The Contractile Properties Human Heart Muscle: Studies On .
Journal of Clinical InvestigationVol. 44, No. 6, 1965The Contractile Properties of Human Heart Muscle: Studieson Myocardial Mechanics of Surgically ExcisedPapillary Muscles *EDMUND H. SONNENBLICK,t EUGENE BRAUNWALD,ANDREW G. MORROW(From the Cardiology Branch and the Clinic of Surgery, National Heart Institute,ANDBethesda, Md.)Previous studies of the performance characteristics of the heart have usually been directed toits function as a pump and, therefore, have beenconcerned principally with measurements of intravascular and intracardiac pressures, flows, andderivatives of these variables. Over the pastthree decades, extensive studies of skeletal musclehave provided an understanding of the mechanical behavior and energetics of this tissue (1-5).Recent studies of isolated segments of mammalianheart muscle (6-8) have permitted extension ofthis approach to the myocardium and have suggested the feasibility of analyzing the performance of the ventricle in terms of its properties asa muscle (9-12). Although efforts have beenmade to characterize normal and abnormal function of the human heart from this point of view(13-15), a necessary first step is a detailed description of the mechanical properties of humanheart muscle. Such a description-is presented inthis report, and a direct extension of these investigations to the intact human ventricle is thesubject of the companion paper (16).MethodsLeft ventricular papillary muscles were obtained at thetime of mitral valve replacement in 19 patients. The patients ranged in age from 21 to 64 years; 13 were malesand 6 were females. The major hemodynamic abnormality in 8 patients was mitral regurgitation, in 5 patients it was mitral stenosis, and in 6 patients combinedstenosis and regurgitation were present. Five patientshad associated aortic valve disease, and in 4 of the 19 patients the aortic valve was also replaced with a prosthesis* Submitted for publication December 28, 1964; accepted February 25, 1965.Presented in part before the American Society forClinical Investigation, May 4, 1964, Atlantic City, N. J.t Address requests for reprints to Dr. Edmund H.Sonnenblick, National Heart Institute, Bethesda, Md.20014.at the same operation. The valvular malformation resulted from rheumatic heart disease in 18 patients, andin the other mitral regurgitation was caused by rupturedchordae tendineae with an otherwise normal valve. All ofthe patients were in functional class III or class IV andwere receiving maintenance digoxin therapy at the timeof operation.The mitral valve was exposed during total cardiopulmonary bypass, and after the valve leaflets had been detached from the annulus, the papillary muscles were divided at their origins from the ventricular wall and thevalve and muscles removed en bloc. The patients' temperatures were usually 34 to 350 C, and bypass had beenin progress for 10 to 15 minutes when the papillarymuscles were transected. Immediately upon removal, thepapillary muscles were placed in Krebs solution intowhich a 95% 02 and 5% C02 gas mixture was bubbled.The thinnest discrete segment of papillary muscle wasthen selected and rapidly transferred to a myograph. Ifthe papillary muscles were unduly thick, they were splitlongitudinally to provide a thin segment and to facilitateoxygenation. The lengths of the muscle segments, at thepeak of the length-active tension curve, averaged 14.0 3.9 (SD) mm, whereas the cross-sectional areas averaged5.5 3.9 mm'.The myograph in which the muscles were studied haspreviously been described in detail (7). The papillarymuscle was held at its lower nontendinous end by a springloaded clip, forming the end of a rigid pin that penetratedthe bottom of the bath and was directly attached to aStatham (GI-4-250) force transducer. The upper tendinous end of the muscle was attached to an isotonic leverfor the measurement of muscle shortening, and the leveritself was mounted on a rigid Palmer stand. With thisarrangement, when the position of the lever was fixed,the force of isometric contraction at any desired musclelength could be measured. The lever could also be freedand, by appropriate loading, the extent and velocity ofshortening of the muscle at any preload (the small loadthat acts on the resting muscle and thereby establishesthe initial length) and afterload (the load encountered bythe contracting muscle when it attempts to shorten)could be measured. The muscles were stimulated supermaximally with square wave DC impulses of 5 msec duration,' delivered through large platinum plates placed966'American Electronics stimulator, model 104A.
