Left ventricular-arterial
coupling
in conscious dogs
WILLIAM C. LITTLE AND CHE-PING CHENG Section of Cardiology, Department of Medicine, Bowman Gray School of Medicine, Wake Forest University, Winston-Salem, North Carolina 27103
LITTLE, WILLIAM C., AND CHE-PING CHENG. Left uentricular-arterial coupling in conscious dogs. Am. J. Physiol. 261 (Heart Circ. Physiol. 30): H70-H76, 1991.-We investigated the criteria for the coupling of the left ventricle (LV) and the arterial system to maximize LV stroke work (SW) and the transformation of LV pressure-volume area (PVA) to SW. We studied eight conscious dogs that were instrumented to measure LV pressure and determine LV volume from three ultrasonically determined dimensions. The LV end-systolic pressure (P&-volume (V& relation was determined by caval occlusion. Its slope (EES) was compared with the arterial elastance ( EA) and determined as PEs per stroke volume. At rest, with intact reflexes, EES/EA was 0.96 k 0.20. EEs/EA was varied over a wide range (0X-2.59) by the infusion of graded doses of phenylephrine and nitroprusside before and during administration of dobutamine. Maximum LV SW, at constant inotropic state and end-diastolic volume (V&, occurred when E&E* equaled 0.99 t 0.15. At constant V EI1 and contractile state, SW was within 20% of its maximum value when EES/EA was between 0.56 and 2.29. The conversion of LV PVA to SW increased as EES/EA increased. The shape of the observed relations of the SW to EEs/EA and SW/PVA to E&E A was similar to that predicted by the theoretical consideration of LV PEs-VEs and arterial PEs-stroke volume relations. We conclude that the LV and arterial system produce maximum SW at constant VEI) when EES and EA are equal; however, the relation of SW to EEs/EA has a broad plateau. Only when EA greatly exceeds EES does the SW fall substantially. However, the conversion of PVA to SW increases as EES/EA increases. These observations support the utility of analyzing LV-arterial coupling in the pressurevolume plane.
PV loop is assumed to be flat and the end-diastolic pressure is negligible, this analysis predicts that the stroke work (SW) (or the area of the PV loop) should be maximized when EA = EES (3, 34). Data obtained from the isolated canine LV ejecting into a windkessel model of the arterial system were consistent with these predictions (34). However, this concept has not been evaluated in the intact cardiovascular system. Sunagawa et al. (34) recognized the difficulty in directly extrapolating their results in isolated hearts to the intact cardiovascular system and stated: “Any hypothesis concerning physiological matching of cardiac performance with arterial load must eventually be tested and validated in an intact animal under various physiologic conditions.” The function of the cardiovascular system is to provide for the perfusion of the tissues. This requires that the LV produce both flow (stroke volume) and perfusion pressure (arterial pressure). The LV SW integrates both these parameters; thus, it provides a simple means of quantitating the performance of the cardiovascular system (34). The interaction of the LV and the arterial system, in addition to determining SW, also importantly influences. the determinants of myocardial oxygen demand (MVo2) (3). Accordingly, this study was undertaken to evaluate, in conscious animals, the effect of alterations of the coupling between the LV and arterial system on LV SW and pressure-volume area (PVA).
