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RESEARCH PLAN AND SUPPORTING DATA

HEART DISEASE PROGRAM

Research Plan

Introduction and Specitic Aims:

Incrcased proliciency.in performance, decreased norbidity froa illncss, increased longevity and similar claims for improved healt. status have besn proposed as tenefits of regular physical exercise. In certain populations, regular gymnastics are a part of daily lire from childhood to advanced age, In Russis, factory vorkers "break" not for coffee and a cigarette, but for calestheuics. Arrican nomado, herders by vocation and necessity of life, with & diet cocparable to that found in Western societies but who walk up to forty ailes a day are reported to have negligible coronary artery ard ischemic heart disesse.

A dccrense in physical exersise has been related to an increased incidencs of coronary and ischemic heart disease. In this setting, the sedentaly lire. "spurt" activity has been incriminated in acute ischemic spisodes. Whether directly related or whether one of several conditioning or predisposing factors. moot investigators nou agres that sedentary living is aot conducive, throush several Jossible mechanisms, vith good cardiovescular health.

Physical excrcise has been purportsd to be of therapeutic benefit. It has been prescribed in the treatment of obesity, in muscular and skeletal disorders, is routine in general rehabilitation from acute ard chronic disease, is. encouraged post-opcratively to preclude puimonary embolism and is reccmmended follcuing acute myocardial infaretion in the hope that inter-coronary artery anastomoiis vill incrcase. Physical medicine is part or the therapy of avoplexy from its onset to recovery. Other examples could be cited and tie physicians regularadmonition to patients is to exercise rerularly.

The physiolory of exercise has been the subject or intensive study, especially since the Sccoa World War. The respiratory and cireulatory adaotations to exercise stress has been studied: in acute mild to severs exercise strcss; during supine and upright cxercise; in thé Mleld and in the laboratory; in "conditioned" and "unconditloned" subjcts;, in various occupational grouos; in age groups from childhood to old a\_/; during and sometime after acute cireulatory disotlers and in various disease states, inclucing chronic lumz disease, dinbetes mellitus and situations or chronie systolle and diastolic lert ventricular overload. Despite this tremendous effort, there is much that remnins obscure about the reaponae to physical vork. while what happens in various situations. in response to this strcss, is knoun, hor nni why it happens is loss clcar. In many of. these studies, the rosults are not consistent. the samnles nre small, the strcas is varioble and the rosults are of qucstionable statistical signiricnnce in extrapolation to populations or penural grouns,

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Physlenl oxoreise has been enployed as a diagncstic tool: to establish resniratory and circulatory adequacy; to deterine and to quantitate shysizal fitncss; to estebliah functional or aerobic eapacity and functional reserve for physical wark and to diagnose or detect latent ischemic heart dlsease in age groups at high risk from covert coronary heert disense. The standard exercise tolerancc test (Masters) has been elarified as to eritoria (attingly). and ruantitnted In teras of degrce of positivity (Robb and Marks) throuth znatoui: and clinical ccrmlations. While this test detects advanced coronar heart diseare, it is inscnsitivc to mild or moderate degrees that cay be equally haznriouc by location or other mcans to overt ischemic heart disease. The studies employing graded and maximal excrcise stress (Bruce, lellerstein) hevc ofrerod a more sensitive nethod of detecting significant coronary artery disease at an early stage. Such sensitivity is essential if mcthods available or teveloped, arc to be applied to pravent the overt cxpttssion of this process ns clinical ischemic beart disease.

Fros she studies avnilable then, it is clear that no one paraaeter will chtractorize an individunl's physiologic or cardiovascular health status at a givon point in tinc. The budy milieu is dynaaic and therefore, dynamie testing vill best descrice its response characteristics ard health status. Through the applicaticn of physical exercise as a stressor, especially if sufficient stress is applied, and through the mensurement of multiple response characteristics or parameters, a physiologi: portrayal of an individual can be described. Horeover, such & portrayal vill remain relativly constant unless imnroved by physical training or deteriorated by intercurrent illness or disense. Health atatus can therefore be desribed and followed in ters of functional capacity and reserve.

Through the applicatlon of chese methods to normal subjects, in quentity and thrcugh longitudinal as vell as vertical observations in different age groupa; through identicel observations in subjects at high risk for circulatory disorders: and In oathological groups suitably gatched vith the norals. the natural hiatory or both normal and disease-affected circulations csn be evolved in Cunctional ter.

