52 J AM CaLL CARDIOL 1983;1:52-62
Cardiac Function and Myocardial Contractility: A Perspective
JOHN ROSS, Jr., MD, FACC
La Jolla, California
Improved understanding of cardiac muscle and whole studying chronic cardiac adaptations. The clinical im• heart function has substantially benefited clinical diag• portance of systolicloading conditions and venous return nosis and therapy. Knowledge of the influence of systolic is illustrated within these frameworks by a description loading conditions has been of key importance in these of responses to a vasopressor stress test to produce an advances, and the role of peripheral circulatory re• apparent descending limb of left ventricular function, sponses is beginning to be appreciated. Dissociations be• the concept of steady state afterload mismatch in chronic tween myocardial contractility and cardiac function are and acute heart failure and the responses to vasodilator described, including acute heart failure due to afterload therapy in the normal and failing heart. The importance mismatch associated with normal myocardial contrac• of changes in venous return in determining the cardiac tility, and normal ventricular function associated with output response to a vasodilator, in addition to the effects depressed contractility in chronic mitral regurgitation. of reduced afterload on the ventricles, is emphasized. Frameworks for assessing cardiac and myocardial func• Finally, the problem of assessingleft ventricular function tion are examined. Standard invasive and noninvasive in patients with chronic mitral regurgitation is examined approaches can now be usefully supplemented by end• and, for the patient with severe mitral regurgitation and systolic pressure-volume and end-systolic wall stress-vol• few symptoms, tentative guidelines for recommending ume frameworks, the former being particularly useful operation to avoid irreversible left ventricular dysfunc• for analyzing the concept of "afterload mismatch with tion postoperatively are presented. limited preload reserve" and the latter being useful for
Increased knowledge concerning the function of cardiac instances, favorable loading conditions or compensatory muscle and the whole heart has greatly enhanced our ability events can mask the presence of depressed myocardial con• to detect and quantify clinical disorders of myocardial con• tractility. In addition, impaired cardiac filling can produce traction. Perhaps most important has been improved un• changes in overall cardiac performance without impaired derstanding of the effects of normal and abnormal loading myocardial contraction. Thus, cardiac pump function and conditions, in particular the critical role of systolic loading myocardial contractility can be dissociated (I). Severe re• or afterload. The effects of preload and instantaneous myo• gional disorders may also exist in association with normal cardial fiber length and various abnormalities of cardiac overall cardiac function, but these are beyond the scope of filling also have become better appreciated. The result has this discussion. been both improved diagnostic ability and more logical ther• apy, based on knowledge of myocardial contractility and associated loading conditions. Such improvements are ev• Dissociations Between Myocardial and ident, for example, in the use of different types of vaso• Pump Function dilators or positive inotropic agents in heart failure, and the more accurate selection of patients with valvular heart dis• Heart Failure Without Myocardial Depression ease for operative treatment. Mechanicaloverload. The level of inotropic state (con• Under certain circumstances altered cardiac loading con• tractility) of the myocardium obviously affects the behavior ditions can produce failure of the heart as a pump. even of the heart, but cardiac performance (as distinguished from though myocardial contractility is not depressed. In other myocardial contractility) is also influenced by the interplay between preload and afterload. For example, sudden aortic From the Division of Cardiology. Department of Medicine. University or mitral regurgitation can rapidly lead to left ventricular of California. San Diego. School of Medicine. La Jolla. California. pump failure without significant myocardial depression; this Address for reprints: John Ross, Jr., MD. Division of Cardiology, Department of Medicine. M-013, University of California. San Diego, situation can be described within a framework of "afterload School of Medicine, La Jolla. California 92093. mismatch with limited preload reserve" (2). Thus when the
© 1983 by the American College of Cardiology 0735-1097/83/010052-11$03.00 CARDIAC FUNCTION AND MYOCARDIAL CONTRACTILITY J AM COLL CARDIOL 53 1983;1:52-62
heart is pushed to the limit of its preload reserve, even in the presence of normal systolic contractile function of normal myocardium responds to a further increase in after• the myocardium (15). Several other conditions (mitral ste• load by reduced wall shortening and stroke volume (3,4). nosis, for example) can also produce signs of overall heart Under these conditions, as discussed in more detail later, failure despite normal left ventricular function. the situation resembles that in the normal heart when the preload is held constant and the afterload is varied (3). The Myocardial Depression Without Heart Failure stroke volume becomes inversely related to the afterload Favorable loading conditions masking depressed and systolic wall stress increases, leading to decreased per• myocardial contractility. The reverse of "afterload mis• formance and vice versa. Increased loading can then lead match" can occur when the preload is adequate but the to an apparent .. descending limb" of ventricular function afterload (or wall stress) on the myocardial fibers is abnor• due to excessive afterload rather than to sarcomere over• mally low. In chronic mitral regurgitation, the low imped• stretch (2,4). ance leak into the left atrium may permit a normal ejection Conditions of severe mechanical overload can, of course, fraction to be maintained until late in the clinical course be altered by acute changes in the inotropic state due to when irreversible depression of myocardial function has administration of positive inotropic agents. Also, in heart occurred (16). Favorable loading conditions, therefore, can failure due to acute afterload mismatch (as in acute valve mask depressed myocardial contractility that, under normal regurgitation), reduction of the overload by vasodilator ther• loading conditions, would produce a low ejection fraction. apy or replacement of a defective valve with a prosthesis Beneficial systolic loading conditions can also be produced will promptly reverse the pump failure because myocardial by treatment of the failing heart with a vasodilator (17, 18). contractility is basically intact (2). However, it may be However, recent experimental studies indicate that in acute postulated that subendocardial ischemia due to high diastolic heart failure improvement in cardiac output by a vasodilator intracardiac pressures can also contribute to heart failure such as nitroprusside, which has mixed arteriolar and ven• (5). odilator properties, results both from decreased afterload In chronic mechanical overload, such as that due to val• and from increased venous return (19,20), as will be dis• vular heart disease or to a large left to right shunt, slow cussed further. adaptations occur primarily through the development of con• Compensatory mechanisms to maintain normal pump centric or eccentric hypertrophy to