MECHANICS OF HUMAN HEART MUSCLEparallel to the long axis of the muscle. Force, musclelength, the first derivatives of these variables, and thestimulus artifact were recorded on a multichannel oscillograph, and in some instances the transducer outputswere displayed on a dual-beam oscilloscope (Tektronixmodel 502) and photographed. The work performed bythe papillary muscle was calculated as the product ofafterload in grams and displacement in millimeters, andwas expressed in units of gram-millimeters; maximalpower was calculated as the product of the maximalshortening rate (dl/dt) and afterload, and it was expressed in units of gram-millimeters per second.Experiments were carried out at 300 C. In order tomaintain optimal performance of the muscles for prolonged periods of time, frequencies of contraction of 6 to12 per minute were employed, except when the effects ofchanges of frequency of contraction were specificallystudied. To assure steady-state performance, a period of1 hour was allowed between the time the muscle wasplaced in the myograph and the initial recordings. Eachstudy was terminated when mechanical performance began to deteriorate. Papillary muscles from three additional patients did not maintain a steady state at the onsetof the experiment and were discarded.Four major aspects of myocardial mechanics were analyzed: 1) the passive and active length-tension curves,2) the force-velocity relation of the contractile componentof the muscle, with considerations of external work andpower, 3) the load-extension ("stress-strain") relationof the series elastic component, and 4) the relationshipbetween the frequency of contraction and the performanceof the muscle, as reflected in force development, velocityof shortening, work, and power. The effects of thecardiac glycoside strophanthidin and of norepinephrineon the force-velocity relation of the muscles were alsodetermined.ResultsI. Length-tension relations. Isometric lengthtension curves were determined in the papillarymuscles from all 19 patients, and the results of atypical experiment are shown in Figure IA. Inorder to allow comparisons among different experiments, all length-tension curves were performed at 300 C at a frequency of 12 contractionsper minute. The actively developed tension wascalculated as the difference between the peaksystolic (total) tension and the resting tension,and that muscle length at which both the restingand active tensions approached zero was definedas L. (Figure 1A). As muscle length was increased, both active and resting tensions rose;the peak of the length-active tension curve wasreached when the muscle was stretched to anaverage length of 151 1 % of Lo, and the maxi-A LENGTH-TENSION RELATION76J.S. 05-13-7534Y M. MITRAL REGURG.FUNCT. CLASS MEB7Moximum xfitlmension of Lo156C-5zTo/of fension0f40"c:I.a1C02F0010 20 30 40%INCREASE IN LENGTH50Lo8MM1IMM12MM96720010RATE OF FORCE DEVELOPMENT (g/sec)FIG. 1. A. LENGTH-TENSION RELATIONS OF HUMAN PAPILLARY MUSCLE.Abscissa: Muscle length in millimeters and the per cent increase in musclelength above L4 (muscle length at which both the resting and active tensionsapproached zero). Frequency of contractions 12 per minute. Cross-sectional area of muscle 3.6 mm'. B. RELATIONSHIP BETWEEN ACTIVELY DEVELOPED TENSION AND THE MAXIMAL RATE OF ISOMETRIC FORCE DEVELOPMENT,
968E. H. SONNENBLICK, E.o0 3 EE@\BRAUN\VALD, AND A. G. MORROW0500-E1Oz(IUi-t4X001234LOAD (g)567FIG. 2. RELATION BETWNEEN INITIAL VELOCITY OF ISOTONIC SHORTENING AND AFTERLOAD. F1reqluency of conltractionls 12 per minute.Muscle cross-sectional area 3.2 mmt2. Preload 1.4 g with a musclelength of 15 mmn. The insert inl the upper right showes several oscillo scopic recordings from whlich the experimental psoinlts were calculated, and the afterload for each of these contractions is indicated.mal actively developed tension averaged 1.81 1.19 (SD) g per mm2. \Vith further increases innuiscle length, actively developed tension reacheda l)lateatu alnd then declined as resting tensionrose precil)itously. The time interval from theonset of contraction to the instant at which