This anproach to eirculatory study of function and henlth also provides an opportunity to test methods and techniques and to evaluate instrumentation for the optimum upplisation of the stress. In a similar way, the effects or exereise strss, beneficial or detrimental, of varied types and mode of application can be evalunted to determine vhich will provide 'the maximua therapeutie effect in disensed states.

In summnry, the plan or investigation is based upon the hypothesis that dynanie testing yields much more meaningrul informstion about health status thonistatic testing and that physical exercise can be used as a research tool to determing and quantitate cardiovascular health status; to deteet latent ischemic hoart disease and, as a therapeutic agent, be used to reverse the decrcmcnts in circulatory function produced by disense.

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Methods of Frocedure:

Ceneral Method:

Each subjeet will serve as his own control fcr longitudinal study. Ia addition, each subjezt will be paired with another normal subject in a different age group and with a pathological control with a specifie abnormality of the circulation. This pairing or matching will be by background, amount of training or physical exercise, body surface area, lean body nass and similar parameters.

Subject Selection:

Normal subjects will be accepted as volunteers for this program from the community available for study. "Norvality" will be determined by the screening evaluation described below.

The study group, at high risk fron coronary artery and ischemic heart disease. will also be determined by the screening procedure. Allocation to this grous will. be according to such indicators' of coronary artery disease as, suggestive.. history or physical findings, asymptomatic positive Double Masters test ischemic ST segments on Screening Procedure, LAD or RV1 patterns on EcG, asymptomatic aquired bundle branch block or other conducticn disturbance. suspect of heart disease, elevated serum cholesterol, serum triglycerides, serum uric acid or clinical gout, a strong family bistory of heart disease or other circulatory disorders, diastolic hypertension. Diabetes Hellitus (elinical or latent) and obesity.

Groups of pathological controls for the above two groups will be accepted by referral from the out-patient services of

and from physicians within the Comsunity. In addition, pathological study groups will be established in the follcwing disease categories:

1. Chroni'e Lung Disease

2. Chronic Systolic Load, Left Ventricle

3. Chronie Diastolic Load, Left Ventricle

4. Cardiomyopathy:

a, Ischemic Heart Disease

b.. Primary Hyocardial Disease

Study Croup Size:

The normal study sroup should ultimately comprise loo subjects in cach decade .from the second through the seventh. Each sub-group slcuid consist of thirty subjects, as a minimum Dumber for statistical significance.

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Procedure:

Thrce basic procedures viil be folloved in this study, according to the group as follous:

Procedare A:

This is a scroening tochnique, adapted to the study of a large nuaber of test subjecis. It is intended ta provide a beseline cardiovascular evaluation ot both static and dynamic nature; to detect latent or potestial circulatory disorders in "normal" volunteers; to provide subjects for the grouo, at high risk from ischcmie heart disease and is the basic evaluation for all subjects.

frocedure B:

This procedure will be a more extensive evaluation of circulatory functional enpacity and reserve. This procedure is an out-patient evaluation that can be accomolished in ons-halr day. It is intended to provide more dctailed information that can be extrapolated to the group studied only by Procedure A. Information obtained in this procedure vill be useful in determining any modifications toward a more meaningful screening technique.

Procedure C:

This procedure is an exhaustive study of cardiovascular health status. It omploys all available racilities and techniques available vithin the Medical center, Convcntional catheterization techniques and ancillary radiographie. rndioisotooe and other pertinent methods or eirculatory study vill be emoloyed as they arc pertinent to achieving the goals of this study. This procedure is ar in-house, in-patient evaluation requiring three hospital days. Facilities for this evaluation are available through the

PROTOCOL: Procedure A

1. Each subject will sign an informal consent authorization for study.

2. Each subjeet vill be intervieved by a social vorker and baseline socieenvironmental data obtained.

3. In the nost-absorptive state, blood vill be obteined for baseline hematolory and blood chomistry (FBS, 2 Hr. post-prandial sugar, cholesterol, urie acid, total lipids, phospholipids and trigiycerides).

h. Complete history and physical exnmination vill be recorded.

