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PERSPECTIVE The uses and limitations of end-systolic indexes of left ventricular function BLASE A. CARABELLO, M.D., AND JAMES F. SPANN, M.D. Downloaded from http://circ.ahajournals.org/ by guest on April 30, 2017 THE EXTENT of left ventricular dysfunction produced by heart disease is a major determinant of clinical prognosis. Consequently, it is important to assess left ventricular function accurately. Ejection phase indexes, particularly ejection fraction, are the most widely used clinical measures of left ventricular function. Ejection fraction is determined easily both by invasive and noninvasive techniques and, because it has no dimensions, it is not necessary to correct it for body size. Unlike isovolumetric indexes such as maximum velocity, ejection fraction does not require extrapolation. These characteristics have made the ejection fraction useful in making clinical decisions regarding left ventricular function. However, ejection fraction is affected by changes in loading conditions independent of changes in muscle function and therefore may not assess the latter accurately in patients with that alter load. For example, in mitral regurgitation, preload is increased due to the regurgitant lesion and afterload may be decreased as the left ventricle empties into the relatively low-pressure left atrium. These factors maintain a normal ejection fraction even when significant left ventricular dysfunction is present. Preoperative ejection fraction may fail to predict the poor or even fatal clinical result of mitral valve replacement in such patients. In patients with aortic stenosis, excessive afterload often reduces ejection fraction when muscle function is relatively normal. Despite a severe reduction in ejection fraction, these patients may still benefit from aortic valve replacement. Thus, reliance on ejection fraction can cause clinical misjudgment regarding the timing and risk of cardiac surgery. New methods to evaluate left ventricular function that are independent of, or account for, loading conditions are currently being evaluated and are reviewed below. These methods, described by From the Section of Cardiology, Department of Medicine, Temple University Hospital, Philadelphia. Address for correspondence: Blase A. Carabello. M.D., Section of Cardiology, Temple University Hospital, Philadelphia, PA 19140. Received Sept. 29, 1983; revision accepted Jan. 4, 1984. 1058 Sagawa in a well-referenced review article and editorial' and by others, rely upon known physiologic principles of the left ventricle at end-systole. Briefly, as shown in figure 1, the volume remaining in the ventricle at end-systole is not dependent on the initial ventricular volume. In practical terms, this means that end-systolic volume is independent of preload. It has therefore been suggested that end-systolic volume index or dimension might be a better indicator of contractile function than ejection fraction in states in which preload is greatly altered. End-systolic dimension and end-systolic volume index Preload is increased in mitral and aortic regurgitation. A large end-systolic volume in patients with these diseases might indicate left ventricular dysfunction that has made the ventricle unable to empty properly despite a normal ejection fraction. Henry et al.2 determined left ventricular end-systolic dimension echocardiographically in the evaluation of patients with aortic insufficiency. In asymptomatic patients, an end-systolic dimension of greater than 55 mm predicted the onset of symptoms within an average of 30 months if the aortic valve was not replaced. In symptomatic patients, an end-systolic dimension of greater than 55 mm predicted persistent symptoms and left ventricular dysfunction even after aortic valve replacement. In mitral and aortic regurgitation, Borow et al.3 found that preoperative end-systolic volume, when indexed for body surface area, was a better predictor of clinical outcome and postoperative shortening fraction than preoperative ejection fraction in patients with these diseases. Limitations. Both afterload and contractile function, as opposed to contractile function alone, determine the end-systolic volume or dimension. Thus, patients with high end-systolic afterloads (recently reported in some patients with aortic insufficiency) may have large endsystolic volumes along with relatively good muscle function. This may explain recent observations that some patients with aortic insufficiency have a good CIRCULATION PERSPECTIVE E E LU 501 z U# > 0-iT VENTRICULAR VOLUME mI FIGURE 1. Pressure-volume loops are shown for an isolated canine ventricle. End-systolic volume is constant despite a wide range of enddiastolic volumes as long as contractile state and afterload remain constant. (Reprinted with permission from Suga et al., Circ Res 32: 314, 1973.) Downloaded from