effects of exercise on myocardial force-velocity relations ... · journal of clinical investigation...

Journal of Clinical InvestigationVol. 44, No. 12, 1965

Effects of Exercise on Myocardial Force-Velocity Relations inIntact Unanesthetized Man: Relative Roles of Changes

in Heart Rate, Sympathetic Activity, andVentricular Dimensions *

EDMUNDH. SONNENBLICK,t EUGENEBRAUNWALD,JOHNF. WILLIAMS, JR., ANDGERALDGLICK

(From the Cardiology Branch, National Heart Institute, Bethesda, Md.)

It is generally agreed that an increase in cardiacoutput is one of the primary circulatory adjust-ments that occurs during exercise. However, thenature of the alterations in the activity of the myo-cardium that permit this augmentation of outputand the relative importance in the response to ex-ercise of the various factors known to affect theperformance of the heart and its contractile statehas not been defined. It has been shown thatthe contractile state of cardiac muscle may be char-acterized by the force-velocity relation (1-3).The applicability of this concept to isolated hu-man heart muscle has recently been demonstrated(4), and a technique has been described by whichthe force-velocity relation of the myocardium ofintact human subjects can be evaluated (5), thusallowing determination of the effect of a variety ofinterventions on the contractile state of the heart.The purpose of the present investigation was toapply this technique in studying the effects of ex-ercise on the force-velocity relations of the humanheart, to define the relative roles of the changesin heart rate and of sympathetic activity that oc-cur during exercise on the force-velocity relation,and to delineate the role of changes in ventricu-lar end-diastolic size in the response of the heartto exercise.

MethodsTwelve studies were carried out in eleven patients

ranging in age from 24 to 55 years (average = 44 years).All had undergone cardiac operations consisting of theclosure of an atrial septal defect in six patients, closureof a ventricular septal defect in two, aortic valve re-

* Submitted for publication April 22, 1965; acceptedSeptember 16, 1965.

t Address requests for reprints to Dr. Edmund H. Son-nenblick, Cardiology Branch, National Heart Institute,Bethesda, Md. 20014.

placement with a Starr-Edwards prosthesis in one, andmitral valvulotomy in two patients. At the time ofcardiac operation small silver-tantalum markers weresutured to the right ventricle in seven patients, the leftventricle in two patients, and to the surface of both ven-tricles in two patients, as described in detail previously(6). Hemodynamic studies carried out 1 to 14 monthspostoperatively are summarized in Table I. The restingcardiac output was normal in all patients (> 2.50 L perminute per m2), as was the right atrial pressure, althoughthe right ventricular end-diastolic pressure was slightlyelevated in one patient (C.D.). The right ventricular sys-tolic pressure was also slightly elevated in four patients(C.D., I.D., M.W., and S.C.).

The techniques for determining ventricular end-dias-tolic dimensions and the force-velocity relation havebeen described in detail elsewhere (5). At the time ofpostoperative catheterization, cineradiograms were ex-posed at 30 frames per second while intraventricularpressures were recorded simultaneously at a paper speedof 100 mmper second. A mechanical marker, activatedby the R wave of the electrocardiogram and recorded onthe cineradiogram, permitted precise temporal correla-tion of ventricular dimensions and pressures. The dis-tances between markers that had been placed in a lineparallel to the frontal plane were measured on successiveframes of the cineradiogram. All observations weremade with the patient in the supine position.

The analysis of the force-velocity relation is predicatedon the finding that throughout the active contraction theposition of the force-velocity curve of the myocardium isdetermined by the instantaneous length of the muscle andby its contractile state (7). Thus, if the force-velocityrelation is always examined at the same muscle length,this relation will define the contractile state of the myo-cardium. Accordingly, the force and velocity of a seg-ment of the ventricle were always determined at the in-stant during the contraction when the segment passedthrough a specific length, termed the isolength point. Itis recognized that the velocity of myocardial fiber shorten-ing is not equal to the velocity of shortening of the con-tractile elements except when the series elastic compo-nent is not changing in length (8). However, the ex-tension of the series elastic component takes place almostentirely during the isovolumetric phase of contraction

2051

SONNENBLICK, BRAUNWALD,WILLIAMS, AND GLICK

TABLE I

Postoperative hemodynamic findings at rest*

Time Pressuresafteroper- Cardiac RA RV PA LA LV BA

Patient Age, Sex BSA Diagnosis ation index (m) s/d s/d (m) (m) s/d s/d (m)