5. Baseline records of the folloving will be recorded:

n. Eleetrocarliogran

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b. Phonocardiogram

c. Vectorcardiogran

d. Ballistocardiogram

G. Standard exercise toleronce test (Double Masters)

T. Post-standard exercise (Double Hesters) vectorcardiogram

8. Total body vater (tritium) and calculated lean body mass will be deteraine?.

9. Exercisc Screenina:

Resting control determinations vill be made of blood pressure (curr) a。 and heart rate (RKG).

b. Wherever possible, blood pressure will be obtained throuzzout the test procedure from an indvelling arterial needle in a brachial artsry The hlood pressure, in this instance, vill be directly obtained together with'the integral and First derivative of the prcssure pulse.

e. Arterial oxygen content will ba monitored by ear oxisetryd. Where direct arterial sampling is available, arterial blood vill te ontained for the direct determination of PO2, PCo2, P4, Lactate and Pyruvate.

e- Radiocardiogram vill be continuously monitored.

r. Exnired air will be collected for three ninutes in a Douglas bas for baseline oxygen consumption and RQ.

g. The subjcct will then perform exercise on the bicycle orgoneter s folloos:

--1 minute (1) 50 Watts (300 Ke1/min.)------ ---- 2 minutes (2) 100 Watts (600 K/min.) --- 3 minutes (3) 200 Watts (1200 Kgi/min.)----- 3 minutes (h) 320 Watts (1800 Kg1/min.)

The radiocardiogran vill be continuously monitored duriat the exrcise. Rocords vilt be obtained at each minute Juring and folloving the coanletion of the cxercise until the rate has returned to thc control levol.

At the completlon or thrce minutes of the maxinun anount of exercise the subject can perfor, expired air wlll be collected ia a Douglns ba tor one sinute. ror the determination of oxygen consunotion and 82.

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Oxycen content vill be continuously monitored by ear oxizetry and a Feco-i made of the level at each increment of work to maxinus. Where direet arterial sampling is possible, a samole will be taken during the aid-peins or the bir collection for POp, Pco2. pK, Lactate aod Pyruvate:

When direet arterial pressure is obtained. records of ths integral of the pressure pulse and the first derivative, of pressure vill be obtained at ench minute during exercise and esch minute follosing exercise watil the pressurc has returned to control levels.

PROTOCOL: Procedure D

1. The subject vill have completed procedure A and have been sclected according to the criteria outlined above under "Selection."

2. The subject vill be alloved a rest period In the iaboratory wntil blood nressure and heart rate are stable.

3. pK vill be attached and continuously monitored.

h. Couraand needles vill be inserted into a convenient artery and vein; the former for arterial blood sampling and pressure monitoring: the latter for the injection of indicator substances snd other test materials.

5. Conirol recording of henrt rate and pressure, pressure intesral and derivative vill be obtained.

6. A Valsalva maneuver vili then be executed and the changes in pressure and and heart rate. continuously monitored and recorded.

7. Whon the subject is stable as shown by heart rate and pressure, expired air will be collected in a Douglas baz for tiree minutes for the determinatics of oxygen consumption and RQ.

8. During the second minute of the collection of expired air; an arterial blood sample wil1 be obtained for PO2, PCOz, pH, Lactate and Pyruvate (12 ce.)

o. Folloving artorial sampling, duplicate deterainations of cardinc cutput will be made by the indicator dilution technique.

Part II: Exercise at 100 Watts (600 Kgi1/min.)

1. Suuject vill exercise on the Fleisch bicycle orçometer for seven minutes.

2. Arterinl orossure. pressure integral and first derivative ans heart rate wili be continuously monitored and recorda taken of this resnonse at cich mizute during exorcise and at each minuto folioving exercisa until these par:umeters have returned to the control levels.

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At tha end of the 4th minute, expired air will be collected in a Douglas bag for one - throe minutes.

At the start of the fifth minute, an arterial blood saople wiil be obtained for PO2, PCO2, pH, Lactate and Pyruvate. :

Cardie: output will then be determined by the indicator dilution technique.

Part III: Exercise at 200 Watts (1200 KgM/win.)

I. Fart II vill be repeated at this level of work.

Part IV: εxercise at 300 Watts (1800 KgM/min.)

The criterion for continued testing at the higher wcrk levels will be a returo to near control levels of heart rate and blood pressure.

The criteria for maximal exercise stress will be an exercise level which the subject cannot sustain for mcre than four minutes, up to seven minutes. That is, the maxinal amount of work which any given subject can carry out for a Fuli seven minutes will be considerad his maximum. Other criteria which will be used to determine that the test vas maximal and that a steady state existed at the time of data aquisiticn are:

1. Heart rate of 17o or more at the two peak levels of work; that is, at the peak level of exercise for seven minutes and a similar rate increase at the exercise level of failure.