stroke work; pressure-volume
Instrumentation. Eight healthy mongrel dogs (28.1 t 1.5 kg body wt) were instrumented as we have previously described (15). A micromanometer pressure transducer
area; elastance
of the cardiovascular system depends on the interaction of its components. The left ventricle (LV) pumps the stroke volume into the arterial system that delivers the flow to the tissues. Thus optimal cardiovascular function requires appropriate coupling of the LV and arterial system. Functional analysis of this interaction requires that the LV and arterial system be described in similar terms. Sunagawa et al. (33-35), and Burkhoff and Sagawa (3) proposed that LV-arterial coupling be analyzed in the pressure-volume (PV) plane. They suggested that the intersection of the LV end-systolic pressure (PEs)-volume (V,s) relation and the arterial PEs-stroke volume relation would predict the stroke volume. The slope of the PEs-VEs relation is the end-systolic elastance (&s) of the LV, whereas the slope of the arterial PEs-stroke volume relation represents the effective arterial endsystolic elastance (EJ. If the ejection portion of the LV THE PERFORMANCE
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$1.50 Copyright
METHODS
and a polyvinyl catheter for transducer calibration were inserted through a LV apical stab wound. Three pairs of ultrasonic crystals (5 MHz) were implanted in the endocardium of the LV to measure the anterior-posterior (DA& septal-lateral (DSL), and long-axis (base-apex) (DLA) dimensions of the LV. Inflatable hydraulic occluder cuffs were placed around the inferior and superior venae cavae to alter loading conditions. The tubes and wires were tunneled subcutaneously to the base of the neck and then exteriorized. The thoracotomy was closed, and the animals were allowed to recover for 1-Z wk. Data collection. Studies were performed with the dogs conscious, lying quietly on their right side in a sling. The LV catheter was connected to a Statham P23 DB pressure transducer calibrated with a mercury manometer, using the vertebral column as the zero reference point. The LV pressure signal from the micromanometer was adjusted to match the fluid-filled catheter. The transit
0 1991 the American
Physiological
Society
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LV-ARTERIAL
time of 5 MHz sound between the crystal pairs was determined and converted to distance, assuming a constant velocity of sound in blood of 1.55 m/ms (Triton Technology, San Diego, CA). The analog signals were digitized using an on-line analog-to-digital converter at 5ms intervals (200 Hz) using a computer system (IBM-AT) and software that we have developed and validated. The LV volume (V) was calculated from the three LV dimensions (&P, DsL, &A) using the formula V = (r/6)
l
DAp DsL DLA l
l
This is the same method we have previously described and validated in our laboratory (6, 15, 18, 19, 28). Generation of PV relation. Our studies required the evaluation of a large range of LV pressures and volumes to determine the PEs-VEs relation. This evaluation was accomplished by the transient occlusion of the inferior and superior venae cavae using the implanted hydraulic occluder cuffs. Only caval occlusions that produced at least a 30 mmHg fall in LV systolic pressure and did not produce ventricular extrasystoles were accepted for analysis. To avoid the possible influence of global LV ischemia, data were not analyzed with a LV PEs of ~40 mmHg. Protocol. The animals were studied following full recovery from the surgery (7-10 days after instrumentation). Measurements were made both under resting conditions with intact reflexes and also after autonomic blockade. First, steady-state measurements were recorded before any medications were administered, and then three transient (12 s) vena caval occlusions were performed. Autonomic blockade was then produced by administering hexamethonium (5 mg/kg iv) and atropine (0.2 mg/kg iv) to prevent reflex changes in LV contractility as arterial pressure was altered. The steady-state measurements and caval occlusions were repeated. Phenylephrine was then infused at a rate sufficient to increase mean aortic pressure by 20-25 mmHg. The steady-state measurements and caval occlusions were repeated. Phenylephrine was then infused to increase the mean aortic pressure by 40-50 mmHg and subsequently 60-70 mmHg over control, and the measurements and vena caval occlusions were repeated at each level of phenylephrine infusion. The phenylephrine was discontinued and 20 min were allowed for reequilibration. Additional atropine (0.5 mg) was administered. Nitroprusside, sufficient to decrease the baseline aortic pressure by 20-25 mmHg, was then given. The steady-state measurements and the vena caval occlusions were repeated. The protocol was repeated on a separate day after inotropic state, and EEs was increased by a continuous infusion of dobutamine (6-8 mg kg-‘. min-I). Data analysis. The 12-s recordings during the steadystate periods with each intervention were used to generate an average beat by aligning each beat in end diastole using software developed in our laboratory. For each condition, the EA was determined as PEs/SV. End diastole was defined as the peak of the R wave of electrocardiographic lead II. End systole was defined as the upper left-hand corner of the LV PV loop, identified using the iterative method described by Kono et al. (13). SW was l
