Evaluation of contractile reserve by dobutamine echocardiography: Noninvasive estimation of the severity of heart failure

Evaluation of contractile reserve by dobutamine echocardiography: Noninvasive estimation of the severity of heart failure Alon M a r m o r , MD, T h e o d o r R a p h a e l , MD, M e i r M a r m o r , MD, a n d D a v i d Blondheim, MD Haifa, Israel

Functional status in chronic heart failure is evaluated in general by subjective means, such as the New York Heart Association class, or by invasive techniques difficult to use routinely. The aim of this study was to evaluate noninvasively the contractile reserve in cases of heart failure as a means to define the functional status of the patients. Cardiac peak power, a new noninvasively obtained afterload-independent index of contractility, was calculated from online Doppler and central arterial blood pressure estimated noninvasively in 35 patients with heart failure and 10 healthy subjects during dobutamine infusion. Cardiac output increased in all patients to the same extent, without differentiation among the functional classes. Contractile reserve, as assessed by peak power, was found to be a good marker of functional class: it was significantly higher in functional class 1 than in functional classes 2 through 4. A correlation of r= 0.99 and probability of p < 0.001 was found with the functional status. This new, noninvasive contractility index, peak power, allows an objective evaluation of the severity of heart failure. (Am Heart J 1996;132:1195-201.)

D o b u t a m i n e , b y its w e l l - k n o w n direct positive inotropic action, 1 is k n o w n to i n c r e a s e cardiac perform a n c e in p a t i e n t s w i t h h e a r t failure. 2 I n c r e a s e in p e r f o r m a n c e is a c h i e v e d m a i n l y b y a n i n c r e a s e in contractility, 1 a r e d u c t i o n in s y s t e m i c v a s c u l a r resistance 3, 4 (SVR), a n d to s o m e degree a n i n c r e m e n t in h e a r t rate. 1 I t is r e a s o n a b l e to a s s u m e t h a t as h e a r t failure p r o g r e s s e s , the contractile r e s e r v e of the h e a r t d e c r e a s e s a n d t h e r e f o r e a u g m e n t a t i o n in cardiac p e r f o r m a n c e would be a c h i e v e d in the adv a n c e d s t a g e s o f h e a r t failure b y l o w e r i n g t h e SVR a n d i n c r e a s i n g t h e h e a r t r a t e , r a t h e r t h a n b y inc r e a s i n g t h e contractility. R e c e n t l y G o r c s a n a t al. 5 d e m o n s t r a t e d a t t e n u a t e d contractile r e s e r v e in chronic severe h e a r t failure by From the Division of Cardiology, Safed Hospital, Safed and Technion Faculty of Medicine. Received for publication Nov. 10, 1995; accepted March 15, 1996. Reprint requests: Alon Marmor, MD, Division of Cardiology, Rebecca Sieff Hospital, Safed 13100, Israel. Copyright © 1996 by Mosby-Year Book, Inc. 0002-8703/96/$5.00 + 0 4/1//5862

using an automated noninvasive pressure-volume r e l a t i o n d u r i n g d o b u t a m i n e echocardiography. However, t h e y did not differentiate b e t w e e n the functional classes a n d did not correlate the s e v e r i t y of t h e h e a r t failure to the degree of contractile reserve. T h e p u r p o s e of t h e c u r r e n t s t u d y w a s to e v a l u a t e the contractile r e s e r v e in p a t i e n t s w i t h t h r e e distinct functional classes of h e a r t failure (New York H e a r t Association class 1, class 2 a n d 3, a n d class 4) b y using a n e w n o n i n v a s i v e a p p r o a c h d u r i n g a given s t a n d a r d inotropic s t i m u l u s of d o b u t a m i n e . T h e hypothesis w a s t h a t contractile r e s e r v e g r a d u a l l y decreases w i t h i n c r e a s i n g s e v e r i t y of h e a r t failure, while left v e n t r i c u l a r p e r f o r m a n c e is m a i n t a i n e d in the a d v a n c e d s t a g e s of h e a r t failure m a i n l y b y a decrease in SVR r a t h e r t h a n a n i n c r e a s e in contractility. METHODS Patient population. From 42 patients referred to our