prevent overall cardiac function. Normal cardiac pump function can often be main• failure (6,7). During such chronic overload, heart failure tained by compensatory mechanisms in mild forms of myo• generally does not occur until the myocardial inotropic state cardial depression. A slight increase in heart size with a becomes depressed (8). mild encroachment on the preload reserve that is also ac• Impaired cardiac filling. In chronic constrictive peri• companied by some reflex increase in heart rate and sym• carditis and acute cardiac tamponade, decreased forward pathetic stimulation of the myocardium can produce normal cardiac output and elevation of cardiac filling pressures are cardiac output and filling pressures despite modest intrinsic usually associated with normal myocardial function (9). There myocardial dysfunction. Under these conditions, it may be is also experimental evidence that in acute volume overload, possible to demonstrate limitations of the preload reserve such as that caused by overtransfusion, elevated cardiac by stressing the heart, perhaps by increasing blood pressure filling pressures and impaired filling of the heart are partly with a vasoconstrictor agent (2,21). Even patients with se• a result of limited pericardial expansion, and are accom• verely impaired myocardial function and low ejection frac• panied by elevation of the intrapericardial pressure with an tion can exhibit surprisingly good exercise capability (22), apparent depression of the ventricular function curve (10• partly because the dilated heart has the ability to produce a 12). Such a response can cause the entire diastolic pres• substantial stroke volume (23). sure-volume relation of the left ventricle to shift upward (11,12) as a result of increased intrapericardial pressure; this shift can be corrected by bleeding or the use of a vasodilator such as nitroprusside (II). Such responses may playa role Useful Frameworks for Assessing in acute downward shifts of the entire left ventricular dia• stolic pressure-volume relation that are observed in the clin• Heart Function ical setting during vasodilator administration in patients with Evaluating basal contractility. In assessing myocardial high cardiac filling pressures (13,14). They might also con• function in human beings, sometimes the goal is to detect tribute to the high filling pressures associated with acute an acute change in contractility. This can usually be ac• heart failure, although such an effect has not yet been complished using a variety of invasive or noninvasive tech• documented. niques (24-26), such as those that induce directional changes Restrictive disease of the ventricular chambers can lead in ventricular end-diastolic pressure and stroke volume, stroke to elevations in diastolic ventricular and atrial pressures even work or peak rate of rise of left ventricular pressure (dP/ 54 J AM CaLL CARDIOL ROSS 1983;I:52-62
dt) . Care must be taken in applying measures that are in• not occur (26 ,27 ,3 I) . Nevertheless, indexes derived from fluenced by changes in afterload, such as the ejection frac• the isovoIumetic phase of left ventricular pressure tracings tion and mean velocity of circumferential fiber shortening may not be adequate for detecting depressed basal levels of (27). Often. a more difficult problem is to determine whether contractility in the individual subject (28,32) . They are val• myocardial contractility is impaired at rest in hearts of dif• uable for separating groups of patients with clearly normal ferent sizes . or it may be desired to compare the same heart or depressed left ventricular function (28.32-34), but they at different times under changing loading conditions (as in appear to be less reliable than ejection phase indexes in serial studies after cardiac valve replacement) (25,28). To individual patients. compare individual hearts under these circumstances. it is Ejection phase indexes. Although these indexes have necessary to "normalize." or to correct for a given initial the advantage of being readily measured by noninvasive ventricular size. Systolic function is then expressed. for approaches, all of them are sensitive to acute changes in example. as shortening per unit length (percent shortening) afterload (27). The ejection phase indexes are most often of a diameter of the ventricle (fractional shortening). used to assess basal contractility (normalized for heart size), Ideally. systolic loading on the ventricles (afterload) should and those most commonly employed include ejection frac• also be known and expressed in normalized terms, and it tion, fractional shortening of the ventricular end-diastolic might be inferred that when myocardial contractility in the diameter. mean velocity of internal diameter shortening cor• basal state is to be assessed. measures of contraction that rected for end-diastolic diameter (mean VCF) and normalized are independent of acute alterations in preload and afterload mean systolic ejection rate (28,35) . must be employed. However, this conclusion is not nec• The ejection fraction is the most widely used ejection essarily relevant to the problem ofcomparing the basal level phase index and, when measured in the resting state by left of inotropic state in one person with that in another, or ventriculography or noninvasive echocardiographic or comparing the level in the same person before and after a radionuclide techniques, it has proved invaluable in many chronic adaptation has occurred (25). Thus , over long pe• patients for detecting depressed basal myocardial contrac• riods oftime the wall stress (afterload) may remain relatively tility. However, this index has limitations for measuring unchanged because of the development of ventricular hy• depressed function when the afterload is acutely elevated pertrophy. as is the case with chronic pressure overloading or when the ejection fraction is low as in mitral regurgita• associated with aortic valve disease (29) . Also. it was shown tion . Because of the known sensitivity of ejection phase that in experimental animals subjected to chronic volume measures to acute changes in afterload, early studies of basal overloading, the preload (as reflected by midwall sarcomere contractility in human subjects also measured wall stress lengths) does not change as chronic ventricular dilation slowly (36) . High fidelity catheters and cineangiography were used occurs. but remains the same as during acute volume over• to define the relation between the extent and velocity of load (30). Therefore, to evaluate basal contractility it may shortening of the circumferential fibers and the correspond• not be necessary to use indexes of contractility that are ing wall stress throughout systole (36). Whereas determin• unaffected by acute changes in preload and afterload (25). nation of the relation between mean wall stress during ejec• Indeed, when the preload reserve has been fully utilized. tion and mean VCF (force-velocity relation) or fractional depressed contractility at rest might be expected to cause shortening can provide a reliable means of assessing basal an "afterload mismatch," which would then be expressed contractility, determinations of mean VCF alone have also as inability of the ventricle to maintain normal performance been shown to correlate well with these more complex mea• per unit of circumference or volume, even if the aortic sures (35). The mean VCF, the ejection fraction and the pressure or afterload (wall stress) is normal (2). normalized mean systolic ejection rate all effectively sep• Isovolumic phase