http://circ.ahajournals.org/ by guest on April 30, 2017 prognosis despite increased end-systolic dimension. It may therefore be necessary to "correct" end-systolic volume for end-systolic afterload to properly gauge contractile function. This concept has led to the investigation of methods that take afterload into account. The slope of the end-systolic afterload-end-systolic volume (or dimension) relationships While independent of preload, the completeness of ventricular emptying is dependent on contractile function and the afterload resisting further ventricular emptying at the end of systole. End-systolic afterload is the counterforce that halts shortening when the afterload equals the force generated by the muscle. At a given contractile state, when afterload increases, the ventricle empties less completely and end-systolic volume is greater. As shown in figure 2, the relationship between end-systolic force (or afterload) and end-systolic length (or volume) is linear. ' Afterload is quantified by force on the Y axis and length is shown on the X axis. Different cycles recorded at different end-systolic afterloads are shown. The slope of the line relating endsystolic force and length, or pressure and volume, which can be determined by solving the equation Y = mX + B for m, is a measure of contractile function. Increases in inotropic state result in a steepening of this slope. Thus, at an increased inotropic state the ventricle can shorten to a smaller end-systolic volume or length at the same or even higher end-systolic afterload (pressure). Simply put, stronger ventricles shorten more against higher loads than weaker ventricles. It has been shown that the end-systolic pressure-volume or pressure-dimension relationship reflects known changes in intropic state. ' The slope of the end-systolic pressure-volume or pressure-dimension relationship has been useful in evaluating contractile function clinically. For example, Grossman et al.4 demonstrated the pressure-volume relationship to be reflective of a clinically apparent decrease in contractile function in patients with cardiomyopathy. In clinical use, the end-systolic volume or end-sys- 2.2 0 FIGURE 2. Force-length loops for a left ventricle are shown at different end-systolic afterloads. As afterload is decreased, emptying is more complete, and end-systolic length is less. The relationship between end-systolic afterload (force or pressure) and end-systolic length is demonstrated to be linear. (Reprinted with permission from Weber and Janicki. Am J Cardiol 40: 740, 1977.) W~~~~~~~~~~~ w0 LL 0.0 15.0 16.3 17.5 LENGTH cm Vol. 69, No. 5, May 1984 1059 CARABELLO and SPANN Downloaded from http://circ.ahajournals.org/ by guest on April 30, 2017 tolic dimension is determined by contrast or nuclear angiography or echocardiography and end-systolic pressure by catheter or cuff at different loading conditions. Pressure is usually altered by infusion of a noninotropic vasoconstrictor or vasodilator. The endsystolic pressure-volume or pressure-dimension relationship is obtained at each level of afterload. The X, Y coordinates obtained in this manner are used to plot the pressure-volume line from which the slope is derived. Since intraventricular pressure varies only modestly from patient to patient, and intraventricular volume varies significantly with body size, some investigators have indexed end-systolic volume for body size. In comparing the contractile state of a normal 50 kg woman with that of a normal 100 kg man, if a 10% change in end-systolic pressure effects a 10% change in end-systolic volume in both patients, the change in pressure will be similar in both patients but the change in volume in the man will be greater than in the woman. The slope will be lower in the man even though contractile state is not different. Indexing for body size tends to cancel out this difference. Potential limitations. One potential limitation of the use of the pressure-volume relationship stems from the fact that pressure may not be an accurate measure of end-systolic afterload. Afterload is the force that opposes ejection. In physical terms, force pressure x area and accounts for the distribution of pressure over the surface to which the force is applied. When the force is applied to a thick-chambered sphere, it is more accurately described by the LaPlace relation stress = P.r/2h, where P = pressure; r = radius; h = thickness. Since wall thickness and chamber radius are quite different in different diseases, and even vary from patient to patient with the same disease, use of wall stress, which corrects for the variability in wall thickness and chamber radius, offers some advantages. For example, in our catheterization laboratory we achieved a marked reduction in the end-systolic volume in a patient with aortic insufficiency by the infusion of the vasodilator nitroprusside, but end-systolic