peaktension was achieved was independent of musclelength and, as a consequence, when muscle lengthwas increased the maximal rate of force development (dpl/dt) was found to be a linear functionof actively developed tension (Figure 1B). Nocorrelation between maximal developed tensionper ullit cross-sectional area and the actual crosssectionial area of the muscle could be perceived.I1. Forcc-vcloc'ity relahtouis. Force-velocity rekit0ions wVcre determine(l in the papillary musclesof sevenl patients. A typical curve is depicted inFigure 2, and in the insert some of the originaloscilloscopic tracings from which the curve wasderived are reproduce(d. The initial length ofthe muscle wXas set by a small preload, which wasmaintained constant for the entire curve. Theeffects on the velocity of shortening of progressively inicreasing afterload were then determined.The maximal velocity of shortening (Vma.x) couldnot be determined directly at zero load, since asmall preload was necessary to establish theinitial muscle lengths, and Vmax lwas, therefore,obtained by extrapolation. An inverse relationbetween the afterload and both the initial velocityand extent of shortening was observed in everymuscle. It weas also noted that the time from thestimnulus to maximal shortening was independentof the afterload.The effects of altering the initial muscle lengthoni the force-velocity curve were examined by determininiihg 32 curv-es in 4 muscles. As seen inFigure 3A, Vnimax appeared to remain constant,but P0 (isometric tension) increased as a functionof initial length. P,) is used in this context as
MECHANICS OF HUMAN HEART MUSCLEisometric force without implying tetanic force aswould be obtained in skeletal muscle. The effectsof altering the frequency of contraction on theforce-velocity curve were examined by determining 13 curves in three muscles (Figure 3B). Inindividual muscles, contraction frequencies werevaried between 6 and 60 per minute, but all threemuscles were examined at rates of 12 and 30per minute. When the frequency of contractionwas increased at a constant initial muscle length,P. remained essentially unchanged, while Vmaxincreased strikingly. For the three muscles examined, Vmax was 38%, 39%, and 23% greaterat 30 contractions per minute than at 12 contractions per minute.The effects of strophanthidin (0.5 ug per ml)on the force-velocity relation were studied in themuscles obtained from three patients, and a representative pair of curves is shown in Figure 4A.The glycoside augmented both P. (39%o, 20%,and 84%o, respectively) and V. (15%o, 140%,and 125%, respectively) in each muscle. Norepinephrine (0.2 pg per ml) also shifted theforce-velocity relation upwards and to the right(Figure 4B); norepinephrine augmented P. by24%o 6%o in the 14 muscles examined. In contrast to the effects of changing initial musclelength, the shift in the force-velocity relation resulting from either norepinephrine or strophanthidin was always accompanied by a decrease inthe time from stimulation to maximal force development. This time interval decreased from anaverage of 725 msec to 660 msec with strophanthidin, and from an average of 720 msec to 530msec with norepinephrine.Inspection of the force-velocity relation indicates that as V.ax and P0 are approached, externalwork and power approach zero, and these twoFORCE- VELOCITYA.7Increosing muscle /ength6Preload Length! (mm) (g)(\00.4 8.0EE 50 1.6 8.6z0w4\IC')969J.S.05-13-75 1-31-6434y d'M it. RegurgFunct class m0-3 LOAD (g)FIG. 3. A. EFFECTS OF INCREASING INITIAL MUSCLE LENGTH ON THE FORCE-VELOCITY RELATION. The maximal isometric force (PO) is augmented without a change in maximal velocityof shortening (Vmax). The time from stimulus to peak shortening was 440 msec for bothinitial lengths. Frequency of contractions 12 per minute. B. EFFECTS OF INCREASING FREQUENCY OF CONTRACTION FROM 6 PER MINUTE TO 50 PER MINUTE. Vm. is increased without achange in Po, while the time from stimulus to peak shortening decreased from 420 to 280 msec.The curves in A and B were derived from the same muscle, which had a cross-sectional areaof 3.6 mm'.