indexes. When the maximal rate of arate normal patients from patients with left ventricular myo• change of left ventricular pressure (peak dP/dt. usually mea• cardial disease and clearly abnormal ventricular function sured with a catheter tip micromanometer) is reduced below (28,32). a level of approximately 1,400 mm Hg/s, myocardial con• End-systolic indexes. The linear relation between the tractility is usually depressed, but this measure is relatively end-systolic volume and the end- systolic pressure of the left nonspecific and is affected by other factors such as the time ventricle has been studied extensively in isolated heart prep• ofaortic valve opening and loading conditions (27) . Because arations. and this relation has been advocated as a useful of this problem. simplified methods that use the brief iso• measure of contractility (37,38) . It has also been extended volumetric phase of ejecting beats have been employed to to the study of intact animals by infusing a range of doses determine load-independent indexes of maximal calculated of a vasoconstrictor drug that does not itself have an ap• contractile element velocity. Such " jsovolumic phase in• preciable inotropic effect, such as phenylephrine, to produce dexe s" may be quite useful for detecting acute changes in a range of end-systolic pressures and volumes (39). In hu• contractility when the afterload is changing. provided that man subjects, the end-systolic ventricular volume can be large alterations in left ventricular end-diastolic pressure do determined by performing two or more angiocardiograms CARDIAC FUNCTION AND MYOCARDIAL CO NTRACTILITY J AM COLL CARDIOL 55 1983:1:52- 62
before and during infusion of the vasoconstrictor. the end• and afterload when contractility is depressed (Fig. IB, beat systolic values being related to the corresponding ventricular 7). pressures at the end of ejection. This approach is also being A basisfo r applying the pressure-volume loop to describe used with noninvasive techniques to measure ventricular ventricularfunction was the finding in isolated cardiac mus• dimensions or volume (echocardiography and radionuclide cle (42) and the whole heart (43) that, when inotropic state methods). The linear relation has been reported to shift did not change, the points relating active tension to muscle downward and to the right in the presence of chronic myo• length or ventricular volume at end-ejection (42-44), or the cardi al disease in human subjects (40) , and to shift upward points relating pressure to ventricular volume (38), formed and to the left (with steepening of its slope) during acute a linear relation over wide range s of preload and afterload, positive inotropic interventions in experimental animals (37) independent of the initial volume (preload) and the afterload. and in patients (41) . Also, this relation still existed when instantaneous loading This linear relation between ventricular end-systolic vol• was altered during left ventricular ejection (Fig. 2). ume and end-systolic pressure is of parti cular importance. In clinical studies. the slope ofthe end-systolic pressure• becau se it provides a method for detecting changes in the volume relation also proved to be linear (40.41) and non• level of inotropic state under acutely changing conditions invasive echocardiographic or radionuclide methods can also independent of the end-diastolic volume (preload), while be used to determine this relation. In one study, peak arterial the aortic pressure (as a measure ofafterload) is incorporated pressure was measured by the cuff method and left ven• into the analysis. Thus. a given heartbeat will arrive at end• tricular dimensions were determined echocardiographically ejecti on and fall on this linear relation which provides the over a range of pressures produced by infusion of phenyl• limit of ejected volume, regardless of the starting point for ephrine or nitroprusside (45). As in experimental studies end-diastolic volume and of the level of aortic pressure that it encounters during ejection. The slope of the entire end• systolic pressure-volume relation shifts acutely when there Figure I. Pressure- volume loops of single contractions of the left ventri• cle . In these counterclockwise loops. the arrow showing a leftward ex• is an alteration of inotropic state (37). Figure IA diagrams cursion on the volume axis indicates ventricular ejection (stroke volume pressure-volume loops of the cardiac cycle as they are al• [SV j is bracketed) . and the arrow moving toward the right indicates tered by chan ges in preload alone (beats I, 2 and 3) and upward movement on the curvilinear diastolic pressure-volume relation duri ng cardiac tilling. Isovolumetric contraction and relaxation are rep• afterload alone (beats 2, 4 and 5) in the normal heart . In• resented by the vertical arms of the loop. Panel A, The responses to creasing the preload while systolic pressure remains constant increased preload (beats 1. 2 and 3) at a constant afterload are shown by increases the stroke volume (beats I to 3). whereas increas• solid lines , and the responses to increased afterload at a fixed preload (beats 4 and 5) are shown by dashed lines . Panel B, The end-systolic ing systolic pressure but keeping preload constant reduces pressure-volume relation is shifted upward or downward by increases and the stroke volume (beat s 4 and 5), and vice versa . The decreases in myocardial contractility. respectively. and three beats are relation shifts to the left with increased slope during posit ive shown origi nating from the same preload (end-diastolic [ED] pressure and volume. arrow) and developing the same systolic pressure during ejection . inotropic interventions, and a negative intervention shifts it The stroke volume is augmented from the control level by increased con• downward (Fig. IB). A larger stroke volume is subsequently tractility (beat 6) and depressed by decreased contractility (beat Tt, (Re• delivered from the same end-diastolic volume at the same printed with permission from Ross J Jr. Pathophysiology of the human heart: function of the heart under abnormal loading conditions. In: Kray• systolic pressure when contractility is increased (Fig. lB. enbuehl HP. Kuebler W. eds . Kardiologie in Klinik und Praxis. vol I. beat 6) , and stroke volume decreases at the same preload Stuttgart: Georg Thieme Verlag. 1981:31.9-3 1.28.)
A B
w w a:: a:: :::l -----.... :::l (I) 15 : (I) (I) --~ - ..I (I) w w a:: I 4 I ~ a:: a.. II I a.. ,II : : SV 1 2 3 ~~--.. I I I ED
VENTRICULAR VOLUME VENTRICULAR VOLUME 56 J AM COLL CARDIOL ROSS 1983;1:52-62
600,-....,.---.,..------,...--,----,---...------, means of studying myocardial contractility in human sub• jects. The end-systolic wall stress-diameter relation at end• DOG 95 ejection, and not the end-systolic pressure-diameter relation, )( Isovolumic 500 • Freely Ejecting has been found useful for defining basal contractility in • Heavily Afterloaded x experimental animals (47) and in patients (45) with hyper• trophy resulting from pressure overload. Therefore, it seems 400 that for assessing basal contractility in certain chronic dis• eases, use of wall stress rather than pressure alone may be
N E necessary. Because the relations between end-systolic pres• o ~ 300 sure or wall stress and end-systolic dimension or volume z are independent of the acute effects of preload or afterload, o they are finding increasing clinical application for invasive Vl z and noninvasive studies on myocardial function and con• ~ 200 tractility, both at rest and during acute stress.