M2 months L/min- mmHgute/M2

J.S. 33, M 1.84 P.O. VSD 6 2.66 2 18/3 16/5, 11 120/65, 81G.N. 55, M 1.80 P.O. AS 6 2.53 0 19/0 15/7, 10 3 124/6 106/60, 78S.J. 28, M 1.77 P.O. VSD 1 5.48 2 20/3 19/5, 10 110/55, 80C.D. 43, F 1.60 P.O. MS 12 2.74 4 32/7 32/12, 21 14 160/9 167/75, 120K.G. 27, M 1.89 P.O. ASD 13 3.76 0 10/-1 10/5, 8 132/75, 96S.C. 28, F 1.52 P.O. ASD 13 4.01 1 44/1 42/20, 32 115/60, 85I.D. 29, F 1.56 P.O. MS 9 3.15 3 40/5 39/19, 28 10 94/6 98/60, 77P.S. 36, F 1.66 P.O. ASD 4 4.64 2 29/3 29/12, 18 140/65, 82M.W. 24, F 1.70 P.O. ASD 14 2.91 5 34/5 23/8, 15 128/70, 95R.W. 35, M 1.93 P.O. ASD 8 3.64 3 20/4 20/8, 12 133/64, 81A.H. 39, F 1.50 P.O. ASD 7 4.09 0 24/1 23/5, 10 106/54, 72

* Abbreviations: P.O. = postoperative, VSD = ventricular septal defect, ASD = atrial septal defect, AS = aortic stenosis with Starr-Edwardsprosthetic valve replacement, MS = mitral stenosis, RA = right atrium, RV = right ventricle, PA = pulmonary artery, LA = left atrium,LV = left ventricle, BA = brachial artery, m = mean, and s/d = systolic/diastolic.

and is virtually complete at the point during the ejectionphase at which the measurements were made. Thus, it isunlikely that alterations of the rate of elongation of theseries elastic component could have altered the relation-ship between the velocity of shortening of the segment ofmyocardium and of the contractile elements.

The instantaneous distances between the markers on

the ventricular surface were plotted below the intra-ventricular pressures of the same cardiac cycles, as

shown in Figure 1. The contour of the dimension curve

and temporal relationships between intraventricular pres-sure and dimensions have been shown to be similar forboth ventricles (6, 9). The isolength point was selectedas a length of the segment of myocardium that was com-

mon to all cardiac cycles and that occurred during thefirst two-thirds of ventricular ejection. The rate atwhich the markers approached each other was deter-mined when the segment of myocardium passed throughthis isolength point (Figure 1, points a and a'), and theinstantaneous velocity of shortening was determined bymeasuring the tangent to the curve relating ventricularlength to time at this point (Figure 1, points b and b').Whereas intramyocardial wall tension could not be meas-

ured directly by this technique, it is known from theLaPlace relation (10) that, at any one ventricular vol-ume, wall tension is a direct function of intraventricularpressure. Therefore, to use intraventricular pressure as

a direct reflection of myocardial wall tension, ventricularpressure was measured relative to the same isolengthpoint (Figure 1, points c and c').

The distances between the markers and the velocitywith 'which they approached each other were initiallyexpressed in centimeters and centimeters per second, re-

spectively. Distances between markers could be repro-ducibly measured within a 1% error (6). However,these measurements represent relative distances and ve-

locities, since the absolute values depend on the magni-fication occurring when the markers are projected on a

screen. Since the degree of magnification was constant

during any given set of analyses, it was possible to ex-

press velocity of shortening in units of "muscle lengthsper second" by dividing the velocity in centimeters per

second by the isolength measurement in centimeters. Sixto fifteen complete cardiac cycles were analyzed duringeach condition, and the average velocities of shorteningand pressures for these cycles are presented in Table II.As described previously, an increase in the velocity ofshortening at any level of intraventricular pressure, i.e.,an upward displacement of the force-velocity relation,denotes an augmentation of the contractile state of themyocardium (5).