pressure did not change. Thus, the calculated slope of the pressurevolume relationship was 0, a theoretic improbability. This occurred because a reduction in afterload allowed greater left ventricular emptying and greater cardiac output at the same blood pressure. Although pressure did not change, radius decreased, producing a decrease in calculated wall stress. In such instances, end-systolic stress, which takes into account changes in left ventricular size as well as pressure, is more useful in demonstrating reduced afterload. Thus, the end-systolic stress-end-systolic volume relationship may be a = 1060 better reflection of the slope of the afterload-volume relationship than is the end-systolic pressure-end systolic volume relationship. The stress-volume relationship has also been used successfully in the assessment of left ventricular contractile function. In our laboratory, for example, noninvasive evaluation of the stressvolume relationship in patients with sickle cell anemia revealed contractile depression not evidenced by shortening fraction.5 In a recent study of patients with aortic stenosis, a reduced slope of the stress-volume relationship identified patients with reduced contractile function. The reduced slope correlated well with clinical evidence of heart failure.6 Limitations. Changes in the X intercept of the stressvolume (or stress-dimension) line may occur with changes in inotropic state instead of a change in slope.4 This produces a parallel shift in the stress-volume line. The explanation for this parallel shift is not known. A parallel shift is likely to occur when inotropic state and loading conditions are changed in a small ventricle; in a small ventricle, a given change in pressure causes less change in stress than the same change in pressure in a large ventricle. Since slope = change in Y (pressure or stress)/change in X (volume), slope will change relatively less in a small ventricle when stress is used instead of pressure. Thus, the slope of the stress-volume relationship may fail to increase when inotropic state is increased and a parallel shift may occur. For enlarged ventricles the use of stress-volume relationships may have an advantage over that of pressure-volume relationships because a change in load on the ventricle is more likely to be due to change in size of the ventricle rather than change in pressure. Such a change in load is better quantified by stress. However, in smaller ventricles, the use of stress-volume relationships may have a disadvantage over pressure-volume relationships. This occurs as a result of changes in stress, which are blunted in comparison with changes in pressure because the small radius present reduces calculated stress. In this situation, afterload is better quantified as pressure. It also must be pointed out that stress is calculated value and its determination is subject to some error. However, calculated stress has been validated experimentally and remains a reasonable estimate of afterload. Finally, an additional limitation might be imposed because reflex changes in heart rate and inotropic state could occur during load-altering maneuvers. However, the linearity of the stress-volume relationship reported in most studies suggests that contractile function does not change very much during loading. CIRCULATION PERSPECTIVE Downloaded from http://circ.ahajournals.org/ by guest on April 30, 2017 Dead volume The X intercept of the afterload-volume relationship is the volume that would be left in the ventricle if there were no load on the ventricle at end-systole. This volume has been termed dead volume or VO. The usefulness of VO as an indicator of inotropic state remains controversial since it is a theoretic value that cannot be actually measured. It is extrapolated from the pressurevolume or stress-volume line. In theory, an increase in inotropic state could decrease VO because the unloaded ventricle could shorten more when inotropic state is increased. Conversely, VO could increase when inotropic state diminishes. Since both pressure and stress are zero at VO (or dead dimension), it should not matter whether the pressurevolume or stress-volume relationship is used to extrapolate this value. However, this does not seem to be the case. Marsh et al.7 found marked differences in dead dimension calculated with a pressure-dimension extrapolation and that calculated with a stress-dimension extrapolation. Some authors have found VO useful in measuring inotropic state. Grossman et al.4 found both VO extrapolated from the pressure-volume relationship and zero circumference (CO) extrapolated from the stresscircumference relationship to be reflective of contractile state. Greater VO or CO indicated poorer contractile function. Conversely, Mehmel et al.8 found no consistent relationship between inotropic state and VO extrapolated from pressure-volume relationships. Since