outpatient clinic with various symptoms, 35 were included in the study. Their mean age was 60 _+ 5 years; there were 26 men and 9 women; and their mean blood pressure (systolic/diastolic) was 135 _+ 10/83 _+ 5 mm Hg. After careful anamnestic evaluation 15 patients were classified as New York Heart Association functional class 1, 13 as functional class 2 and 3, and 7 as functional class 4. Patients were assigned to functional classes by two independent experienced cardiologists unaware of the study. For only 2 patients was there a discrepancy between the two specialists, and a third competent cardiologist decided the functional class in these subjects. None of the patients had had an acute coronary event in the preceding 6 months. All patients had a history ofischemic heart disease and had documented myocardial infarction. Twenty of the 35 had had more than one myocardial infarction. All patients with symptoms of heart failure were treated with digoxin and diuretic agents, and all patients from the groups of functional classes 2 through 4 were treated with captopril 25 mg two times per day or three times per day in addition to digoxin and diuretic agents. In 10 additional subjects referred to our outpatient clinic for atypical chest pain, coronary artery disease was ex1195

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Table I. Cardiac output (liters per minute) during dobutamine infusion Infusion rate (ttg/kg/min)

Healthy

FC1

FC2 and FC3

FC4

Rest 5 10 20 30 40 A_NOVA

5.55 ± 0.7 5.48 _+0.7 6.69 + 0.5 8.43 ± 1.1 10.54 _+1.5 8.93 ± 2.0 <0.001

4.38 _+0.5 4.90 -- 0.4 5.30 +_0.7 5.57 ± 0.6 6.91 _+1.0" 8.01 ± 0.7 <0.001

4.15 ± 0.2 4.31 _+0:4 5.67 +_0.3 6.17 ± 0.4 6.60 +_0.4* 8.03 ± 0.9 <0.001

4.27 +_0.5 5.55 +_0.8 5.06 _+0.5 6.14 _+0.8 6.31 _+0.8* 7.31 _+0.9 <0.001

ANOVA, Analysis of variance; FC, New York Heart Association functional class. *p < 0.016 for comparison with healthy group.

cluded by exercise testing, exercise thallium perfusion scanning, and echocardiographic dobutamine stress testing. All other organic heart conditions were excluded by Doppler echocardiography. These subjects were included in the study as a control group, and their functional class was considered to be 1. Measurements of aortic flow. Aortic velocities were measured by continuous-wave Doppler in an apical fivechamber view. Aortic diameter was measured in a two-dimensional parasternal long-axis view, just below the aortic orifice, from the inner to inner echo at rest only because aortic valve is thought to remain constant during exercise or dobutamine infusion. 6 Aortic valve area was also measured. The following variables were obtained at rest and during dobutamine infusion: stroke volume6 ([~/4 x (Aortic diameter] 2 x [Aortic velocity-time integral]) and aortic flow. Aortic flow was calculated as the Velocity-time integral x Valve area/ejection time. Doppler measurements of exercise stroke volume at the aortic orifice have been previously validated by comparison with thermodilution 7 and recently by Dahan at al. 6 and Borow et al. s End-diastolic volume was measured by using the established area-length method. Central arterial pressure measurement. Central arterial pressure was obtained noninvasively by a newly designed computer-controlled device. 9' i0 This device consists of three components: a sphygmomanometric arm cuff attached to an air pressure unit; a Doppler transducer attached to the arm at the antecubital space over the brachial artery; and an electrocardiographic monitoring system. Noninvasive pressure waveforms are generated by measuring the time delay between the R wave on the electrocardiogram and the onset ofbrachial artery flow (Doppler) during computer-controlled upper-arm deflation. This delay shortens with decreasing cuff pressure, so that a plot of pressure versus time delay yields the ascending portion of the arterial waveform. These waveforms were compared with the simultaneous invasive ascending aortic pressure, and correlations of r = 0.98 for systolic pressure and r = 0.99 for diastolic pressure were found, ii Cardiac peak power measurement. Peak power, representing the maxima] product of systolic pressure and flow, occurs early in ejection and is not significantly affected by