The effects of light exercise performed on a bicycleergometer while the patient was in the supine positionwere studied in all 11 patients. The contribution of heartrate to the exercise response was studied in six patients(experiments 1 to 6). The heart rate attained duringthe normal bout of exercise was recorded, and after re-

covery, with the patient at rest, the right atrium was

stimulated with an electrode catheter in a manner de-scribed elsewhere (11) at the rate previously attainedduring exercise, and measurements of force-velocity re-

lations were repeated. The patient was then exercisedagain while electrical stimulation of the atrium was con-

tinued, and the force-velocity relation was redetermined.The contribution of the sympathetic nervous system to

the response of the heart to exercise was studied in sixpatients (No. 7 to 12). After recovery from an initialbout of exercise, each patient received propranolol 1 (0.17mg per kg), a beta-adrenergic blocking agent (12). Fiveminutes later, an identical bout of exercise was repeated.In two patients (No. 10 and 11), total body 02 consump-

tion was measured to ensure that the levels of exercisewere similar before and after sympathetic blockade. Inthree patients (No. 7, 8, and 10), 2 mg atropine was

given intravenously to inhibit the vagal response during

1 l-Isopropylamino-3- (l-naphthyloxy) -2-propanol hydro-chloride.

2052

EXERCISE AND MYOCARDIALFORCE-VELOCITY RELATIONS

exercise, and both control and exercise measurementswere repeated. In one patient (No. 12) the effects ofbeta blockade on the response to exercise were determinedat a constant heart rate, as described above.

In three patients (No. 8-10), the rate of right ven-tricular pressure development was measured with aAllard-Laurens micromanometer catheter system and lin-ear resistance-capacitance network differentiating circuit,as described previously (13). In every experiment, eachdetermination of the force-velocity relation was accom-

REST

15

14

R.V. 13LENGTH

12-

panied by a measurement of cardiac output by the indi-cator-dilution method as detailed elsewhere (14).

Results

Effects of spontaneous exercise. During the ini-tial bout of exercise the cardiac response was al-lowed to occur spontaneously, without control ofheart rate or of autonomic nervous activity. Car-

EXERCISE

R.Vmm. Hg

- 20

FIG. 1. METHOD FOR DETERMINING THE INSTANTANEOUS MYOCARDIAL

FORCE-VELOCITY RELATION ON A BEAT-TO-BEAT BASIS. From above downwardsare shown the electrocardiogram, the right ventricular (RV) pressure pulse,and the curve relating right ventricular dimensions, determined at 1- to 30-second intervals, to time. On the left are the data obtained during the con-trol period and on the right the observations made during exercise. Pointsa and a' represent the isolength points at which both instantaneous velocityof shortening and intraventricular pressure are determined. Line b and b'are the tangents to the length curves at points a and a' and represent thevelocity of shortening at these points. The steeper slope of b' as comparedto b signifies an augmentation of velocity. Points c and c' represent thetemporally related points on the ventricular pressure curve.

2053

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diac output rose from an average value at rest of6.03 L per minute to 8.17 L per minute, and heartrate increased from an average level of 74 perminute to 111 per minute, whereas stroke volumedeclined slightly from an average of 83.7 ml perminute to 76.5 ml per minute. The contractilestate of the heart was augmented, as attested to bythe shift of the force-velocity relation upward andto the right. Ventricular pressure, measured atthe time of the isolength point (pressurei8) in-creased in 10 of the 11 patients; in the eight stud-ies on the right ventricle, it rose from an averagevalue of 21.8 to 28.8 mmHg (+ 32%), whereasin the three studies on the left ventricle it rosefrom an average value of 124 to 136 mmHg

(+ 10%). In all 11 studies the instantaneous ve-locity of shortening, also measured at the isolengthpoint (velocityil) increased from an average of0.84 muscle lengths per second to an average of1.51 muscle lengths per second, representing anaverage increase of 80%o. In every patient ven-tricular end-diastolic length decreased with spon-taneous exercise diminishing by an average of3.1%o in the left ventricle in four patients andby 4.3%o in the right ventricle in nine patients.Examples of cardiac dimensions at rest and duringspontaneous exercise are illustrated in Figure 2,panels A and B, and Figure 4, panels A and B,whereas the shift in the force-velocity relation up-

101 1 10FIG. 2. THE EFFECTS OF CONTROLLING HEART RATE ON THE END-DIASTOLIC DI-

MENSIONS OF THE HEART AND THE COURSEOF VENTRICULAR CONTRACTIONDURINGEXERCISE. The distances between markers on the right ventricle as a function oftime for single contractions are shown for the study in patient J.S. Panel A rep-resents the resting state; panel B is during spontaneous exercise. The broaddashed line at the top labeled RVEDL represents the end-diastolic dimensions atrest. RVESL= right ventricular end-systolic length. Panel C is during electri-cal stimulation of the right atrium with the subject at rest, and panel D is duringexercise performed at the same heart rate. The top broken line in panels C and Dcorresponds to the RVEDLin panel A. H.R. = heart rate, C.O. = cardiac output,and S.V. = stroke volume.