2. Agreemant of expiratory volume and a plateau in oxygen consumption. (Less than soo cc. difference between two consecutive levels of work in VO2).

3. RQ and 2 uptake/minute/M².

Wherever possible, the following cata will be aquired both at rest and during each exercise period:

1. A-a PO2 and PCO2 gradient.

2. External recording of apex and base phonocardiogram with apexcardiogram.

PROTOCOL: Procedure C

The procedures used in this portion of the study will combine exercise stress and the determination of hemodynamic response by intra-cardiac techniques. The specifie procedure will depend upon the pathological problem under consideration but will be directed to the measurement of the same parameters determined in the other protocols. Angiccardiographie, radio-isotope and other indicated ancillary rethods will be used as indicated to obtain the required data (eg. cornary arteriography).

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DATA ACOUISITION:

The raw data obtained directiy in analogue form during the test procedures will ta obtained using a multi-channel photographic recorder and simultaneously recorded on magnetic tape in either analogue or digital form (after A-D conversion). The raw data obtained by interview (Social and environmental history, medical history) and by physical examination will be recorded by the examinar on suitable forms (check sheets), key punched and card filed or placed on magnetic tape. Free fimld-data will be provided for. All diagnoses will comply with the Inter» national nomenclature and the diagnostie,-funstional and therapeutic classifi. cations of the Ney York Heart Association and wiil be adhered to for cardiovescvlar classification.

A dictionary of terms has been compiled for the above purposes and for the derived physiologic parameters. Programs for the ADP of raw data to obtain the derived data is now in process.

Automatic data processing equipment is available for this work on a time available basis at the present time and other facilities can be employed, should Funds be available.

The following parameters will be measured. as noted belou ani on the followine two tables:

1. Cardio-pulmonary Index:

Age + vital capacity (l00 ml.) t breath holding (sec.) + Pressure bresthing
(mm, Hg.)
Systolic pressure \* diastolic pressure + heart rate

The normal value is 1.000; values belou 0.752 sufgest impairment of cardiovascular function.

2. RKG amalysis; (interpretation according to a:tached EcG code)

3. Double Masters analysis; (positive. negative, equivocal)

4. Analysis of phonocardiogram, with other paraneters to determine q-l time. mechanical systole, ADC, VDC, ete.

5. Ballistocardiogram (see attached code)

6. Maximal exercise and exercise screening (see Tables 1. 2).

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TABLE 1

PARAHETERS HEASURED

Farameter

1. Height 2。 Weight 3. Body Surface Area 4. Fat free body mass 5. Total body water 6. Pulse rate 7. Systolic pressure Diastolic pressure 9. Mean Pressure 10. Integral of pressura 11. First derivative of pressure 12. First derivative duration, A-B 13. BA duration, onset to peak 14. Systolic ejection period 15. Hemoglobin 16. Arterial PO2 17. Arterial PCO2 19. Arterial pH 19. Arteriai\_ lactate (Lo, Ln 20. Arterial pyruvats (Po, P,) 21. Respiratory rate 22. Minute volume (Ve) 23. End tidal CO 24. Duration of bag collection 25. Tidal volume 26. Anatomic dead space 27.. Physiologic' dead space 28. VE (BTPS) 29. t oxygen in VE 30.  carbon dioxide in VE 31. nitrogen in VE 32. Cardiac output

Dimension

feet, Inches; meters pounds; kilograms
square meters
kilograms
liters
Deats pac minute
mo Hg.
mm Hg.
om Hg.