100 Clinical Importance of Loading Conditions and Venous Return oL--_---'-__ ~_.!.-~--:.----'-__ __'___~__ ....J After/oad Mismatch in Acute and Chronic 20 30 40 50 60 70 80 LV VOLUME ml Heart Failure
Figure 2. Left ventricular wall tension plotted against left ventricular (LV) The effects of afterload on the failing heart considered in volume in milliliters from an intact sedated dog. Peak tension developed terms of afterload mismatch (2), as mentioned previously, by induced isovolumetric contractions over a range of preloads is indicated may occur whenever the preload reserve is fully utilized (or by the crosses, and a linear relation of end-systolic volume and active tension is apparent. A series of ejecting contractions is plotted from the unavailable, as might take place in severe concentric hy• beginning of contraction until shortly after the end of ejection, (points at pertrophy, or with inadequate venous return). Such mis• end-ejection indicated by arrows). Even in the three upper contractions match can occur when the afterload is too high for either a when abrupt increases in loading are produced during ejection by partial inflation of a balloon in the ascending aorta, the ventricle reaches the same normal or a depressed level of contractility (Fig. 3), and its linear relation at end-ejection, regardless of the preload and afterload. effects can be demonstrated in the following three (Reprinted from Taylor RR, Covell JW, Ross J Jr [43], with permission.) circumstances: 1. Experimental pressure or volume loading. Under (39), the end-systolic pressure-dimension relation was dis• the experimental conditions of a fixed (held constant) pre• placed with alterations in inotropic state but, unlike the end• load and a varied afterload (3), the response of the ventricle systolic pressure-volume relation, its slope was not altered can be diagrammed within the left ventricular pressure-vol• (45). ume loop and end-systolic pressure-volume framework. The Wall stress. When there is a chronicchange in the shape stroke volume progressively decreases as the afterload is and size of the ventricle, or the thickness of its wall, the incremented, and vice versa (Fig. IA). Likewise, a normal systolic pressure is not indicative of the level of afterload. ventricle forced to the limit of its preload reserve by acute Under these conditions, the wall force must be calculated pressure and volume loading will respond to further incre• in order to define a relation between end-systolic volume ments in volume or pressure by increasing the systolic wall and wall stress (46,47). Also, the linear end-systolic pres• stress and decreasing the stroke volume to produce an ap• sure-volume relation may not provide an adequate descriptor parent descending limb of function that is related to the of inotropic state when the transmural pressure of the ven• afterload effect (4). As discussed earlier, this setting can be tricle is altered (as in pericardial disease). As mentioned compared with that occurring in severe acute overload of previously, the relation between ventricular end-systolic wall sudden aortic or mitral regurgitation, or sudden extreme stress* and end-systolic volume is also linear (Fig. 2) (40). hypertension. Because wall stress can be calculated by the echocardi• 2. Myocardial failure. It can be postulated that in myo• ographic method (45), this approach provides a practical cardial failure, afterload mismatch exists in the steady state when the level of systolic wall stress is too high for the *By utilizing a simplified Laplace relation. wall stress is a function of depressed level of myocardial contractility (even when sys• the diameter of the chamber, the systolic pressure and the thickness of the ventricular wall. Other measures of afterload. such as the peripheral vas• tolic pressure is normal) (2) and leads to a reduced extent cular resistance (impedance at zero frequency) and the aortic input imped• and velocity of fiber shortening in the basal state (Fig. 3). ance (a measure that is affected by the stiffness of the aortic wall and other Plots of systolic wall stress-volume in the ventricle with factors), contribute to the afterload. Our studies indicate that the wall stress is influenced by the impedance and suggest that the wall stress is the most severely depressed myocardial function are diagrammed in useful measure to define the afterload (19). Figure 4. Under these conditions, because the sarcomere CARDIAC FUNCTIONAND MYOCARDIAL CONTRACTILITY J AM COLL CARDIOL 57 1983:1:52-62
NORMAL LIMIT OF MISMATCH at the onset of ejection (Fig, 5, left panel) (36). In contrast, PRELOAD RESERVE the severely failing ventricle can exhibit a clockwise loop during left ventricular ejection, so that the wall stress at the end of ejection actually exceeds that at the onset, indicating impaired ability of the left ventricle to "unload itself" dur• ing ejection (Fig, 5, right panel), Thus, increases of stroke volume in the failing heart during vasodilator administration with little change in systolic pressure or end-diastolic vol• ume may be explained by altered instantaneous aortic impedance and afterload (19), so that the wall stress is lowered primarily early and late during ejection, thereby allowing a larger stroke volume (Fig, 4, beat 3),
After/oad Reduction and Venous Return END DIASTOLE END DIASTOLE END SYSTOLE Cardiac reserve mechanisms. Under normal condi• Figure 3. Diagrammatic representation of afterload "mismatch." From tions, cardiac output is limited by the rate of venous return a normal end-diastolic volume (left panel), the preload is markedly in• creased either acutely or chronically so that the limit of preload (sarcomere length) reserve is reached (middle panel). Under these conditions, in the absence of preload reserve and if myocardial contractility is normal or Figure 4. Diagram of left ventricular (LV) wall stress-volume loops and abnormal, an increase in afterload will cause decreased muscle shortening end-systolic wall stress-volume relations. The normal end-systolic pressure• during systole (arrows, right panel). Moreover, when myocardial con• wall stress relation is shown by the dashed line, and in severe heart failure tractility is depressed, afterload mismatch may exist at rest even with a this relation is shifted downward and to the right. In beat I, the left ventricle normal level of systolic pressure or wall stress. The afterload is represented is shown operating on a steep portion of the passive pressure-volume curve here for simplicity as an arrow opposing the level of myocardial contrac• and at the limit of