2056


wards and to the right during these two bouts ofexercise is shown in Figures 3 and 5.

Effects of exercise at a constant heart rate. Af-ter study of the effects of spontaneous exercisewith the patient at rest, the heart rate was in-creased to that level attained during the previousbout of exercise. This augmentation of heart ratealone resulted in no significant change in thecardiac output (average = + 1.6%), whereas aconsiderable decrease in stroke volume was noted(average =- 37%). Increasing heart rate inthe resting state resulted in a decrease in the end-diastolic ventricular dimensions to levels that weresmaller than those observed during spontaneousexercise at a comparable heart rate (Figure 2,panels B and C). Tachycardia with the patientat rest increased velocity151 by an average of 23%,whereas the changes in pressures were small andinconstant. Thus, the extent of the shift in theforce-velocity relation resulting from an increasein heart rate alone was considerably less than thatobserved when similar heart rates were achievedin the same patients during exercise where the ve-locity18j increased by an average of 89%.

When the exercise was repeated at a constantheart rate, cardiac output and stroke volume roseto the levels attained during the first bout of exer-cise. However, rather than a decrease, an in-crease in ventricular end-diastolic dimensions nowoccurred, averaging 9% (Figure 2, panels C andD). The contractile state of the myocardium wasagain augmented during this bout of exercise;velocityi81 rose by an average of 57% and pres-sure151 increased an average of 47%, even thoughheart rate was held constant (Figure 3).

Effects of exercise during beta-adrenergic block-ade. After the study of the effects of spontaneousexercise, propranolol was administered to six pa-tients (Table II, experiments 7 to 12). Slightdecreases in resting heart rate (average = - 12%of control) and cardiac output (average = - 19%oof control) were observed, whereas little change intotal 02 consumption occurred in the two patientsin whom it was measured. No consistent changesin stroke volume or ventricular end-diastolic di-mensions were observed at rest (Figure 4, panelsA and C). Beta-adrenergic blockade did not ap-pear to affect the myocardial contractile stateunder resting conditions significantly; velocity15changed by an average of only - 7% while pres-

EFFECTS OF HEARTRATE AND EXERCISE ON THE FORCE-VELOCITY RELATION IN MAN

16 20 24 28 32 36 40 44R. V. PRESSURE SL - (m m.Hg)

J.S. 05- 10-36 3-3-64

FIG. 3. THE EFFECTS OF HEARTRATE AND EXERCISE ONTHE FORCE-VELOCITY RELATIONS OF THE VENTRICLE FROMTHE SAMEEXPERIMENTAS ILLUSTRATED IN FIGURE 2. Onthe ordinate is the velocity of shortening of the segmentof myocardium between the markers at isolength, and onthe abscissa is the corresponding right ventricular pres-sure. Each symbol represents a single ventricular con-traction. The crossbars represent 1 SD. ISL = iso-length.

sureis1 rose by an average of 3%o. This conclusionwas further substantiated by the finding that therate of ventricular pressure development (dp/dt)was little altered in the three experiments in whichit was measured (Table II, no. 8 to 10).

When exercise was repeated after beta-adrener-gic blockade, the augmentation of cardiac outputwas comparable to that observed before proprano-lol in two studies (no. 7 and 9). The increasewas substantially less in three studies (no. 10 to12), and in one study (no. 8) cardiac output failedto rise after beta blockade. Despite beta-adrener-gic blockade, heart rate rose with exercise, al-though the increments and absolute levels achievedwere lower than during the control bout of exer-cise. In contrast to exercise in the unblockedstate, ventricular end-diastolic dimensions nowfailed to decline. Little augmentation of the con-tractile state was observed during exercise afterbeta-adrenergic blockade; velocity of shorteningi81increased by an average of only 10%o, as comparedwith an average increase of 69%o in the same pa-

2057


7

R.V.LENGTH,Cm.

6

7

R.V.LENGTH,Cm.