E. H. SONNENBLICK, E. BRAUNWALD, AND A. G. MORROW970FORCE-VELOCITY IN HUMAN PAPILLARY MUSCLEEEI-EzwzI-0UA.0x0-JwLOAD (g)FIG. 4. A. EFFECT OF THE ADDITION OF STROPHANTHIDIN ON THE FORCE-VELOCITY RELATION.Initial muscle length 10.0 mm with a preload of 0.8 g. Muscle cross-sectional area 3.6 mm'.The addition of strophanthidin increased both Vmax and PO while decreasing the time fromstimulation to maximal shortening from 390 to 340 msec. B. EFFECT OF THE ADDITION OF NOREPINEPHRINE ON THE FORCE-VELOCITY RELATION.Initial muscle length 15.0 mm with a pre-load of 1.4 g. Muscle cross-sectional area 3.2 mm'. Norepinephrine augmented both Vmaxand PO while decreasing the time from stimulation to peak shortening from 730 to 540 msec.variables reach a maximal value at some intermediate load. In the seven muscles in whichforce-velocity curves were obtained, it was observed that the peak values of work were achievedwith afterloads that ranged from 45% to 55%o ofisometric force (P.), while the peak values ofmaximal power were achieved with afterloadsranging from 50% to 60%o of the isometric force(P.). Increasing initial length of the muscle elevated the afterload-work and afterload-powercurves and raised the afterload at which the peakvalues of work and power were achieved (Figure5,A and B). At a constant initial muscle lengththe addition of norepinephrine also elevated andshifted the load-work and load-power curves tothe right (Figure 5,C and D). Increasing thefrequency of contraction did not significantly affect the load-work curve in the three musclesexamined (Figure 5E). However, in all instances a significant elevation of the load-powercurves resulted from increasing frequency (Figure 5F), peak power rising by 40%o, 28%, and22%, respectively, in the three muscles as fre-quency of contraction was elevated from 12 to30 per minute.III. Load-extension curve of the series elasticcomponent. The series elastic component of thepapillary muscles was characterized in musclesfrom 5 patients by an analysis of afterloaded isotonic contractions relative to time after stimulation. In Figure 6A a typical force-velocity curveis shown, whereas in Figure 6B the velocities ofshortening (dl/dt) and the force for the samecontractions are plotted as functions of the timeafter stimulation. As described in detail elsewhere (17), at the time the muscle stops developing force and begins to shorten, the serieselastic component is being stretched at a velocity(dl/dt) equal to but opposite in direction to thatof the contractile element. Therefore, the curverelating dl/dt to time after stimulation (Figure6B) applies to both the contractile element andthe series elastic component. By integrating dl/dtas a function of time, the extension of theseries elastic (SE) component with increasingforce (load) was determined (AL of SE fptO
971MECHANICS OF HUMAN HEART MUSCLEla0P1FIG. 5. RELATIONS OF WORK AND POWER WITH INCREASING AFTERLOAD, ASINITIAL MUSCLE LENGTH WAS CHANGED (A AND B), NOREPINEPHRINE WASADDED (C AND D), AND THE FREQUENCY OF CONTRACTION INCREASED (E ANDF).dl/dt- dt). The load-extension curve of the series elastic component was not altered by changingelastic component obtained in this manner is re- frequency of contraction nor by the addition ofproduced in Figure 6C, and shows that with norepinephrine or strophanthidin.IV. Force frequency relations. The effects ofprogressive extension of the series elastic the forcedeveloped increased exponentially. In the five changing frequency of contraction were studied inmuscles in which this analysis was carried out, papillary muscles obtained from 16 patients. Ait was observed that during an isometric con- representative study on a muscle relating fretraction the series elastic was stretched by 8.4%o quency to extent of shortening, time to maximal 0.5%o of the initial length of the muscle at shortening, and velocity of shortening is shownwhich the force-velocity curve was obtained. in Figure 7A, whereas a representative study onFurther, the load-extension curve of the series an isometrically contracting muscle relating fre-