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calculated as the integral (PdV) of each beat’s PV loop. The data from the caval occlusions were fit to the following equation P ES = EES'[VES - VO] (1) using least-squares technique. Since V0 is an extrapolated value (11, 16, 17), we quantitated the position of the PEsVEs relation by calculating the volume (V& associated with a PEs of 100 mmHg V 100 = VO + lOO/EES (2) We have previously evaluated this method of quantitating the position of the P ES’VES relation (15). we quantitated the dependence of SW on VEn by fitting the data to SW = M[VEn - Vi] (3) where M is the slope of the SW-VEn relation, and Vi is the volume axis intercept (9). Although the theoretical consideration of LV-arterial coupling predicts a more complex, nonlinear relation of SW and VEn (see Eq. 6 below), the linear relation provides a reasonable approximation of the response of SW to VEn under most physiological conditions (9,16). We used the VEn-SW relation to compare the SW produced at constant VEn under the various experimental conditions. The comparison was made at a VEn that was in the middle of the range of steady-state V En occurring during the interventions. We calculated the total PVA as defined by Suga et al. (29). The SW was calculated as the integral of the PV loop. The remaining PVA (potential work PVA) was calculated as potential work PVA = PEs* [VEs - Vo]/2 (4) The total PVA was calculated as PVA = SW + potential work PVA (5) The conversion of PVA to SW was calculated as SW/ PVA (24). To correct for the effect of changes in VED, SW/PVA were compared at constant VED for each intervention using the same strategy as for SW. The coupling of the LV and arterial system was quantitated as E&E*. We chose to use this ratio, since the theoretical analysis proposed by Sunagawa et al. (33-35) and Burkhoff and Sagawa (3) predicts that at constant EES and VED, SW, and SW/PVA are determined by this ratio. We compared our results to the predictions of this model. As derived by Burkhoff and Sagawa (3) SW = EEs(VED - VO)"*(EA/EES)/(l + EA/EEd2 (6) Since, according to this model, SW is maximal when EA = EES, normalized SW (SW,) (SW/maximum SW) at constant VED and EES can be predicted as SW, = 4*(EA/EES)/(1 + &I/EEd2 (7) Similarly, from the work of Burkhoff and Sagawa (3), PVA is predicted to be PVA = EEs(VED - Vo)2
l [(&/EES)/(1
+
&4/EEd2]
l [I
(8) +
WAIEES)I~I
Thus SW/PVA
= l/( 1 + o.h!?~/&s)
(9)
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Our data were grouped by &S/E* ratios, and the SW, and SW/PVA at each E&E* were compared with the predictions of the P-V model. Statistical methods. We summarized the data as means t SD. Comparisons were performed by analysis of variance. If a significant effect was present, intergroup comparisons were performed using the Student-NewmanKeuls test or paired Bonferroni t tests (8). RESULTS
The data before and after autonomic blockade are shown in Table 1. An example of variably loaded PV loops acquired before autonomic blockade and the resulting PES-Vb:s relation and the steady-state PV loop are shown in Fig. 1. For the group, before autonomic blockade, EES (7.2 t 2.7 mmHg/ml) and EA (6.9 t 3.1 mmHg/ml) were nearly equal. After autonomic blockade, EES increased in response to dobutamine and was not significantly altered by the infusion of phenylephrine or nitroprusside (both before and after dobutamine). During phenylephrine infusion, V,0,1tended to decrease, indicating a leftward shift of the PES-VESrelation. This change reached statistical significance at the highest dose of phenylephrine both before and after dobutamine. In response to vasodilation with nitroprusside, V 100tended to increase, indicating an opposite rightward shift. As expected, EA increased in response to phenylephrine and was decreased by nitroprusside. This resulted in a range of mean E&E* from 1.93 t 0.40 (d ob ut amine and nitroprusside) to 0.43 t 0.06 (high-dose phenylephrine). Individual values of E& EA ranged from 0.18 to 2.59. Figure 2 shows the relations between SW and VED, while loading conditions were altered. While inotropic state was held constant, the SW-VEII relation was shifted progressively toward the right (i.e., smaller SW at conTABLE
DISCUSSION
In this study, we examined the criteria for the coupling of the LV and arterial system of the conscious dog to maximize SW and SW/PVA. It is important to recognize that SW is strongly influenced by both LV VED and the contractile state. This can be quantitated as the SW-VED relation (9, 16, 21). In our study, we compared SW at constant V ED, while contractile state was held constant. We found that SW is maximized when the LV EES and EA are equal (i.e., E&E* = 1). However, there is a broad plateau to the relation of SW to E&E*. SW was within 95% of its maximum value when E&E* was between 0.74 and 1.20. When EES further exceeded EA, the SW remained high, still being approximately 83% of its maximum with an E&E* equal to 2.2. Only when EA markedly exceeded EES (i.e., E&E* < 0.56) was SW substan-
1. Data before and after blockade
Unblocked Blocked Phenyl
stant VED) as E&E* deviated from 1.0. The relation of SW (at constant V& to E&E* is shown in Fig. 3, and the relation of SW/PVA to E&E* is shown in Fig. 4. The maximum SW at constant VED occurred at E&E* of 0.99 t 0.15. This is similar to the E&E* of 0.96 t 0.20 (P = NS) observed in the absence of autonomic blockade. There was a broad plateau to the relation between SW and V ED. For example, SW was within 5% of its maximum value (i.e., normalized SW > 0.95) when E&E* was between 0.74 and 1.20 and was within 20% of its maximum value when E&E* was ~0.56. SW declined rapidly when E&E* was reduced to lower values. In contrast to the relation of SW to E&E*, SW/ PVA increased steadily over the range of E&E* studied (0.18-2.59). The responses of SW and SW/PVA to varying E&E* are similar in shape to that predicted by Sunagawa et al. (34) and Burkhoff and Sagawa (3) (Fig. 4). However, SW and SW/PVA were consistently less than predicted.