afterload. Experimental data 12-i4 indicate that cardiac peak power is a relatively afterload-independent contractility index. It is obtained with the following formula: Peak power = Maximal product of(P x dV/dt), where P is central aortic pressure and dV/dt is aortic flow. Aortic flow was computed as (Velocity-time integral × Aortic valve area)/ Ejection time, measured in the apical five-chamber view by Doppler echocardiography. By aligning the beginning of the flow with the simultaneously recorded central aortic pressure, instantaneous power measurements are made and maximal peak power is obtained. Statistics. The results are expressed as means +--SD. For repeated comparison between the healthy and patient groups, repeated-measures analysis of variance was used. One-way analysis of variance was performed for comparison within the same group of patients at different rates of dobutamine infusion. When analysis of variance showed statistical significance (p < 0.05), the Student-NewmanKeuls test was used for comparison of the groups. Correlations between functional class and change in cardiac output, SVR, heart rate, and peak power were calculated by linear regression analysis, i5 Functional classes were scored on a scale of 1 to 3, where 1 is healthy and 3 is functional class 4. RESULTS

Results were obtained in 42 p a t i e n t s a n d were of good e n o u g h quality for a c c u r a t e analysis in 35 subjects, who were included in t h e study. Acute ischemic episodes were ruled out by looking at regional wall m o t i o n abnormalities a n d electrocardiographic c h a n g e s d u r i n g d o b u t a m i n e infusion. Only p a t i e n t s w i t h o u t n e w regional motion abnormalities or other d o c u m e n t e d ischemic episodes were included in the study. Therefore the p a t i e n t p o p u l a t i o n was h o m o g e n e o u s with respect to lack of active ischemic events. Seven p a t i e n t s were assigned to functional class 4, 13 p a t i e n t s to class 2 a n d 3, a n d 15 to functional class 1. All 10 h e a l t h y subjects h a d good quality studies a n d were included as the control group. The m a x i m a l increase in cardiac o u t p u t w a s ob-

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+Cardiac Output Mean Healthy 6,3 FC1 3.42 FC2-3 2,89 FC4 4.27 r = 0.57 p = NS

SEM 0.8 0.74 0,48 0,89

Healthy

FCI

FC2-3

FC4

+Peak Power 15

Mean Healthy 10.89 FC1 7.76 FC2-3 5,53 FC4 3.47 r = 0.995 p<0.005

SEM 1.28 1.22 0.95 0.64

10 5 a..

0 +

Healthy

FC1

FC2-3

FC4

Healthy

FC1

FC2-3

FC4

Healthy

FC1

FC2-3

+Heart Rate = 60

Mean Healthy ,52.3 FC1 28,91 FC2-3 24.45 FC4 36.58 r = 0.54 p=NS

g

SEM 5.56 7.16 4.95 4.94

~

4o

e~ •I~

20

-SVR Mean Healthy 512 FC1 966 FC2-3 666 FC4 1184 r = 0.73 p = NS

SEM 172 161 190 239

A

=~ 15oo 1000

T

u " 500 n,

o

i

FC4

Fig. 1. Maximal changes in four hemodynamic parameters induced by dobutamine stress testing. Maximal differences in cardiac output (CO), peak power, heart rate, and SVR are shown for each functional class. FC, Functional class; NS, not statistically significant; r, correlation between functional classes and hemodynamic parameters.