972E. H. SONNENBLICK, E. BRAUNWALD, AND A. G. MORROWB.FORCE AND VELOCITY ASA. FORCE -VELOCITY RELATION:FUNCTIONS OF TIMEC.LOAD-EXTENSION CURVE OF3.0,.EO5;-; 2.04-!:crno 1.0I---J -000400800TIME AFTER STIMULATION-msec642LOAD(g)FIG. 6. PROPERTIES0j.O0.81.2 1.6EXTENSION OF SE-mm04OF THE SERIES ELASTIC COMPONENT OF A HUMAN HEART MUSCLE WITH13.5 MM AT A PRELOAD OF 1.0 G. Muscle cross-sectional area AN INITIAL MUSCLE LENGTH OF3.5 mm'. A. Velocity of isotonic shortening in millimeters per second as a function of increasingafterload. B. Velocity of shortening and force of contraction as functions of the time afterstimulation of the muscle. C. The load-extension relation of the series elastic component.quency to isometric force, time to peak force,and rate of development of force is shown inFigure 7B. At a frequency of 6 contractions per minute, the time from the onset ofcontraction to peak tension averaged 876 150msec, while the rate of force development averaged 20.8 g per second. At a frequency of 50A.3.5 [contractions per minute, the time to peak tensiondecreased in every muscle to an average of 455 89 msec, whereas the maximal rate of forcedevelopment increased in every muscle to an average value of 35.0 g per second. Similarly, inevery muscle the time to peak shortening decreased from an average of 410 48 msec toB.Shortenng-Frequency-C)- p4E02 ;,,2.5[4100oIAfm: 0-u0I-z0E)ITSom,u Z-1J , C10203021601050FREQUENCY OF CONTRACTION /min.40FIG. 7. A. VELOCITY OF SHORTENING, THE EXTENT OF SHORTENING (AL), AND THE TIMEFROM STIMULATION TO PEAK SHORTENING ARE SHOWN AS FUNCTIONS OF FREQUENCY OF CONTRACTION. Preload 0.4 g; afterload 2.0 g. Muscle length 15.0 mm; cross-sectional area 3.5 mm'. B. RELATION OF ISOMETRICALLY DEVELOPED FORCE, THE TIME FROM STIMULATION TOPEAK FORCE DEVELOPMENT, AND THE RATE OF FORCE DEVELOPMENT AS FUNCTIONS OF FREQUENCYOF CONTRACTION. Muscle length 9.0 mm; cross-sectional area 7.5 mm'.
MECHANICS OF HUMAN HEART MUSCLE280 32 msec, while the velocity of shorteningincreased in every muscle, from an average of4.63 0.57 to 6.58 0.42 mm per second. Onthe other hand, alterations in frequency of contraction produced little change either in isometricforce or in the extent of shortening of the isotonically contracting muscle. At 6 contractionsper minute, force averaged 12.4 g and at 50 contractions per minute 10.4 g. In the isotonicallycontracting muscle the extent of shortening atthese rates averaged 1.85 0.27 and 1.79 0.22mm.DiscussionThe left ventricular papillary muscles, whichmay be obtained from patients in the course ofcorrective cardiac operations, provide a uniqueopportunity for analyzing in vitro the contractileproperties of human heart muscle. Since thepreparation described in this report has not beenemployed previously, it is important to comment upon certain limitations inherent in its use.Perhaps the most important of these is thethickness of the human papillary muscle, whichmay not allow for adequate o
ance of the ventricle in terms of its properties as a muscle (9-12). Although efforts have been made to characterize normal and abnormal func-tion of the human heart from this point of view (13-15), a necessary first step is a detailed de-scription of the mechanical properties of human heart muscle. Such a description-is presented in
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