6

FIG. 4. THE EFFECTS OF BETA-ADRENERGICBLOCKADEON THE RESPONSEOF THE HEART

TO EXERCISE. The distance between right ventricular markers during individual con-tractions are shown as a function of time for the study in patient A.H. A = controlstate, B = spontaneous exercise, C = rest after propranolol, and D = exercise after pro-

pranolol.

EFFECTS OF ,-BLOCKADE ON THE RESPONSEOF FORCE-VELOCITYRELATION TO EXERCISE

20 25 30 35

R.V. PRESSURE-ISL (mmHg)A.H. 05-46-17 10-13-64

FIG. 5. EFFECTS OF BETA-ADRENERGICBLOCKADEON THE

RESPONSEOF THE FORCE-VELOCITY RELATION TO EXERCISE

FOR THE STUDY ILLUSTRATED IN FIGURE 4.

tients during the initial control exercise period,whereas the changes in pressures were comparablein the blocked and unblocked states.

In four patients an attempt was made to studythe effects of exercise after beta blockade withoutaccompanying changes in heart rate. This was

entirely successful in experiment 12 (Figure 6),in which electrical stimulation was employed,whereas in experiments 7, 8, and 10, in whichatropine was given, the heart rate still increasedduring exercise, although to a smaller extent thanduring beta blockade alone. In these experimentsventricular end-diastolic dimensions again did notdecline during exercise, but actually tended to in-crease (Table II). More striking, however, was

the finding that the increase in velocityi81 was

blocked; this variable changed by an average ofonly + 3% in the four studies.

Discussion

Previous investigations on the circulatory ef-fects of exercise have placed primary emphasis on

the over-all response of the heart as a pump,

whereas the major objective of the present study

®. REST

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2058

(5) EXERCI SE


was to examine the effects of this stimulus on thecharacteristics of the heart viewed as a muscle.It is now widely appreciated that the circulatorychanges that occur during exercise in man are de-pendent upon the intensity of the stress as well ason the position of the body during the exercise.In this investigation the effects of relatively mildmuscular effort carried out in the supine positionwere studied. It has been shown previously thatunder these circumstances the increase in cardiacoutput is mediated primarily by an increase inheart rate with a relatively constant stroke volume(15, 16), whereas ventricular end-diastolic di-mensions decline (9, 17). The findings of thepresent study are in accord with these views.

In this investigation it was observed that thewell-known responses of the pumping action of theheart are accompanied by striking alterations inthe contractile state of the myocardium. This wasshown by a marked shift of the instantaneousforce-velocity relations of the myocardium. Aver-age velocity181 increased 80%, although this mildlevel of exercise induced only modest elevationsof cardiac output (average = 36%) and no sig-nificant increases in stroke volume. Thus, eventhough the performance of the ventricle as a pumpwas not altered strikingly, the shift of the force-velocity relation indicates that the exercise stateinduced an elevation of the velocity of fiber short-ening at any given intraventricular pressure anddimension.

It is appreciated that determination of the rateof shortening of a segment of the ventricle, as car-ried out in this and the previous study (5), pro-vides a measurement of the velocity of shorteningof the myocardial fibers but not of the contractileelements. From a consideration of studies car-ried out both on skeletal muscle (18, 19) and onthe isolated papillary muscle (2, 3), it is clearthat the contractile element velocity is identical tothe myocardial fiber velocity only when myo-cardial force is constant. Furthermore, the physi-cal characteristics of the series elastic componentin heart muscle have been defined (20), allowingcalculation of the differences between the veloci-ties of shortening of myocardial fibers and of thecontractile elements. Levine and Britman (8)have compared the shortening velocities through--out systole in the canine left ventricle and havedemonstrated that the major discrepancy betweenthem occurs during isometric contraction and dur-

EFFECT OF HEART RATE AND1-BLOCKADE ON THE FORCE-VELOCITYRELATION IN EXERCISE

T

2.3

2.1

1.9

1.7

1.5

1.31

1.1

.9

,7

10 5 20 25 30 35 40 45R.V. PRESSURE- ISL ( mmHq)

S.C. 05-21-60 10-6-64

FIG. 6. THE EFFECTS OF HEART RATE AND BETA-ADREN-ERGIC BLOCKADEON THE FORCE-VELOCITY RELATION DURINGTHE EXERCISE RESPONSE. The symbols denote the aver-age values for pressure and velocity; the crossbars rep-resent 1 SD.