the value is only a theoretic one and cannot be verified clinically, this index of contractile function may be of limited use. Attempts at simplification Substitution of peak systolic pressure for end-systolic pressure. An attractive feature of pressure-dimension and stress-dimension relationships is their potential for being determined noninvasively. End-systolic dimension and thickness can be determined with echocardiography and blood pressure by sphygmomanometry, but end-systolic pressure is not the same as either peak systolic pressure or diastolic pressure, which are the parameters normally measured by sphygmomanometry. In some studies, however, peak systolic pressure has been substituted for end-systolic pressure. In one investigation Marsh et al.7 found a close correlation (r = .99) between slope of the pressure-volume relationships obtained using peak pressure vs the slope obtained during end-systolic pressure. However, the close relationship between peak and end-systolic pressure may not be constant. It is conceivable that when Vol. 69, No. 5, May 1984 large stroke volumes and pulse pressures are present (e.g., in aortic regurgitation) the relationship of peak systolic pressure to end-systolic pressure might be different than the relationship when a small stroke volume and narrow pulse pressure (e.g., in severe heart failure) are present. In such situations, substitutions of peak systolic pressure for end-systolic pressure might not be justified. Marsh et al. have described a method whereby a noninvasively determined carotid pulse tracing can be calibrated to the patient's blood pressure as determined by sphygmomanography. The dicrotic notch pressure so obtained is considered to be endsystolic pressure. Further use of this technique and examination of the peak systolic pressure-end-systolic pressure relationship over a wide range of diseases will be needed to ascertain which is most applicable noninvasively. The end-systolic pressure-end-systolic volume ratio. As noted, the determination of the pressure-volume relationship requires derivation of the pressure-volume or stress-volume relationship at different loading conditions to establish the slope of the line describing this relationship. Thus, an intervention must be performed and a measurement of ventricular size must be made at each load. This is cumbersome and, in some patients, hazardous. To avoid these problems, the simple ratio of pressure and volume at end-systole has been used as a measure of contractile function. If the pressure-volume line runs through or near the 0 origin of both X and Y, then any single pressure-volume ratio determination defines the pressure-volume slope m = Y/(X + 0). Since the Y intercept of the pressure-volume line varies from patient to patient, this assumption is usually not justified and thus the pressure-volume ratio does not truly represent the pressure-volume slope. However, a rationale for the use of the pressurevolume ratio does exist. The end-systolic volume or dimension by itself is a useful indicator of prognosis in some patients.2 Correction for the changes of endsystolic volume produced by variations in ventricular end-systolic pressure may make this measurement even more useful. The use of the pressure-volume ratio requires the assumption that at higher pressures there are larger volumes at the same inotropic state. A smaller volume for a given pressure suggests more complete contraction and should indicate that the inotropic state has increased. The clinical use of the pressure-volume ratio is currently controversial; while some authors have found the simple pressure-volume ratio useful in segregating patients with left ventricular dysfunction from those without dysfunction, others have not. End-systolic stress-end-systolic volume ratio. As noted 1061 CARABELLO and SPANN MITRAL REGURGITATIO N EJECTION FRACTION END SYSTOLIC INDEX 7.0- 00 0 0.8- A o 6.0- 0 0.75.0- 0 0 0 a 80 0 0 0) 4.0- 0 ". 0 0.6- 0* a 0 0 0 S0 0 3.00.5- A * 2.0- A Downloaded from http://circ.ahajournals.org/ by guest on April 30, 2017 0.4- A I AUl. FIGURE 3. Left, The end-systolic stress-end-systolic volume index ratio for normal subjects (open circles), patients with mitral regurgitation who improved clinically after valve replacement (solid circles), and patients with mitral regurgitation who died or did not improve with surgery (open triangles). The ratio allowed separation of these groups of patients while use of ejection fraction (right) did not. (Reprinted with permission from Carabello et a.') above, the use of data on stress often has advantages over use of that on pressure in quantitating afterload when ventricular size and thickness are abnormal. The use of end-systolic wall stress instead of pressure is thus a better way to correct end-systolic volume for afterload. Therefore, the end-systolic stress-volume ratio should be more