1
Pheny12 Pheny13 NTP Dobutamine Dob + Phenyl Dob + Pheny12 Dob + Pheny13 Dob + NTP
1
Heart Rate, beats/min
PEI,, mmHg
P ES, mmHg
V ED, ml
111* t16 148 +18 135 +7 1:3* +10 137 +17 145 +12 145 +24 140 +36 744 -+33 143 +33 742 +14
6.2 k5.1 9.7 +6.5 16.5 k9.1 20.5” +6.7 ;2.6* +8.3 -6.0 +4.2 -8.4
126 t8 117 AI9 140* t8 165* k9 177* +31 -94* k12 143* +23 151t t22 17ot k16 184t t29 941 +18
55.4 t16.0 49.3 k22.1 54.9* k20.5 58.2* 222.2 58.4* t20.2 41.9* t18.0 49.5 t19.0 51.0 219.0 53.8 k22.4 55.5 t22.8 43.6 k18.2
+8.5 11.1 k6.8 18.2t +7.8
i3.74 k9.7 5.2 -+8.1
V KS, ml 36.2 t12.7 35.9 t18.9 41.1” k17.3 45.6* t19.6 45.6* t15.3 31.4 t14.8 34.0 t16.6 35.8 k14.9 37.8 t17.8 39.8 t16.5 31.3 t14.0
Data are means t SD of 8 animals. Blocked, after administration progressively increasing doses); NTP, nitroprusside; Dob, dobutamine. vs. dobutamine.
sv, ml 19.2* k5.9 13.4 +4.9 13.8 +3.3 12.5 +4.1 12.8 +5.1 13.4 +7.5 17.4* 25.0 16.2 k6.2 15.8 +4.8 16.8 k9.3 14.2 k6.4
E ES, mmHg/ml 7.2 +2.7 -9.0 +4.3 -7.5 t3.8 6.9 +3.8 -6.8 22.9 10.7 k5.0 13.1* k7.2 11.0 +4.8 il.7 26.0 10.5 t5.6 15.0 k8.8
of hexamethonium Other abbreviations
V 10th ml
mmHg/ml
33.6 k10.8 34.2 +16.1 -34.5 k15.4 33.2 t14.3 32.3* t13.7 35.5 t17.6 31.0* t15.7 30.7 t15.6 29.ot k14.5 29.ot t15.7 34.8 t14.7
6.9* t3.1 10.5 +6.2 10.7* t3.0 14.4* t4.6 16.7” t9.0 8.5* t3.6 8.8 +3.0 I1.2t t6.6 12.ot +4.8 14.2t t7.8 8.2 t4.9
and atropine; are defined
EA,
phenyl, in text.