its preload reserve (sarcomeres maximally elongated). tility, but it is recognized that the afterload is best represented as the force With acute pressure loading (as with angiotensin infusion), there is a rise on the myocardial fibers. in end-diastolic pressure but little change in end-diastolic volume; the ventricle behaves as if the preload were fixed, and the stroke volume (SV2) decreases (beat 2). In beat 2 there is a further increase in end-systolic wall stress compared with wall stress at the onset of ejection. Beat 3 shows the reserve is utilized, when an acute pressor stress is applied, response to vasodilator treatment of the failing ventricle, and illustrates a substantial increase in the stroke volume (SV3) compared with that of beat the left ventricle should behave as if the preload were fixed, I (SVI). The impedance reduction in beat 3 is produced primarily by a Any further increase in the afterload under these conditions fall of the instantaneous afterload early and late during ejection, with only causes a decrease in stroke volume (Fig. 4, beat 2), as dem• a small reduction in end-diastolic volume. In these circumstances there is only a minor change in peak left ventricular wall stress in beat 3 compared onstrated in clinical studies on the response of the failing with beat I, and peak systolic pressure may remain unchanged. (Reprinted ventricle to the infusion of angiotensin (21). Again, this from Ross J Jr [23], with permission.) response may represent an apparent descending limb of function (decrease in stroke volume with an increase in ~~/ ~~/ ventricular end-diastolic pressure) produced by pressure ~/ loading, due primarily to afterload mismatch. Although end• / / diastolic pressure increases (21), it seems unlikely that marked / / changes in end-diastolic volume occur because the ventricle / is operating at the limit of preload reserve on the steep / en / portion of its diastolic pressure-volume curve (Fig. 4). en / U.l 3. Vasodilator therapy. Vasodilator therapy can cor• a:: / I• / rect afterload mismatch due to heart failure. There is ample en / evidence that such short-term treatment of the failing heart ....J / ....J / improves the stroke volume, and if a mixed venous and ~ / arteriolar dilator is employed there is usually an accompany• / > / ing decrease in the cardiac filling pressure (17). Because ....J there is little change in the systolic arterial pressure or left ventricular size during vasodilator therapy in chronic heart failure, it is proposed that the mechanics of systolic un• loading are altered in the manner shown in Figure 4, beat 3. We have demonstrated that the normal human heart ex• hibits a counterclockwise loop between shortening velocity and wall stress, wall stress at end-ejection being lower than LV VOLUME 58 J AM COLL CARDIOL ROSS 1983;1:52-62
2.5 the venous return curve are increased by a decrease in ve• nous resistance (and to a lesser degree by a decrease in arteriolar resistance), with opposite effects when resistance 2.0 is increased. It is also established that in the steady state, the crossover point between the cardiac output curve, as defined by Guyton et al. (48), and the venous return curve u identifies a given set of steady state conditions. UJ en 1.5 ...... When nitroprusside was administered intravenously in U Q: the relatively normal circulation, a fall in the cardiac output U ensued, despite lowered systemic vascular resistance (and I "- (.) 1.0 therefore more favorable loading conditions on the normal > left ventricle). This response occurred because nitroprusside induced concomitant dilation of the venous bed that was .5 only partially compensated by a small shift of blood volume from the central to the peripheral circulation (mean ± stan• dard error of the mean 2.4 ± 0.4 milkg) (20). Therefore, o...,1-----"--_-.1....- the venous return curve was displaced downward because 300 400 500 of a decrease in the effective systemic blood volume (Fig. 2 LV WALL TENSION - Gm./cm. 6, left panel). The consequent reduction of venous return EDC-em. 14.5 22.4 to the right heart chambers caused a reduction in right ven• ACIRC.-cm. 5.1 1.6 tricular output and, hence, in left ventricular output by way Figure 5. Relations between left ventricular (LV) wall tension and the of the Frank-Starling mechanism, despite a reduction of the instantaneous velocity of shortening of the left ventricular circumference afterload on the left ventricle (Fig. 6, left panel) (20). (VCF), corrected for end-diastolic circumference (EDC), in a normal ven• In acute experimental left ventricular failure produced tricle (left panel), and in a patient with severe myocardial dysfunction (right panel). Note the counterclockwise loop in the normal subject (ar• by multiple coronary ligations, in which the left ventricular rows) and the counterclockwise loop in the patient with heart failure in end-diastolic pressure was elevated to more than 20 mm whom tension at the end of ejection exceeds that at the onset. indicating Hg, an opposite effect occurred, and the cardiac output inability of the failing ventricle to unload effectively. ,6. eire = change in circumference. (Modified from Gault et al. [36]. by permission of the increased during the infusion of nitroprusside. Again, ni• American Heart Association, Inc.). troprusside produced venodilation in the peripheral circu• lation; however, in acute heart failure there was a large shift of blood volume from the distended central circulation to the peripheral circulation (mean 7.4 ± 1.3 ml/kg), presum• (48), so that the heart serves as a "demand pump," with ably because the failing left ventricle was able to unload a pumping capability far exceeding the level of cardiac more effectively and thereby release blood stored within the output required under normal circumstances (except, per• heart and lungs. Under these circumstances, nitroprusside haps, during the most extreme exercise). There are three did not cause the venous return curve to shift downward significant cardiac reserve mechanisms: I) the heart rate (a (Fig. 6, right panel), indicating that the shift in blood volume reserve of about 130 beats/min, up to a maximum of about from the central circulation counterbalanced the effect of 200 beats/ min is available), 2) the stroke volume (a reserve nitroprusside to reduce the effective systemic blood volume. is available from the Frank-Starling mechanism, if needed), The marked upward shift of the cardiac output curve due and 3) the end-systolic volume (positive inotropic stimu• to correction of afterload mismatch on the failing ventricle* lation or