useful than the pressure-volume ratio. The determination of the end-systolic stress-volume ratio does not require load manipulation and thus is simple and safe and the ratio is useful because whether an increase in inotropic state produces an increase in slope of the stress-volume line or a decrease in the X intercept (parallel shift to the left), the endsystolic volume for any given end-systolic stress will be less. Thus, the stress-volume ratio will increase in either case and properly indicate the positive inotropic change. Also, a reduction in inotropic state will result in a larger end-systolic volume for any level of endsystolic stress and the ratio will decrease, properly indicating reduced inotropic state. When applied clinically, the end-systolic stress-end-systolic volume index ratio separated patients with a good prognosis for valve replacement for mitral regurgitation from those with a poor prognosis .9 The ratio was useful despite the difficulty in defining end-systole in mitral regurgitation, in which volume may still be ejected into the left atrium in early diastole. Four of five patients with a reduced ratio died in the perioperative period and the fifth was clinically unimproved after surgery. As 1062 shown in figure 3, this ratio was a better predictor of clinical outcome than ejection fraction. We have also demonstrated a reduction in the end-systolic stressvolume index ratio in patients with aortic regurgitation and congestive heart failure and in patients with sickle cell anemia, who also had a reduced stress-volume slope. Thus, in these studies, the ratio of end-systolic stress to end-systolic volume index has clinical usefulness. However, it is likely that limitations will be noted since this ratio, like the pressure-volume ratio, is not a substitute for the stress-volume slope. The ratio might be particularly limited in very small ventricles. The formula for the straight line describing the endsystolic relationship is stress - m(ESV -V0), where ESV is end-systolic volume. The smaller the ventricle at end-systole, the larger V0 becomes in relation to end-systolic volume, and the more important V0 becomes in the equation. Shortening fraction-stress and ejection fraction-stress relationships. Several authorsv have noted an inverse correlation between ejection fraction and end-systolic stress. As end-systolic stress rises, ejection is limited by the increased load and ejection fraction decreases. This relationship is linear. A decrease in contractile function is suggested when ejection fraction, at any given stress, is lower than predicted (figure 4). This suggests that high afterload alone cannot account for the observed reduction in ejection fraction and that left ventricular dysfunction is present. We and others have CIRCULATION PERSPECTIVE H .6 6.5 I-. c: .4 v \ * \ *- X .2 X X i* \ X Downloaded from http://circ.ahajournals.org/ by guest on April 30, 2017 I I 150 200 250 a (dyneo-s X 3/CI m 103/c' M2t 400 FIGURE 4. The ejection fraction-stress relation iship for patients with aortic stenosis, congestive heart failure, and a go()d operative result (D) is shown together with that for similar group of paitients who had a poor operative result (X). The latter had a lower ejecti( n fraction for a given afterload, suggesting that muscle dysfunction wais present. (Reprinted with permission from Carabello et al. `) used this relationship to examine left ventricular function in patients with a pressure ov(erload and have found it useful in identifying patients with left ventricular dysfunction. ° Potential limitations. This relationshiip may not hold true in patients with mitral regurgitattion in whom increased preload might elevate ejectiorn fraction despite left ventricular dysfunction. In such c;ases, the ejection fraction-stress relationship might fa il to shift to the left, concealing diminished contractil e function. In patients with mitral stenosis reduced pre load may reduce ejection fraction. The ejection fractioyn-afterload relationship might falsely indicate contraLctile dysfunction when none exists in patients with th is disease. Our perspective Historically, clinical indexes of leflt ventricular contractile function have gained acceptanice and then have fallen into disuse because their limitattions were identified. It is likely this process will con tinue. Currently, ejection fraction is the most widely applied index of ventricular function. It should remain clinically useful in the treatment of those with corornary disease and other diseases that do not severely alt' er loading conditions. However, in patients with hleart disease, in Vol. 69, No. 5, May 1984 whom major alterations in loading conditions occur, ejection fraction is not an accurate measure of contractile function. In these patients a measure of contractile function that is independent of or accounts for load is needed to