VI, J%s/EA
0.96 to.20 0.91 to.32 0.61” to.17 0.48* to.20 0.43” to.06 1.27” to.36 1.33* kO.57 1.04 to.41 0.89 t to.27 0.76t kO.28 1.93t kO.40 *
M’ mmHg
ml
84.6 k7.2 82.0 k16.1 77.0 k11.4 75.0 k19.4 61.9* t11.9 71.7* t18.8 106.0* t25.6 102.3 k34.6 104.8 231.5 105.8 t34.5 94.4t t24.5
31.8 klO.6 30.4 k14.9 30.6 t12.5 30.4 t11.6 29.8 t13.3 31.6 t15.4 28.6 k15.2 30.2 k15.3 27.2 k14.5 28.1 t15.0 33.0 k13.5
phenylephrine (1, 2, 3, indicates P < 0.05 vs. blocked; t P < 0.05
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sures (4,10,17). However, over a 30- to 60-mmHg range, as evaluated in this study, the PEs-VEs relation is closely approximated by a straight line (17). The theoretical -120 analysis assumed that the LV PEs-VEs relation is independent of the mode of ejection. In contrast, we found I” 100 E that arterial vasoconstriction tended to shift the PEs-VEs E 60 relation to the left (decreased VloO), whereas vasodilation i! tended to shift the PEs-VEs relation toward the right 3 60 co (increased V&. This is consistent with previous obserxi 40 vations in isolated dog hearts (20) and intact animals (7, k 2 20 14,28). However, despite marked changes in the arterial system, the slope of the PES-VESrelation is relatively unchanged. The afterload-dependent shifts of the PEsVEs relation help preserve SW as EA increases (5). In addition, the theoretical analysis of Sunagawa et al. (34) LV Volume (ml) and Burkhoff and Sagawa (3) assumed that mean ejection pressure was closely approximated by PEs, and diaB160 stolic LV pressures were zero. Despite some inaccuracy *\\\ in these simplifying assumptions, we found that the \ 140 shape of the SW-E&E* relation (Fig. 3), as directly EEs/EA=I -08 determined in the intact cardiovascular system of conscious animals, was very similar to the model’s predic\\ \\\ tion. However, the SW at each E&E* was consistently \\\ \\ less than predicted by the theoretical PV analysis. This \\\ \\\ lower than predicted SW may at least partially be due to \\\ the nonzero diastolic pressures and deviation of mean \\\ \\ ejection pressure from PEs. With this quantitatively \\\ \\ small exception, our results are consistent with the pre\\ dictions of the PV analysis and suggest it provides an \\ accurate approximation of LV-arterial coupling in conscious animals. 0 10 20 30 40 50 60 The coupling of the LV and arterial system also influences the determinants of myocardial oxygen demand LV Volume (ml) (MOON). Suga and colleagues (29, 30, 31) have demonL I I I I 1 50 40 30 20 10 0 strated that MOON, at constant contractile state, is linearly related to the total LV pressure-volume area. SW/ Stroke Volume (ml) PVA indicates how much of the PVA produces useful FIG. 1. A: variably loaded left ventricular (LV) pressure-volume work. If the contractile state is unchanged, and thus the loops produced by transient caval occlusion in a conscious dog at rest in absence of autonomic blockade. Top left-hand corner of loops MVO~-PVA relation is constant, an increase in SW/PVA indicates LV end-systolic pressure-volume relation. B: steady-state LV indicates that the ratio of SW to MVO~ will be higher. pressure-volume loop is superimposed on end-systolic pressure-volume Thus more of the MVO~ will be utilized to generate useful line from A. Arterial end-systolic pressure-stroke volume relation is external work or SW. We found that as E&E* increased, shown in dotted line. End-systolic point of pressure-volume loop occurs SW/PVA increased over the entire range of E&E* that at intersection of LV and arterial end-systolic lines. In this animal, at rest with intact reflexes, LV end-systolic elastance (&s) and arterial we studied. This is in agreement with the observations elastance (EA) are almost equal. of Nozawa and Suga (24) in anesthetized dogs. The relation we observed between SW/PVA and E&E* is tially (~20%) reduced. Our data indicate the cardiovassimilar, although slightly and consistently lower than cular system of the resting, conscious dog with intact predicted from the analysis of Burkhoff and Sagawa (3). autonomic reflexes operates near the center of the pla- Again, this is probably a consequence of their assumption teau with nearly equal E Es and EA. Thus, during most that the LV end-diastolic P was negligible, and the physiological perturbations in EES and EA, it appears ejection portion of the PV loop is flat. These findings that the LV would still operate on the plateau of the indicate that the EA that produces maximal SW at a SW-E&E* relation, where