decreased afterload can increase the degree of was then expressed as an increase in the cardiac output systolic emptying to further augment the stroke volume). because the left ventricle, not the venous return, was the Venous return and cardiac output responses. limiting factor (Fig. 6, right panel) (20). Recent experiments in dogs with a normal heart and in dogs These studies emphasize that the effects of vasodilator with induced acute heart failure emphasize the importance drugs on the peripheral circulation, as well as on the heart, of venous return in the cardiac output response to vasodi• are highly important in determining overall cardiac and lators. These studies indicate that vasodilator therapy with circulatory responses. Venous return has not been studied nitroprusside is effective in increasing cardiac output only directly in chronic circulatory congestion in patients with if peripheral factors permit an increase in venous return (20). heart failure, or during chronic vasodilator administration. It is well recognized that the venous return curve, as defined However, drugs such as hydralazine hydrochloride (which by Guyton et al. (48), is shifted in a parallel upward or downward manner by increases or decreases in blood vol• *In the framework of Guyton et al. (48). such shifts in the cardiac ume, respectively, and that both the slope and plateau of output curve do not always indicate a change in inotropic state. CARDIAC FUNCTION AND MYOCARDI AL CONTRACTILITY J AM COLL CARDIOL 59 1983:1:52-62
NORMAL A B HEART FAILURE RV OUTPUT LV OUTPUT c: <:: 'E 'E <, <, RV OUTPUT E E z :2 a: a: :::l :::l ~ 3000 I:"( / ~ UJ UJ a: a: (I) -1~ " ' '' '' '' '' '' ';,~''------lV OUTPUT (I) :::l --- - :::l o , \~ A I ______o Z :2 UJ ~.A: UJ :> 2000 " "::...../ ..... :> a: a: o o ~ \ \ ~ :::l Q.. \ :::l ~ \ Q.. :::l ~ 1000 \ :::l o " -- CORONARY OCCLUSION (A) o «Co) \ --- NITROPRUSSIDE (8) U C \ s a: \ o « \ a: Co) \ ~ \ u -4 o 4 8 12 16 2420
RIGHT OR LEFT ATRIAL PRESSURE RIGHT OR LEFT ATRIAL PRESSURE (mmHg)
appear to have little direct dilat ing effect on the venous bed) Figure 6. Panel A, Relation betwee n cardiac output and venous return in might greatl y improve cardiac output by lowering the in• the normal heart (open chest. anesthetized dog) . The inverse relation be• twee n right atrial pressure and venous return is shown under control con• stantaneous afterload on the failing ventricle during ejection ditions (solid lines ) and during nitroprusside infusion (dashed lines ). Seg• and by facilitating an increase in venous return to some ments of cardiac output curves relating both right ventricular (RV) outp ut degree through decreased arteriolar resistance. to right atrial pressure and left ventricular (LV) output to left atrial pressure are also shown in these two circumstances. Under control conditions. the cardiac output is limited by the venous return and the equilibrium point (point A). where the venous return and cardiac output curves intersect, is The Problem ofMitral Regurgitation on the plateau of the venous return curve . In the steady state. the right ventricular and left ventricular outputs are in equi librium (dashed horl• Any of the valvular lesions that severely overload the left zontal line and point Ad . During infusion of nitroprusside. venodilation ventricle (aortic stenosis, aortic regurgitation and mitral re• produces a decrease in mean systemic pressure and a down ward shift of the venous return curve . This causes the right ventricle to reach a new gurgitation) will produce severe left ventricular hypertro• equilibrium point at a lower cardiac output (point B). This point. in turn. phy , which can eventually cause irreversible left ventricular is in equilibrium with a lower left ventricular output at a lower mean left myocardial dysfunction (8). In patient s with severe mitral atrial pressure (point Bj ). Thus. despite upward shifts of the right and left ventricular function curves due to lowered impedance to ejection. with regurgitation, surgery is usually recommended when symp• reduced afterload the cardiac output falls with the infusion of nitropru sside. toms become significant. However, preoperative detection Panel B, In acute heart failure. Under control conditions (solid lines ). the of such dysfunction is difficult in patients with severe mitral intersect between right ventricular output and venous return (point A) is on the ascending portion of the venous return curve. Cardiac output is regurgitation and few symptoms. and such dysfunction may limited by the failing left ventricle that operates on a flat and depressed persist after surgical correction of the valve defect. The cardiac output curve (point Ad. After infusion of nitroprusside (dashed cardiac response to chronic volume overload within the lines ). there is no shift of the venous return curve, a downward shift being prevented by a redistribut ion of the central blood volume to the periphery framework of the pressure-VOlume loop and end-systolic (see text). There is a marked upward shift of the function curve of the left pressure-volume relation are diagrammed in Figure 7A . The ventricle as a result of reduced afterloa d with correction of afterload mis• passive pressure-volume relation is shifted to the right by match . and a marked decrease in the left ventricular filling pressure then occurs . The upward shift of the left and right ventricular output curves is eccentric left ventricular hypertrophy, and as long as myo• now acco mpanied by an increase in the cardiac output (point B). and at cardial function is unimpaired the ventricle can deliver a equil ibrium the left ventricle (point Btl operates at a lower filling pressure much larger total stroke volum e with normal shortening of with an improved cardiac output. (Modified from Pouleur et al. [20]. by permission of the American Heart Association, lnc.) each unit of the enlarged circumfe rence (6). Role of measuring the ejection fraction. Even in the relatively asymptomatic patient with severe mitral regur• eccentric hypertrophy coupled with low mean wall stress gitation, the possib ility of developing irreversible myo• caused by the low impedance leak early and late in systole cardial dysfunction is an important problem. As mentioned allows maintenance of a high normal ejection fraction pro• previously, mitral regurgitation places relatively favorable vided that myocardial contractilit y remains normal (Fig. systolic loading conditions on the left ventricle, and the 7A). An ejection fraction near the normal range can be 60 J AM COLL CARDIOL ROSS 1983:1:52-62
MITRAL REGURGITATION
A.