ing the first 30 msec of ejection, a time when myo-

cardial force is changing rapidly. Thereafter,since force changes much less rapidly, the veloci-ties of shortening of the myocardial fibers andcontractile elements are quite similar although notidentical. Similar conclusions were reached byFry, Griggs, and Greenfield (21). In a more

recent study from this laboratory on the canineheart (22), specific comparisons were made be-tween the velocities of shortening of myocardialfibers and contractile elements at constant ven-

tricular volumes. A close correlation was foundduring the midportion of ejection at a variety ofafterloads; in 14 experiments carried out on seven

dogs the contractile element velocity exceeded thevelocity of fiber shortening by an average of 9.0 +

1.5% (SE). Furthermore, the close relation-ship between these variables was not altered dur-ing the profound inotropic stimulation provided byinfusion of norepinephrine (22). Thus, althoughtechniques for the direct measurement of con-

tractile element velocity in the intact human heartare not available, the theoretical considerationsand experimental findings presented above indi-cate that a useful and reasonably reliable estimateof this variable can be obtained by determining

o Control HR86* Eperfcse HR 1/.3

_ Control Poce HR /35 _: 4,-Stock-Poce HR 86A 6-Block-Pore HR /35 _* ,8-Block-Poce HR /35

+ Exercise

2059


myocardial fiber velocity. Since the measure-ments in the present study were made at a timeduring the midportion of ejection when the ratesof change in the length of the series elastic com-ponents of the muscle are minimal (8, 21), it islikely that the observed increase in the velocity offiber shortening during exercise reflects an aug-mentation of contractile element velocity, whichimplies that the rates of the chemical reactions re-sponsible for the generation of force and shorten-ing have also been increased (23).

In an attempt to elucidate the mechanism re-sponsible for the marked shift in the force-velocityrelation that occurred during exercise, considera-tion was given to the possible roles played by al-terations in heart rate and sympathetic activity,since previous studies had shown that tachycardiaas well as infusion of sympathomimetic aminesshifted the force-velocity relation in a similar man-ner (5). It was observed in this investigationthat tachycardia with the subject at rest shifted theforce-velocity relation to a relatively small extentin comparison to the shifts produced by exercise.However, since pressures tended to decrease withincrements in heart rate alone, some of the in-crements in fiber shortening rate that were ob-served might reflect the reduction in afterloadrather than a shift in the force-velocity relations ofthe myocardium. Furthermore, when exercisewas performed at a constant heart rate it was ob-served that the major shift of the force-velocityrelation occurred then (Figure 3). Thus, al-though the increase in heart rate observed duringspontaneous exercise helps to explain the relativeconstancy of stroke volume, it does not play an im-portant role in the increase of the contractile stateof the myocardium that occurs.

The possibility that the exercise-induced in-crease in the velocity of contraction resulted fromsympathetic stimulation of the myocardium hasbeen investigated with the aid of the beta-adrener-gic blocking drug propranolol. This agent hasbeen shown to block adrenergic receptors in themyocardium in doses that do not exert a directdepressant effect on the heart (24), and, in thedose used in the present investigation, to producea moderate reduction of cardiac output both dur-ing maximal and submaximal levels of exercise(25). It was observed in this investigation thatbeta blockade prevented the increase in the exer-

cise-induced shift in the force-velocity relation al-most completely. The small residual increases inthe contractile state that occurred after propranololcould be attributed to the elevation of heart ratethat still occurred, since when heart rate was alsocontrolled even these small shifts were abolished(Figure 6).

The finding that the administration of proprano-lol does not alter the contractile state of the myo-cardium at rest, apart from the changes resultingfrom the slowing of heart rate, lends support tothe view that there is relatively little basal sympa-thetic stimulation of the heart in supine, restingindividuals (26). On the other hand, the markedeffect of the drug on the force-velocity relationduring exercise indicates that the sympathetic sys-tem profoundly affects the contractile state of themyocardium at this time. Despite the loss of thenormal exercise-induced shift in the contractilestate after beta blockade, exercise could still beperformed with some rise in the cardiac output.Thus, it is clear that mechanisms are still availableto increase the performance of the ventricle as apump even when the improvement in the contrac-tile state of the myocardium is blocked.