c: / minute

liters / minute

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TABLE 2

Variable

DERIVED VARIABLES

1. Oxygen capacity 2. Ox/gen saturation 3. Oxygen content 4。 VI (BPTS) 5。 Oxygen consumption 6. Oxygen consumption index 7. Oxygen consumption / F.F.B. 日。 CO2 produced 9. Rtspiratory quotlent 10. Functional capacityi functional reserve; reserve capacity (VO2 Max.) 11. Functional reserve index 12. Functional reserve / F.F.B. 13. Cardiac output 14。 Cardiac index 15. Cardiac output / F.F.B. 16. Stroke volume 17. Stroke volume index 18. Stroke voIume / F.F.B, 19. Mixed venous PO2 20. (a-v) PO2 difference 21. Effective left ventricular work 22. Effective stroke work LV 23。 Minuts work index 24. Stroke work index 25. Minute work index / F.F.B. 26. Stroke work index / F.F.B. 27. Mean systolic ujection rate 28。 Total systemic resistence 29. Tension time index 30. Physislogic dead space 31. Anatonic dead space 32. Dead space ventilation 33. Alveolar ventiiation 34. VD / VT ratio 35. A-a oxygen gradient 36. A-a CO2 gradient 37. XS lactate 38. Lactate/pyruvate ratio 39. Anerobic metabolic rate 40. Acrobic capacity 41. Oxygen pulse 42. Oxygen pulse index 43. Oxygen pulse indax / F.F.B. 44. Calorlc work equivalent 45. Percent efficiency (t of energy transformed into work) 45. Work equivalent

Dicension

cc.
cc./100 cc. cc./minute cc.
ec./k²
cc./Kg/
ec. cc.
cc./M²
ce./Kg-
Liters / minute
Liters / minute / M2
Liters / einute / F.f.Bcc. / beat
cc. / beat / y2
cc. / beat / Kg.
cc. / 100 cc.
cc.
Kg.M / minute
Cm.M / ninute
Kg.M / minute / H2
Gm.M / minute / M2
Kg.M / minute / Kg.
Gm.M / minute / Kg.
cc/systolic sec.
dyne cp.
cc.
cc.
liters / minute
liters / ninute
mp
me.
cc.
cc. VO2 / heart beat
ec. VO2 / heart deat / H2 ce. VO2 / heart beat / Kg. kilocalories

4

Watts, foot pounds. Kg.M/nin

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Significance of this Research

A dynamic test procedure will be applied to a commnity population, at risk from ischemic heart disease. Through a broad approach to the evaluation of test subjects, including consultations where indicated, a broad social and environmental perspective and the response to stress, latent ischemie heart disease will be detected. Further investigation of individual subjects so detected, will confira the value of the screening technique and wili provide information, alloving patho-physiologic correlations in the epidemiology of coronary artery and ischemic heart dissase.

In additisn, the natural history of "normal" physiologic function will be delineated. Results obtained in pathological groups will allow description of decrements produced by cordiovascular disease. The natural history of specific diseases of the circulatory system will be described in functional physiologie terms Within this framework, fartors vill be delineated which may lead to the early e tection of functionally significant abnornalities; discovery at a tins when pre» ventive measures may be nost effective. Within this framework, methods may be tested for their ability to arrest, retard or reverse the functional decrements produced by disease.

Facilities Available:

The screening procedure will requlre approximately 400 square feet of additionsl space.. Procedure B can be carried out in the facilities sa h

I as currently constituted. Procedure C can be accomplished in the in-patient facilitias of the ntiehed in the in-oatiant facilitias of the

which this investigator now has allocated two fuli work days. Ultimately and ideally this phase of the study could best be accomplished in a facility established within the medical center, specifically for this purpose, that is, Clinical research applied to the problems of Public health and Preventive Medivine and the Epidemiology of circulatory disease.

SUPPCRTING DATA:

Previous Work Done in This or Related Fields:

The principal investigator first carried out resaarch in exercise physiology in 196l-6?. This involved the usa of exercise in subjects with hyperthyroidism. before and after ganglionic blockade and normal subjects. The overall project was an investigation into hyper-dynamic circulatory states and included thyrotoxicosi physical exercise and aspirin, He and the co-investigators have been engaged in Clinical Medicine and Cardiology and ClinicalResearch in these fields for the past five years; for the past eighteen months as independent investigators.

In the past eighteen months, 750 normal subjects have been evaluated. In addition,:l26 subjects with known disease of the circulation have been seen in consultation. In the former group, 637 Double Masters tests have been perforted. (Report in preparation). In this group, one subject was detected with ischemie

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heart disease. Aiso in the normal group (Procedure B),'exercise stress testing has been performed in s8 subjects. Three subjects. in addition to the one found by the double Masters test, were found to hava definite ischemic ST changes (see attached abstract; repcrt in preparation), (see attached tracing).

In the pathological group, the evaluation of 78 suSjects with known episodes of clinical ischemic heart disease were evaluated. The period of observation in this group averaged 8 years from the ischemic episode. The double Masters test was positive in 47% of thls group and negative in 539. Prognosis couid not be made on the basis of this exercise response, and average longevity did not differ between these two groups. (report in prsparation). It is concluded that this test does not elicit sufficient stress to determine functional capacity of the heart afflicted with ischemic heart disease.