accurately assess ventricular function. Studies by Sagawa and others have demonstrated that the end-systolic afterload-end-systolic length relationship is sensitive to changes in contractile state and insensitive to load. We believe that this relationship offers an important advance for the investigator and for the clinician in the evaluation of ventricular function. It is not yet clear what the best method is for determining the end-systolic relationship. We believe that, for the purposes of clinical investigation, the end-systolic pressure-volume (or dimension) relationship, constructed from several points obtained under different loading conditions, is currently the most precise way of assessing muscle function. This relationship has been shown to be sensitive for the detection of depressed contractile state but insensitive to load. The method has already advanced our knowledge of muscle function in patients with diseases such as thalassema, sickle cell anemia, and cardiomyopathy. Stress-volume or stress-dimension relationships should be used when cardiac hypertrophy is present since stress is a better estimate of afterload than pressure in this circumstance. However, because of the difficulties with performing load manipulation in sick patients, either technique is limited as an aid to the clinician in daily decision making. For clinical use, the ratio of end-systolic stress to end-systolic volume index offers a promising, easily obtained measure of ventricular function. We believe it should be particularly useful in estimating prognosis in patients with valvular regurgitation, in whom loading conditions are abnormal and V0 is probably of reduced importance. However, before this ratio can gain wide acceptance, normal values and laboratoryto-laboratory variation must be identified. Furthermore, prospective studies to establish the prognostic value of the end-systolic stress-volume index ratio are needed to confirm or refute its usefulness. We thank Maxine Blob, Sharon Jankowski, and Rosalie Ratkiewicz for preparation of the manuscript. References 1. Sagawa K: The end-systolic pressure-volume relation of the ventricle: definition, modifications and clinical use. Circulation 63: 1223, 1981 2. Henry WL, Bonow RO, Rosing DR, Epstein SE: Observations on, the optimum time for operative intervention for aortic regurgitation. II. Serial echocardiographic evaluation of asymptomatic patients. Circulation 61: 484, 1980 3. Borow KM, Green LH, Sloss LJ, Braunwald E, Collins JJ, Cohn 1063 CARABELLO and SPANN 4. 5. 6. 7. L. Grossman W: End-systolic volume as a predictor of post-operative left ventricular performance in volume overload from valvular regurgitation. Am J Med 68: 655, 1980 Grossman W, Braunwald E. Mann T. McLaurin LP. Green LH: Contractile state of the left ventricle in man as evaluated from endsystolic pressure-volume relations. Circulation 56: 845, 1977 Denenberg BS. Criner G. Jones R. Spann JF: Cardiac function in sickle cell anemia. Am J Cardiol 51: 1674. 1983 Spann JF. Bove AA. Natarajan G. Kreulen T: Ventricular performance, pump function and compensatory mechanisms in aortic stenosis. Circulation 62: 576. 1980 Marsh JD. Green LH. Wynne J. Cohn PF. Grossman W: Left ventricular end-systolic pressure-dimension and stress-length rela- tions in normal human subjects. Am J Cardiol 44: 1311, 1979 8. Mehmel HC. Stockins B. Ruffman K, Olhausen K. Schuler G. Kubler W: The linearity of the end-systolic pressure-volume relationship in man and its sensitivity tor assessment of left ventricular function. Circulation 63: 1216. 1981 9. Carabello BA, Nolan SP. McGuire LB: Assessment of preoperative left ventricular function in patients with mitral regurgitation: value of the end-systolic wall stress-end-systolic volume ratio. Circulation 64: 1212, 1981 10. Carabello BA. Green LH. Grossman W. Cohn LH, Koster JK. Collins JJ: Hemodynamic determinants of prognosis of aortic valve replacement in critical aortic stenosis and advanced congestive heart failure. Circulation 62: 42, 1980 Downloaded from http://circ.ahajournals.org/ by guest on April 30, 2017 1064 CIRCULATION The uses and limitations of end-systolic indexes of left ventricular function. B A Carabello and J F Spann Downloaded from http://circ.ahajournals.org/ by guest on April 30, 2017 Circulation. 1984;69:1058-1064 doi: 10.1161/01.CIR.69.5.1058 Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Copyright © 1984 American Heart Association, Inc. All rights reserved. Print ISSN: 0009-7322. Online ISSN: 1524-4539 The online version of this article, along with updated information and services, is located on the World Wide Web at: http://circ.ahajournals.org/content/69/5/1058.citation Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published in Circulation can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial Office. 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