tained with 40 pg dobutamine in the patients in functional classes I through 4 and with 30 pg in the healthy subjects. As expected, the increase in cardiac output was substantially higher in the healthy subjects t h a n in all patient groups (Table I). However, cardiac output achieved at the peak dobutamine dose was remarkably similar in all patient groups, regardless of their functional class (Table I). In the healthy group, cardiac output increased from 5.5 _+ 0.7 L/minto 10.5 _+ 1.5 L/min (p < 0.01) at 30 ~g of dobutamine and reached a plateau of 8.9 L/rain at 40 pg (Table I and Fig. 1). Stroke volume

increased by 31%, from 73 to 96 ml at 40 pg (p < 0.05). The main component responsible for the increase in stroke volume, and subsequently in cardiac output, was the massive increase in contractility. Peak power/end-diastolic volume increased from 11.46 to 21.97 W/ml (p < 0.001) at 40 pg dobutamine (Table II), representing an increase of 92% in this contractility index. Heart rate increased from 74 _+ 3 beats/min to 102 _+ 10 beats/rain (p < 0.01) (Table III). SVR decreased from 1483 to 917 dyne • cm -5 • sec (38%), a relatively modest decrease compared with the change in peak power (Table IV).

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Table II. Cardiac peak power/end-diast01ic volume (watts per milliliter) during dobutamine infusion Infusion rate (Ttg/kg/min)

Healthy

FC1

FC2 and FC3

FC4

Rest 5 10 20 30 40 ANOVA

11.46 _+ 1.4 12.28 ± 1.3 13.97 -+ 1.6 17.36 _+ 1.9 20.11 ± 2.6 21.97 ± 5.4 <0.001

8.81 ± 1.1 9.66 ± 1.1 11.44 ± 1.3 12.45 ± 1.3 14.73 -+ !.2 18.11 -+ 1.9 <0.001

7.98 -+ 0.9 10.14 -+ 1.7 10.80 ± 2.0 11.80 ± 1.5t 12.47 ± 1.8t 10.56 ± 2.5 <0.001

6.56 -+ 1.0' 6.89 _+ 1.8 7.71 ± 1.1 8.35 -+ 1.2t 8.82 -+ 1.2t 9.53 _+ 2.15 <0.001

Abbreviations as in Table I. *p < 0.02 for comparison with healthy group. tp < 0.01 for comparison with healthy group. Sp < 0.04 for comparison with healthy group.

Table III. Heart rate (beats per minute) during dobutamine infusion Infusion rate (Itg/kg/min) Rest 5 10 20 30 40 ANOVA

Healthy

FC1

FC2 and FC3

FC4

74.10 -+ 3.2 75.70 + 2.9 83.20 -+ 4.1 95.70 -+ 8.0 110.25 ± 7.4 102.25 _+ 10.2 <0.001

79.36 _+ 5.0 80.70 -+ 4.6 81.40 ± 6.6 90.90 -+ 6.3 104.38 ± 10 95.40 -+ 10.2 <0,001

81.73 ± 5.2 78.73 -+ 7.1 91.00 _+ 5.9 98.00 -+ 5.3 97.17 -+ 5.6 116 -+ 24 <0.001

83.50 -+ 5.1 95.14 -+ 6.6 88.75 _+ 4.4 94.83 -+ 6.3 110 _+ 5.6 126 ± 4.2 <0.001

Abbreviations in Table I.

Table IV. Systemic vascular resistance (dynes. centimeter -5 • second) during dobutamine infusion Infusion rate ~tg/ kg/min

Healthy

FC1

FC2 and FC3

FC4

Rest 5 10 20 30 40 ANOVA

1483 _+ 144 1548 ± 196 1328 _+ 164 1096 + 147 877 -+ 120 917 -+ 121 <0.001

2097 - 202 1831 ± 174 1857 + 223 1768 ± 228 1465 ± 199" 1 1 5 8 -+ 91 <0.001

1830 -+ 202 1735 -+ 189 1418 -+ 177 1281 -+ 147 1090 +- 153 996+196 <0.001

2217 -+ 288 1475 +- 177 1867 +- 323 1530 +- 223 1112 -+ 136 1034+-110 <0.001

Abbreviations as in Table I. *p < 0.05 for comparison with healthy group.