(/.) (/.) (/.) (/.) LoU LoU a: a: to• to• (/.) (/.) ....J ....J ....J ....J VOLUME VOLUME Figure 7. Diagrammatic representation of left ventricular function during suggests that the ejection fraction was maintained at an mitral regurgitation. Panel A, Responses of the ventricle to volume over• artificially high value preoperatively, despite depression of load diagrammed by pressure-volume loops. The normal ventricle responds to a large acute volume load by increasing the end-diastolic volume. and myocardial contractility (Fig. 7B). The afterload mismatch the stroke volume is increased (beats I and 1). The development of eccentric that occurs after correction of the low impedance leak re• hypertrophy results in a marked increase in ventricular volume and a slight veals the previously masked myocardial depression; left increase in ventricular wall thickness to shift the curvilinear diastolic pres• sure-volume relation well to the right. The ventricle can then deliver a ventricular ejection must occur entirely into the relatively much larger stroke volume (beat 3) than during acute dilatation. and the high impedance of the aorta, and the ejection fraction falls ejection fraction (EF) can be maintained at a high normal level (650/<). (Fig. 7B). Additional studies are needed to confirm these Panel B, The development of depressed myocardial function shifts the linear end-systolic volume-wall stress relation downward and to the right. preliminary clinical findings. In this setting, before mitral valve replacement, the ventricle can still Optimal timing of mitral valve replacement. If initial maintain a relatively low average wall stress during ejection because of or serial studies in the follow-up of the relatively asympto• the severe regurgitant leak. and therefore. the ejection fraction (EFl is only mildly reduced (beat 1). After mitral valve replacement. despite some matic patient with severe mitral regurgitation and cardiom• reduction of end-diastolic volume. the ventricle is subjected to the higher egaly reveal a left ventricular end-diastolic diameter ap• impedance of the aorta. causing the wall stress throughout ejection to proaching 8.0 ern, an end-systolic diameter greater than 5.0 increase substantially and the ejection fraction to fall (beat 1). (Reprinted from Ross J Jr [8]. with permission.) em, a fractional shortening of less than 30% or a calculated ejection fraction that drops below 55%. cardiac catheter• ization should usually be undertaken to determine the degree of mitral regurgitation and the status of left ventricular func• maintained even when contractility becomes depressed tion (8). If the echocardiographic findings are confirmed. (Fig. 7B), although mean VCF is sometimes reduced operative intervention to protect myocardial function should (49). Ifsignificant cardiomegaly is seen on the chest roent• be considered. The limited usefulness ofthe ejection fraction genogram or is found on physical examination in such in quantifying the depression of myocardial function in pa• patients with few symptoms. a baseline M-mode echo• tients with mitral regurgitation has led to a search for other cardiographic study confirmed by a two-dimensional echo• measures; it has been reported that when the ratio of end• cardiogram. or by a radio nuclide ejection fraction. may systolic wall stress to left ventricular end-systolic volume establish the presence of a low normal or reduced ejection index is below 2.0. patients do not survive or do not show fraction. or a relatively low fractional shortening. improvement postoperatively (52). Because further severe Effect of mitral valve replacement on ventricular deterioration of ventricular function can occur after mitral Studies before and after mitral valve replacement function. valve replacement in patients with greatly depressed myo• indicate that, in contrast to aortic regurgitation (50). left cardial contractility. it is probably not advisable to rec• ventricular function tends to be reduced after operation even ommend operation if the ejection fraction is greatly reduced. if it was within the normal range preoperatively (51). When cardiomegaly is moderate. a progressive reduction in ven• tricular size and mass occurs after valve replacement (51). However, if the preoperative left ventricular size is greatly References increased. even if the ejection fraction is low normal or only I. Ross J Jr. Assessment of cardiac function and myocardial contractility. slightly reduced. ventricular function deteriorates further In: Hurst JW. ed. The Heart. New York: McGraw-HilI. 1981:310• 33. and ventricular hypertrophy and dilation fail to regress after 1. Ross J Jr. Afterload mismatch and preload reserve: a conceptual frame• surgery (51). The marked reduction in the ejection fraction work for the analysis of ventricular function. Prog Cardiovasc Dis after valve replacement in patients with the latter condition 1976:18:155-64. CARDIAC FUNCTION AND MYOCARDI AL CONTRACTILITY J AMcou, CARDlOl 61 1983:J :5 2~6 2 3. Ross J Jr. Covell JW. Sonnenblick EH. Braunwald E. Contractile RM. Sperelakis N. Geiger SR. eds. Handbook of Physiology. Bal• state of the heart characterized by force-velocity relations in variably timore: Waverly. 1979;533- 80. afterloaded and isovo lumic beats. Circ Res 1 9 66 :1 8 :1 4 9 ~ 6 3 . 27. Mahler F. Ross J Jr. O'Rourke RA, Covell JW. Effects of changes 4. MacGregor DC. Covell lW. Mahler F. Dilly RB. Ross llr. Relations in preload. afterload. and inotropic state on ejection and isovoiumic between afterload, stroke volume, and descending limb of Starling's phase measures of contractility in the conscious dog. Am J Cardiel curve. Am J Physiol 1974:227:884-90. 1975:35:626-34. 5. Hoffman HIE. Buckberg GO. The myocardial supply-demand ratio• 28. Peterson KL. Sklovan D. Ludbrook P. Uther lB . Ross J lr. Com• a critical review. Am J Cardiol 1978:41:327- 32. parison of isovolumic and ejection phase indices of myocardial per• 6. Ross J Jr. Adaptation of the left ventricle to chronic volume overload. formance in man. Circulation 1974:49:1088-10I. Circ Res 1974:35:64-70. 29. Dodge HT. Baxley \VA. Left ventricular volume and mass and their 7. Sasyama S. Ross J Jr. Franklin D, Bloor CM. Bishop S. Dilley RB. significance in heart disease. Am J Cardiol 1969:23:528- 37. Adaptations of the left ventricle to chronic pressure overload. Circ 30. Ross J Jr. Sonnenblick EH. Taylor RR. Coveli l W. Diastolic geometry Res 1976:38: 1 72~ 8 . and sarcomere lengths in the chronically dilated canine left ventricle. 