the LV and arterial system given EES is higher than the EA that results in maximum interact to produce nearly maximal SW. transformation of PVA to SW. Burkhoff and Sagawa (3) The relation between SW and E&E* that we observed also predicted the efficiency of the LV (MVOJPVA). is similar to that predicted by Sunagawa et al. (34) and When they plotted efficiency vs. EA, efficiency rose to a maximum at a point where EA was less than EES and Burkhoff and Sagawa (3). They modeled LV arterial coupling in the PV plane, using linear PEs-VEs and PEs- then declined. Since we did not measure Mi’02 in our SV relations to describe the LV and the arterial system. study, we cannot evaluate this prediction. We found that in conscious animals with intact reTheir analysis includes several assumptions that are not completely correct. For example, the PEs-VEs relation is flexes, the LV and arterial system operated in the range not perfectly linear, instead it is concave toward the that maximizes SW. Several other observations also volume axis when evaluated over a wide range of pres- suggest that at rest the LV and arterial system may I
I
L
1
1
I
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B
2500
2000
2500
2000
1500
1500
SW mmHg-ml
SW
mmHg-ml loo0
1000 Ees/Ea=0.8
500
0 40
50
60
70
80
60
Ved (ml)
C
80
Ved (ml)
2500
D
2500
2000
1500
1500
SW mmHg-ml
SW
mmHg-ml 1000
1000
500
500
0
0 40
50
60
70
80
40
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Ved (ml)
E
2500
2000
FIG. 2. Left ventricular stroke work (SW)-end-diastolic volume (V& relation determined by transient caval occlusion in a conscious dog after autonomic blockade. Ratio of slopes of LV end-systolic pressure-volume relation and arterial end-systolic pressure-stroke volume relation (&s/&J was close to 1.0. SW-VED relations, produced after incremental doses of phenylephrine (23, C, and D) and nitroprusside (E), are compared with control SW-VEh relation. As E&EA is progressively decreased (B, C, and D), SW-VED relation is progressively shifted toward the right so that a smaller SW is associated with each V ED.Similarly, as E&E* is increased (E), SW-VED is also shifted toward the right.
1500 SW
mmHg-ml 1000
500
0
t 1: 40
60
70
80
Ved (ml)
operate close to the point that results in maximal SW (23,26,36-39). For example, Wilcken et al. (39) observed that LV SW in conscious dogs fell following a sudden, marked increase or decrease in aortic impedance. Similarly, van den Horn et al. (37) found that maximum mean stroke power of ventricles of anesthetized cats occurred when loaded with “normal” arterial impedances. In contrast, Piene and Sund (26) found in the cat right ventricle that maximum pump efficiency, not SW, occurred with a normal pulmonary artery impedance. However, Myhre et al. (23) observed that anesthetized openchest dogs operated close to the point of maximum SW, not mechanical efficiency. Similarly, Toorop et al. (36) found in anesthetized open-chest cats that the physio-
logical load on the heart produced maximal SW. Thus it appears that the LV and arterial system are coupled so that SW is maximized in both anesthetized preparations and conscious animals. This is probably due to the plateau of the SW-&s/EA relation, in which SW is near maximal over a broad range of &s/EA. Asanoi et al. (1) recently reported that &s/EA was approximately two in normal human subjects. This is a higher value than we observed in instrumented animals with intact reflexes but still in the range in which SW is near maximum. The differences in our results may, at least partially, be due to the different method employed by Asanoi et al. to determine &s. They assess LV endsystolic volume with M mode echocardiography and used
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LV-ARTERIAL 1.1
1 Predicted
0.8-
0.3
1 1
0.2
0.6
1.0
1.4 EEsE
1.8
2.2
2.6
A
at constant end-diastolic 3. Plot of stroke work (S W) occurring SW produced at each contractile state volume normalized by maximum and vs. ratio (EEs/EA) of slopes of LV end-systolic pressure-volume SW arterial end-systolic pressure-stroke volume relation. Maximum by theoretical model proposed occurs when E&EA = 1. SW predicted by Sunagawa et al. (3, 4) and Burkhoff and Sagawa (7) is also shown. Data are shown as group means & SE. FIG.
0.2
0.6
1.o
1.4
1.8
2.2
2.6
EESE A to format of Fig. 3, ratio of LV stroke work (SW) to total pressure-volume area (PVA) is shown as a function of E&E*. SW/PVA increases as EEs/EA increases. Line shows predictions of theoretical model. FIG.