A different pattern was found in patients with moderately reduced cardiac function (functional class 2 and 3). Cardiac output increased substantially, from 4.15 to 8.03 L/min (p < 0.001) at 40 pg dobutamine (Table I). This increase of more t h a n 93% was achieved by a substantial increase in contractility (peak power/end-diastolic volume increased by 57%, from 7.98 to 12.5 W/ml) and by a substan-

tial, 45% decrease in SVR from 1830 to 996 d y n e . cm -5- sec (p < 0.001) (Tables II and IV). In the functional class 4 group, cardiac output increased by 71%, from 4.27 to 7.31 L/min at 40 llg of dobutamine (Table I). This substantial increase can be explained also by some increase in contractility; peak power increased significantly (by 46%, from 6.56 to 9.53 W/ml at 40 llg) (Table II). However, the increase in cardiac output can be explained mainly by a marked decrease in SVR (Table IV). At the same dose the absolute value of SVR decreased by half, from 2217 +_ 288 to 1034 +_ 110 d y n e . cm -5 • sec (p < 0.001) (Table IV). Thus the increases in cardiac output and stroke volume (51 to 58 ml) can be explained by the direct vasodilatory effect of the drug. The cardiac output increase was achieved mainly by the 50% increase in heart rate, from 83.5 to 126 beats/min, rather t h a n the modest increase of 13% in stroke volume and a decrease in SVR. The best discriminator among functional classes was the contractile reserve, as reflected by the increase in cardiac peak power. Contractile reserve also showed excellent correlation with functional status when functional classes were scored from 1

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(healthy) to 3 (functional class 4). A correlation of r = 0.995 and probability ofp < 0.005 was found, in contrast with the relatively low correlation found with cardiac output (r = 0.57; p not significant).

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Table V. End-diastolic volume (milliliters) during dobuta-

mine infusion Infusion rate ~tg/ kg/min

Healthy

FC1

FC2 and FC3

FC4

Rest 5 10 20 30 40 ANOVA

1 2 4 -- 8 1 2 5 -+ 8 1 2 6 -+ 7 1 2 8 _+ 6 1 2 1 _+ 11 1 3 1 +- 2 1 p = NS

1 3 4 _+ 6 1 3 6 _+ 7 1 3 7 -+ 7 1 3 3 _+ 7 1 3 2 _+ 11 1 2 1 _+ 15 p = NS

1 8 3 _+ 3 0 1 8 0 _+ 2 7 1 8 5 _+ 3 1 1 7 7 +_ 3 0 1 6 5 _+ 2 3 2 2 0 ~- 3 0 p = NS

2 1 7 _+ 2 7 2 4 8 _+ 3 3 2 0 9 _+ 2 3 2 0 6 +_ 2 2 2 0 7 _+ 2 4 1 7 3 '__ 4 0 p = NS