8. Ross J Jr. l eft ventricular function and the timing of surgical treatment Circ Res 1971:28:49- 61. in valvular heart disease. Ann Intern Med 1981:94:498- 504. 31. Grossman W. Haynes F. Paraskos JA. Saltz S. Dalen lE . Dexter L. 9. Shabetai R, Mangiardi L, Bhargava V, Ross J Jr. Higgins CB. The Alterations in preload and myocardial mechanics in the dog and in pericardium and cardiac function. Prog Cardiovasc Dis 1979:22: 107• man. Circ Res 1972:31:83- 94. 34. 32. Kreulen T, Bove AA, Mclronough MT. Sands MJ. Spann JF. The 10. Misbach GA, Glantz SA. Changes in the diastolic pressure-diameter evaluation of left ventricular function in man: a comparison of meth• relation alter ventricular function curves. Am J Physiol 1979:6:H644• ods. Circulation 1975;51 :677- 700. 8. 33. Nejad NS. Klein MD. Mirsky E. Lown B. Assessment of myocardial I I. Shirato K. Shabetai R. Bhargava V, Franklin D. Ross 1 Jr. Alteration contractility from ventricular pressure recordings. Cardiovasc Res of the left ventricular diastolic pressure-segment length relation produced 1971;5:15- 23. by the pericardium: effects of cardiac distension and afterload reduc• 34. Krayenbuehl HP. Rutishauser W. Wirz P. Amende I. Mehmel H. tion in conscious dogs. Circulation 1978:57:1191- 8. High-fidelity left ventricular pressure measurements for the assessmerit 12. Glantz SA. Parmley WW. Factors which affect the diastolic pressure• of cardiac contractility in man. Am J Cardiol 1973:31:415- 27. volume curve. Circ Res 1978:42:171- 80. 35. Karliner JS. Gault JH. Eckberg DL. Mullins CB. Ross J lr. Mean 13. Alderman EL. Glantz SA. Acuie hemodynamic interventions shift the velocity of fiber shortening: a simplified measure of left ventricular diastolic pressure-volume curve in man. Circulation 1976:54:662- 71. myocardial contractility. Circulation 1971;44:323-33. 14. Brodie BR. Gross W. Mann T. McLaurin LP. Effects of sodium 36. Gault JH. Ross J lr. Braunwald E. Contractile state of the left ventricle nitroprusside on left ventricular diastolic pressure-volume relations. 1 in man: instantaneous tension-velocity-length relations in patients with Clin Invest 1977:59:59-68. and without disease of the left ventricular myocardium. Circ Res 1968:22:451-63. 15. Meaney E. Shabetai R. Bhargava V. et al. Cardiac amyloidosis. con• strictive pericarditis and restrictive cardiomyopathy. Am J Cardiel 37. Suga H. Sagawa K. Shoukas AA. Load independence of the instan• 1976;38:547- 56. ianeous pressure-VOlume ratio of the canine left veniricle and effects of epinephrine and heart rate on the ratio, Circ Res 1973;32:314- 22. 16. Schuler G. Peterson K. Johnson A. et al. Temporal response of left ventricular performance to mitral valve surgery. Circulation 1979: 38. Sagawa K. The end-systolic pressure-volume relation of the ventricle: 59:121 8-31. definition. modifications and clinical use. Circulation 1981 :63:1223• 7. 17. Chatterjee K, Parmley WW. The role of vasodilator therapy in heart failure. Prog Cardiovasc Dis 1977:19:301-25. 39. Mahler F. Covell JW. Ross J Jr. Systolic pressure-diameter relations in the normal conscious dog. Cardiovasc Res 1975:9:447-55. 18. Franciosa JA, Cohn IN. Hemodynamic responsiveness to short and long acting vasodilators in left ventricular failure. Am J Med 40. Grossman W, Brai.mwald E. Mann T. McLaurin LP, Green LH. Con• 1978:65:126-33. tractile state of the left ventricle in man as evaluated from end-systolic pressure-volume relations. Circulation 1977:56:845-52 . 19. Pouleur H. Covell JW. Ross J Jr. Effects of alterations in aortic input impedance on the force-velocity-length relationship in the intact canine 41. Mehmel He. Stockins B. Ruffmann K. von Olshausen K. Schuler G. heart. Circ Res 1979:45:126- 36. Kubler W. The linearity of the end-systolic pressure-volume relation• ship in man and its sensitivity for assessment for left ventricular func• 20. Pouleur H. Covell JW. Ross J Jr. Effects of nitroprusside on venous tion. Circulation 1981:63:1216-22. return and central blood volume in the absence and presence of acute heart failure. Circulation 1980;61:328-37. 42. Sonnenblick EH. implications of muscle mechanics in heart. Fed Proc 1962:21:975- 90. 21. Ross J Jr. Braunwald E. The study of left ventricular function in man by increasing resistance to ventricular ejection with angiotensin. Cir• 43. Taylor RR. Covell JW. Ross J Jr. Volume-tension diagrams of ejecting culation 1964:29:739- 49. and isovolumic contractions in left ventricle. Am 1 Physiol 1969; 216:1097-1 02. 22. Franciosa JA. Park M. Levine BT. Lack of correlation between ex• ercise capacity and indexes of resting left ventricular performance in 44. Bums JW. CovelllW. Ross J Jr. Mechanics of Isotonic left ventricular heart failure. Am J Cardiol 1981:47:33-9. contractions. Am 1 Physiol 1973;224:725- 32. 23. Ross J Jr. Mechanisms of cardiac contraction: what roles for preload. 45. Takahashi M, Sasayama S. Kawai C. Kotoura H. Contractile perfor• afterload and inotropic state in heart failure'? Eur Heart J (in press). mance of the hypertrophied ventricle in patients with systemic hy• pertension. Circulation 1980;62: 11 6- 26. 24. Ross J Jr. The assessment of myocardial performance in man by hemodynamic and cineangiographic techniques. Am 1 Cardiol 46. Sasyama S. Ross 1 Jr. Franklin D, Bloor CM. Bishop S. Dilley RB. 1969:23:511-5. Adaptations of the left ventricle to chronic pressure overload. Circ Res 1976;38:172-8. 25. Ross J Jr. Peterson KL. On the assessment of cardiac inotropic state: an editorial. Circulation 1973;47:435-48. 47. Sasayama S. Franklin D. Ross 1 Jr. Hyperfunction with normal ino• tropic state of the hypertrophied left ventricle. Am 1 Physiol 1977: 26. Braunwald E. Ross 1 Jr. Control of cardiac performance. In: Berne 232:H418-25. 62 J AM COLL CARDIOL ROSS 1983:I:51-62 48. Guyton AS. Jones CEoColeman TG . Circulatory Physiology: Cardiac 51. Schuler G. Peterson K. Johnson A. et al. Temporal response of left Output and Its Regulation. 2nd ed. Philadelphia: WB Saunders. 1973. ventricular performance to mitral valve surgery. Circulation 1979: 49. Eckberg DL. Gault JH. Bouchard RL. Karliner JS. Ross J Jr. Me• 59:1218- 31. chanics of left ventricular contraction in chronic severe mitral regur• 52. Carabe llo BA. Nolan SP. Lockhart BM. Assessment of preoperative gitation . Circulation 1973;47:125 1-9. left ventricular function in patients with mitral regurgitatio n: value of 50. Schuler G. Peterson KL, Johnson AD. et al. Serial noninvasive as• the end-systolic wall stress-end-systolic volume ratio. Circulation sessment of left ventricul ar hypertrophy and function after surgical 1981;64:1212-7. correction of aortic regurgitation. Am J Cardiol 1979:44:585- 94.