The report of the first thirty subjects studies (Procedurs 3) is attached. This was supposedly a "normal" group.

Also these same studies have been utilized in the past eighteen months to establish laboratory norms and procedures and a preliminary funetional rating for normal subiects.

Personal Publicationst

Curriculum Vitae of Investigators is attached.

REVIEW OT PERTINENT LITERATURE

The work of Hill (l) demonstrated that there was an upper limit to the ability of the respiratory and circulatory system to deliver oxygen to the tissues during heavy work. This is the maximum oxygen consumpticn and in normal subiects, the major limiting factor is the status of the circulation. This fact was early put to experimental use. Its use as a test of functica, its limitations, sensitivity as well as its validity were conclusively demonstrated (2,3). Oxygen consumption at maximum work has been shown to decrease with age (4,S,6), to be higher in upright than supine work (s) and to be a sensitive index of cardiovascular disease (7). For adults. it remains relatively constant unless altered by either disease or physical truining-

The hemodynamics of exercise have been extensively studied (l,4,\$,6,0). The entire subject has been recently reviewed (io).

The anerobic costs of mild work in health and'in disease have been presented by Huckabee (li) and in normal men and trained subjects by Bruce (l2).

The exercise test of Hasters (13) has been clarified and modified by Mattirigly (14) and placed on a pathophysiologic basis through the studies of Robb and Karks (15).This test however, detects Ischemic heart disease only in its advanced stages Coronary artery disease is much more prevalent than its ischemic panifestations and a more sensitive test is needed to detect it at a time when prevention ean be applied, The studies of Bruce appear to be a more sensitive metnod but requires wider implementation for validity to be determined (16, 17, le).

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PERSONNEL:

Personnel Available:

1. Physicians (2) a. b.

2. Technicians (2) A. b. Yacant

3. Secretarial Staff (1) a.

Personnel Desired:

1. Physicians (1)

2. Physiologist, exercise (1)

3. Anthropologist (1)

4. Interviewers (2) (Social service and Community Health trained)

5. Pegistered Nurse (1)

6. Technicians (2)

7. Secretarisl Staff (4)

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EQUIPMENT:

Equioment available:é

1. 16 Channel Elactronics for Medicine photographic recorder

2. Pre-ampliFiers and amplifiers (Efor M) 1. 2 ea. SGH (Pressure). 7. 1 ea. LLD (Semi-log) 3. 1 ea. DCA-8L (DC amplifier) 4. 5 ea. Single ended push-pull single ended tape converter (14 Channei)

3. Consolidated Electronics Tape Transport Mechanism

4. GilFord densitometer and withdrawal systens.

5. Fleisch bicycle orgometer

A.Only major items are listed. Necessary support items are also available..

Equipment Required:

1. Pre-amplifiers: 1. 1 ea. SGH 2. 1 ea. 8 Channel tape 3. 1 ea. εEP-a 4. 2 ea. DC Amplifiers

2. 1 ea, 12" Remote Monitor with stand

Quinton; Model l86o Treadmill with 3. programer

4. 1 ea. Lanooy Orgometer 1 ea. Crgometer pedaling assembly

s. 1 ea. Cas-gas chromatograph

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MISCCLLANEOUS:

The following additional points are felt to be highly desirable to this investigator, for the proper accomplishment of this program.

1. Sodce:

while only uoo additional square feet of space was requested above as reçuired, the addition of soo square faet would allow establishment of a suitable space for blood and gas analysis and space for electronie equipment and repair shop, both of which are highly desirable in view of the number of subjects projected and the consequent number of 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 bio-medical statistician in the design of this study, the data acquisition and interpretation is deemed to be a virtual necessity. in view of the number of observations to be made on the projected number of subjects.

b. The.full time services of an electronie technician for equipment maintainance and assistance in data acquisition is considered most desirable and advantageous to the accomplishrent of the study.

3. Establishment of an Advisory and Consultation Staff:

This program will utilize moderate to severe stress in normal subjects with known circulatory disorders. So as to safeguard the rights of the test volunteers and the moral and ethical aspects of this work and aiso to assist as consultants in the overall management of this progran, it is recommended that a Senior Advisory Board be established, The folloving are sucgested as participants:

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BUDGET:

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