DISCUSSION

Numerous attempts have been made to assess noninvasively, on line, ventricular performance, s Left ventricular ejection fraction, though a good performance index, is affected mainly by afterload 16 and does not reflect adequately the exercise capacity or severity of functional class. 16 Analysis of pressure-volume relations is essential to define the complex determinants of ventricular performance, including preload, afterload, and contractile state. 17-22 Until recently, invasive methods were used to measure pressure-volume indexes. Noninvasive methods of estimating end-systolic pressure-volume relations by echocardiography or nuclear medicine techniques have been described. The difficulty in noninvasively measuring pressure-volume indexes resides in the lack of accurate measurement of volume and of the central arterial pressure. The method used in the current study accurately estimates central arterial pressure noninvasively.11 By multiplying the time-velocity integral obtained by Doppler ultrasonography with the aortic valve area measured by echocardiography, a reasonable estimate of stroke volume and aortic flow can be obtained. This method was recently extensively validated. 6.s At the beginning of ejection both the calibrated central aortic pressure and aortic flow curve can be aligned and a power curve can be calculated. The peak value of this curve, peak power, is the index used in the current study to measure contractile reserve. During dobutamine infusion very little change in end-diastolic volume was observed (Table V). Thus, in the same patient changes in peak power are not substantially affected by changes in end-diastolic volume. Similar results were found by using a ~/ camera during exercise. 23,24 Thus, although great effort was made to measure end-diastolic volume accurately, the accuracy of this measurement was not critical in our opinion for the interpretation of the results. Recently Gorcsan at al. 5, 25 reported assessment of left ventricular performance by on-line analysis of the pressure-area relation through echocardiographic automated border detection, but they used the peripheral arterial pressure obtained from a finger cuff photoplethysmograph for their calculation, thus allowing substantial errors in the estimation of pressure-based ventricular performance. As shown in previous studies 11, 26 the contour ofperiphera] ar-

NS, Not statistically significant; other abbreviations as in Table I.

terial pressure is completely different from t h a t of central arterial pressure because of numerous reflections and summations of peripheral arterial waves. It is therefore erroneous to calculate work or power indexes of the heart from peripheral pressure data. This principle is especially important when dobutamine infusion is used for evaluating contractile reserve. Dobutamine has certain vasodilatory effects t h a t change peripheral vascular resistance and affect the peripheral pulse waveform. However, with pressure-volume area relations and indexes such as stroke work, the error involved in measurement is reduced, and serial changes during dobutamine infusion within the same subject m a y have an important physiologic meaning. As shown in previous studies, 1214 cardiac peak power is a reliable noninvasive afterload-independent index of left ventricular performance t h a t reflects changes in contractility. In a previous study, 14 preload-adjusted maximal power was shown to be an afterload-independent index very sensitive to inotropic changes. When compared with the end-systolic pressure-volume relation, there was excellent correlation, withlinearregressiongivenby%AEes = 0.91 * %APWRmJEDV2 + 5.8 (r = 0.9, p < 0.001), where Ees is ventricular elastance, P ~ is maximal cardiac power, and EDV is end-diastolic volume. Similar correlations were obtained in comparisons of the power index to the slope of stroke work-end-diastolic volume relation (r = 0.67; p = 0.002). Dobutamine infusion, in addition to producing the expected increase in contractility, substantially reduces peripheral resistance, thereby improving ventricular-arterial coupling and thus the energy transfer from the heart to the periphery. Similar results were obtained by Binldey at a1.,27 who showed a marked reduction in aortic input impedance during dobutamine infusion. They also showed t h a t reduction in pulsatile load, especially in patients with heart failure, iraproves the efficiency of energy transfer, an improve-

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ment that is beneficial for the patients. Thus dobutamine, having a direct vasodilatory effect through [32 stimulation of the vascular smooth muscle, 3, 4 reduces pulsatile load. Reduced aortic input imped: ance allows the vasculature to adapt to the enhanced contractility, therefore facilitating ventricular-vascular coupling. The final result is the overall improvement in ventricular performance associated with dobutamine infusion. Using dobutamine-induced adaptation of the ventricular-arterial system as a test to evaluate the degree of severity of ventricular impairment in heart failure, Gorcsan et al.5 showed an attenuated contractile reserve in chronic heart failure. Graded increase in stroke work observed with dobutamine inotropic modulation was substantially reduced in the patients with heart failure. These investigators suggested that such a method m a y be useful in assessing contractile reserve in patients with chronic heart failure. The results reported by Gorcsan at al. 5, 25 from noninvasive measurements of cardiac work are comparable with the results in the current study. Contractile reserve was the lowest for functional class 4, increased gradually as the functional class improved, and was highest in healthy subjects, showing an excellent correlation with functional status (r = 0.995; p < 0.005) (Fig. 1). Changes in SVR, heart rate, and cardiac output showed only a weak and nonsignificant correlation with functional classes (Fig. 1). It appears therefore that contractile reserve is a better descriptor of the functional status of the heart than rest indexes and indexes based on volumetric measurements alone, such as ejection fraction, 16 stroke volume, or cardiac output. The current study also suggests that for a given increase in cardiac performance, patients with a more severe disease are more dependent on the ability to vasodilate and reduce SVR. S t u d y limitations. Brachial arterial pressure was used to estimate left ventricular ejection pressure. Although numerous validation studies have been performed by ourselves and others, we recognize that brachial arterial pressure is only an estimate of left ventricular ejection pressure and not a direct measurement. Other limitations of the study are related mainly to the indexes derived by Doppler echocardiography. In patients with low cardiac output, variations in sampling site or angle of incidence, and errors in aortic diameter measurement may have the potential to cause significant errors in the calculation of SVR, especially when these errors are compounded. Although this technique was validated it still is observer dependent. In our echocardiography laboratory the intraobserver and interobserver vari-