In studies on the circulatory adaptations to ex-ercise there has long been an interest in the ef-fects of this stimulus on ventricular volume anddimensions. The finding that the end-diastolicsize of the heart usually does not increase and, infact, most commonly declines (9, 27-31), has beenused to support the view that the Frank-Starlingmechanism does not play a role in the cardiac re-sponse to exercise (32). It is clear from the pres-ent study that induced tachycardia in the absenceof exercise reduces ventricular dimensions to agreater extent than do similar changes in heartrate during exercise. In other words, at any givenheart rate ventricular end-diastolic dimensions,end-systolic dimensions, and stroke volume are alllarger during exercise than at rest. Thus, theFrank-Starling mechanism does in fact participatein the adaptation of the heart to exercise, even inthe presence of an actively functioning sympatheticnervous system. However, the increase in end-diastolic volume is not seen because of the oppos-ing effects produced by the tachycardia per se.In addition to tachycardia the increased sympa-thetic activity also contributes to the decrease inend-diastolic dimensions during exercise, since

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after propranolol exercise no longer reduced end-diastolic size (Figure 4). This latter conclusionis consonant with studies on denervated dogs (31,33) in which exercise resulted in increases in ven-tricular end-diastolic volume as well as strokevolume.

Previous studies have indicated that the sys-tolic ejection rate reflects the velocity of myo-cardial contraction (34, 35). However, from thepresent study it is apparent that these measure-ments do not necessarily reflect a change in therate of myocardial fiber shortening. In accordwith the findings of other investigators (11, 34),increments in heart rate alone have been foundto abbreviate the sytolic ejection time significantly(Table II). However, this abbreviation of thesystolic ejection time was accompanied by onlyminor changes in the velocity of myocardial fibershortening (Table II). Furthermore, when ex-ercise was performed in the absence of a change ofheart rate, only small or inconstant changes in thesystolic ejection time were found, although largeincrements in the velocity of myocardial fibershortening occurred (Table II). Similarly, themean systolic ejection rate, i.e., the stroke volumedivided by the duration of ejection, did not reflectthe velocity of myocardial fiber shortening in allinstances, since significant increments in this vari-able occurred in the presence of beta-adrenergicblockade that prevented the augmentation of thecontractile state of the ventricle resulting fromsympathetic stimulation.

In conclusion, the present investigation carriedout on intact, conscious subjects- has allowed ananalysis of the interplay that occurs between threefundamental adaptive mechanisms available to theheart during exercise: 1) augmentation of thecontractile state of the myocardium, 2) increase inheart rate, and 3) augmentation of the force ofcontraction ensuing from an increase of end-dias-tolic dimensions (Frank-Starling mechanism).During relatively mild exertion in the supine posi-tion a marked improvement of the contractile stateof the heart occurs, as evidenced by a shift in themyocardial force-velocity relation. This shift al-lows the ventricle to eject blood more rapidly atany given force. The augmentation of the con-tractile state is mediated primarily by an increasein sympathetic nervous activity, and only to aminor extent by the increase of heart rate per se.

On the other hand, the decrease in ventricular end-diastolic dimensions observed during spontaneousexercise may be explained primarily by the ac-companying tachycardia. Since exercise carriedout at a constant heart rate actually increasesstroke volume and end-diastolic dimensions, theFrank-Starling mechanism is operative but over-shadowed by the increase in heart rate.

Summary

The responses of the heart to mild exercise werestudied in 11 patients utilizing a cineradiographictechnique, which allows an evaluation of myo-cardial force-fiber shortening rate relations as wellas cardiac dimensions. The technique consistedof exposing cineradiograms at 30 frames per sec-ond and measuring the velocity of movement ofroentgenopaque markers that had been sutured tothe external surface of the ventricles while simul-taneously recording intraventricular pressure. Abeat-to-beat analysis of the force-velocity relationwas then accomplished by measuring the velocityand the pressure at a constant length point in eachcontraction. It was observed that exercise resultedin an augmentation of the contractile state of themyocardium as evidenced by an increase in thevelocity of contraction at any given force, and thatthis shift of the force-velocity relation could beblocked almost completely with the beta-adrener-gic receptor blocking agent propranolol. Thecontribution of heart rate changes to this shift inthe force-velocity relation was minor. Tachy-cardia induced without exercise reduced ventricu-lar end-diastolic dimensions to a greater extentthan exercise, thus providing evidence for theparticipation of the Frank-Starling mechanismduring exercise. It is concluded that the responseof the heart to exercise results from a synthesis ofthree fundamental adaptive mechanisms: 1) shiftof the myocardial force-velocity relation, 2) tachy-cardia, and 3) the Frank-Starling mechanism.

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