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4. Similar
the dicrotic notch of the brachial arterial pressure as an approximation of LV PEs. Graded infusions of phenylephrine and nitroprusside were used to generate a variety of points. These interventions may both shift the PEsVEs relation (7,14,20) and also alter the relation between dichrotic notch arterial pressure and PEs (32). Connecting points generated in this manner result in a steeper PEs-VEsrelation (7,20) than produced by caval occlusion,
as utilized in our study. In addition, the instrumentation used in our study may have resulted in some depression of &s. These factors may partially explain the higher value for &s/& observed by Asanoi et al. (1) in patients than observed in unblocked conscious dogs in our study. The description of the arterial system by EA ignores the contribution of the higher frequency components of arterial impedance to LV-arterial coupling. Under normal circumstances, these components of arterial impedance account for only about 10% of the energy loss; however, their importance may be increased with slower heart rates, increased vascular tone, or other conditions (25). Our results and the observations of Sunagawa et al. (34) in isolated hearts suggest that, under most circumstances, considering the arterial system in terms of EA provides a framework for understanding LV-arterial coupling. Analysis of the dynamic coupling throughout the period of LV ejection will require consideration of the higher frequency components of arterial impedance. Our methods of varying EES and EA should be considered. We held contractile state constant by autonomically blocking the animals while varying EA by infusing vasoconstrictors or vasodilators. Then contractile state was augmented by infusing dobutamine at a constant rate while EA was again altered. While at constant inotropic state, E Es did not significantly vary. We used phenylephrine to increase EA, which may augment contractile state (2). However, this effect is probably minimal in the dog (22, 27), and we observed no increase in EES to indicate an increase in contractile state. Our observations may have clinical implications. In the normal operating range, SW is insensitive to changes in EA. This is reflected in insensitivity of the SW-VEn relation to afterload changes in the physiological range (9, 12, 16). This is not the case when EA greatly exceeds EES, as may occur in many patients with heart failure in whom EES is reduced and EA increased. In this situation, SW is very sensitive to changes in EA, and both SW and SW/PVA would be improved by a reduction in EA, as would be produced by a vasodilator. In conclusion, this study indicates that LV SW is maximal when EES and EA are equal (i.e., E&E* = 1). The conversion of PVA to SW (SW/PVA) increases as E&E* increases. There is a broad range of E&E* over which SW is only minimally reduced from its maximal level. The arterial system and LV of the intact conscious dog, with intact reflexes, operates in this range where SW is maximized. Only when EA greatly exceeds EES does SW fall substantially. We are grateful for Mary Ann Hayner’s expert secretarial assistance, the technical assistance of Todd A. Hall, Donald C. Bengtson, and Robert Rhode, and to Drs. Sidney Klopfenstein and Yuichiro Igarashi for review of the manuscript and suggestions. This study was supported in part by National Heart, Lung, and Blood Institute Grants HL-37324 and HL-42364 and a grant-in-aid from the American Heart Association. W. C. Little is an Established Investigator of the American Heart Association. Address for reprint requests: W. C. Little, Section of Cardiology, Bowman Gray School of Medicine, 300 South Hawthorne Rd., Winston-Salem, NC 27103. Received
7 December
1990; accepted
in final
form
12 March
1991.
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H76
LV-ARTERIAL
COUPLING 20. MAUGHAN,
REFERENCES
H., S. SASAYAMA, AND T. KAMEYAMA. Ventriculoarterial coupling in normal and failing heart in humans. Circ. Res. 65: 483-
1. ASANOI,
493,1989. 2. BRUCKNER, R., W. MEYER, A. MUGGE, W. SCHMITZ, SCHOLZ. Alpha-adrenoceptor-mediated positive inotropic
phenylephrine
AND H.
effect of in isolated human ventricular myocardium. Eur. J.
Pharmacol. 3. BURKHOFF,
99: 345-347, 1984. D., AND K. SAGAWA. Ventricular efficiency predicted by an analytical model. Am. J. Physiol. 250 (Regulatory Integrative Comp. Physiol. 19): R1021-R1027, 1986. 4. BURKHOFF, D., S. SUGIURA, D. T. YUE, AND K. SAGAWA. Contrac-
tility-dependent curvilinearity of end-systolic pressure-volume relations. Am. J. Physiol. 252 (Heart Circ. Physiol. 21): H1218H1227,1987. 5. FREEMAN, G. Effects of increased afterload on left ventricular function in closed-chest dogs. Am. J. Physiol. 259 (Heart Circ. Physiol. 28): H619-H625, 1990. 6. FREEMAN, G. L., W. C. LITTLE, AND R. A. O’ROURKE. Influence of heart rate of the left ventricular performance in conscious dogs. Circ. Res. 61: 455-464, 7. FREEMAN, G. L., W.