AmericanHeartJournal

abilities were 2% and 4%, respectively, in 20 consecutive patients examined by two independent Doppler echocardiography specialists. An additional limitation is the small sample size in each group, so much so that we had to combine patients from functional classes 2 and 3 into one group. This necessity attenuates the discriminatory power of the technique. However, the substantial differences between functional classes 1 and 4 revealed by the study have clinical importance and imply that by increasing the numbers of subjects in classes 2 and 3 we will be able to differentiate between these two classes also. REFERENCES

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16. Marmor A, Jain D, Zaret B. Beyond ejection fraction. J Nucl Cardiol 1994;1:477-86. 17. Suga H, Sagawa K, Shoukas AA. Load independence of the instantaneous pressure-volume ratio of the canine left ventricle and effects of epinephrine and heart rate on the ratio. Circ Res 1973;32:314-22. 18. Suga H, Sagawa K. Instantaneous pressure-volume relationships and their ratio in the excised, supported canine left ventricle. Circ Res 1974;35:117-26. 19. Sagawa K. The ventricular pressure-volume diagram revisited. Circ Res 1978;43:677-87. 20. Khalafbeigui F, Suga H, Sagawa K. Left ventricular systolic pressurevolume area correlates with oxygen consumption. Am J Physiol 1979;237:H566-9. 21. Maughan WL, Kallman CH, Sheukas AA. The effect of right ventricular filling on the pressure-volume relationship of the ejecting canine left ventricle. Circ Res 1981;49:382-8. 22. Sunagawa K, Maughan WL, Burkhoff D, Sagawa K. Left ventricular interaction with arterial load studied in isolated canine ventricle. Am J Physiol 1983;245:H773-80.

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23. Marmor A, Jaln D, Cohen LS, Nevo E, Wackers FJT, Zaret BL. Left ventricular peak power during exercise: a noninvasive approach for assessment of contractile reserve. J Nucl Meal 1993;34:1877-85. 24. Marmor A, Marmor M, Nero E. Inadequate peripheral vascular adapration is associated with exercise intolerance in patients with left ventricular dysfunction [abstractJ. Circulation 1993;88:][-213. 25. Gorcsan J HI, Romand JA, Mandarino WA, Deneault LG, Pinsky MR. Assessment of left ventricular performance by on-line pressure-area relations using echocardiographic automated border detection. J Am Coll Cardiol 1994;23:242-52. 26. O'Rourke ME. Steady and pulsatile energy losses in the systemic circulation under normal conditions and in simulated arterial disease. Cardiovasc Res 1967;1:313-26, 27. Binkley PF, van Fossen DB, Nunziata E, Unverferth DV, Leier CV. Influence of positive inotropic therapy on pulsatile hydraulic load and ventricular-vascular coupling in congestive heart failure. J Am Coll Cardiol 1990;15:1127-35.