie of blood-preisure (cuff) and heart rate (RYG). ".r possibl2e, blood pressure vill be obtained throti@@out the b. ldhere test procedure from an in,nent available:L, 16 Chainel Electronics for Medicine photographic recorder 2. Pre-amolifiers and amplifiers (Efor M) 1. 2 ea. SG:i (Press,4re). 2. 1 ea. LL2D (Semi_ log) 3. 1 ea. DCA-81 (DC amplifier) verter s ea. Single ended push-Pull single ended tape cOn (L4 Channel) 3. Consolidated Eler-tronics Tape Transport MechaDism Gilrord densitometer and withdrawal systems. 2 S. Fletach bicycle orgometer r items are listed. Necessary SuPPOrt items are &'-S* available. Only cajo Equipment Pkeaquuirree(d,,'. 1. Pre-amplifiers: 1. 1 ea. SGM 2, 1 ea. a C,@annel tape 3. 1 ea. EEP-8 4. 2 ea. DC Amplifiers 2. 1ea4 1211 Remote monitor with stand 3. Quinton; Model 1860 Treadmill with prc>p-ramer 4. 1 *a@. Lanocy Orgoveter I ea. orgometer Pe2daling assembly S. I ea. Gas-gas chromatagraph ?AISCELLA@ICOUS: The following additional points are felt to be highly desirable t* this investif %is pmer,am. .,ator, for the proper accomplishment of t, Soace: WhfLe only 400 additional square feet of spac2e was requested above 6$ 1 required, the addition of 600 square feet would allow establishvent of a suitable space for blood and gas analysis and space for electronic equipment and repair shop, both of which are highly desirable in view of the number of subjects projected and the consequent number of 2 samples to be analysed; and also in view of the amount and frequency of use of complex electronic instrumentation and supporting gear. 2. Personnel: a. The services of bic-iredical statistician in the design of this study, the data acquisition and interpreta-,ion is deemed to be a 2 vi.rtual necessity. in view of the number of observations to be made on the projected number of subjects. b. The-full time services of an electronic technician for eauipment c.aintainance and assistance in data accuisition is considered most desirable and advantageous to the atcomplishrenz of the study. 2 3. EstablishT.%ent of an Advisor and Consultat;-on Staff: This program will util-ize moderate to sever-- st-ress in normal subjects with knvrn circulatory disorders.- So as to safeguard the rights of the test volunteers and the moral and ethical asdects of this work 2 and a:,So to assist as consultants in the over&U ranagament of this prograr.-, it is recommended that a Senior Advisory Board be established. The fo',- lowing are saggested as participants: 2. 3. 4. 6. 4 7. S. .17- NMI BUDG@.,T: ------ imp_wpm=