1987.
C. LITTLE, AND R. A. O’ROURKE. Effect of vasoactive agents on the left ventricular end-systolic pressurevolume relation in closed-chest dogs. Circulation 74: 1107-l 113, 1986. 8. GLANTZ, S. A. Primer of Biostatistics. New York: McGraw-Hill, 1981. 9. GLOWER, D. D., J. A. SPRATT, N. D. SNOW, J. S. KABAS, J. W. DAVIS, C. 0. OLSEN, G. S. TYSON, D. C. SABISTON, AND J. S. RANKIN. Linearity of the Frank-Starling relationship in the intact heart: the concept of preload recruitable stroke work. Circulation 71: 994-1009, 1985. 10. KASS, D. A., R. BEYAR, E. LANKFORD, MAUGHAN, AND K. SAGAWA. Influence
curvilinearity
M.
HEARD,
W.
L.
of contractile state on of in situ end-systolic pressure-volume relations.
Circulation 79: 167-178, 1989. 11. KASS, D. A., AND W. L. MAUGHAN. From “Emax” to pressurevolume relations: a broader view. Circulation 77: 1203-1212, 1988. 12. KASS, D. A., W. L. MAUGHAN, Z. M. Guo, A. KONO, K. SUNAGAWA, AND K. SAGAWA. Comparative influence of load versus
inotropic states on indexes of ventricular contractility: experimental and theoretical analysis based on pressure-volume relationships. Circulation 76: 1428-1436, 1987. 13. KONO, A., W. L. MAUGHAN, K. SUNAGAWA, C. KALLMAN, K. SAGAWA, AND M. L. WEISFELDT. Left ventricular end-ejection
14. 15.
16.
17.
18.
19.
pressure and peak pressure to estimate the end-systolic pressurevolume relationship. Circulation 70: 1057-1065, 1984. LITTLE, W. C. The left ventricular dP/dt,,,-end-diastolic volume relation in closed-chest dogs. Circ. Res. 56: 808-815, 1985. LITTLE, W. C., F. R. BADKE, AND R. A. O’ROURKE. Effect of right ventricular pressure on the end-diastolic left ventricular pressurevolume relationship before and after chronic right ventricular overload. Circ. Res. 54: 719-730, 1984. LITTLE, W. C., C. P. CHENG, M. MUMMA, Y. IGARASHI, J. VINTENJOHANSEN, AND W. E. JOHNSTON. Comparison of measures of left ventricular contractile performance derived from pressure-volume loops in conscious dogs. Circulation 80: 1378-1387, 1989. LITTLE, W. C., C. P. CHENG, T. PETERSON, AND J. VINTENJOHANSEN. Response of the left ventricular end-systolic pressurevolume relation in conscious dogs to a wide range of contractile states. Circulation 78: 736-745, 1988. LITTLE, W. C., R. C. PARK, AND G. L. FREEMAN. Effect of alterations on the left ventricular activation sequence on left ventricular systolic performance. In: Activation, Metabolism and Perfusion of the Heart: Simulation and Experimental Models, edited by S. Sideman, and R. Beyar. The Hague: Nijhoff, 1987. LITTLE, W. C., AND R. A. O’ROURKE. Effect of regional ischemia on the left ventricular end-systolic pressure-volume relationship in chronically instrumented dogs. J. Am. Coil. Cardiol. 5: 297-302, 1985.
W. L., K. SUNAGAWA,
D. BURKHOFF,
AND K. SAGAWA.
Effect of arterial impedance changes on the end-systolic pressurevolume relation. Circ. Res. 54: 595-602, 1984. 21. MISBACH, G. A., AND S. A. GLANTZ. Changes in the diastolic pressure-diameter relation alter ventricular function curves. Am. J. Physiol. 237 (Heart Circ. Physiol. 6): H644-H648, 1979. 22. MUKHERJEE, A., Z. HAGHANI, J. BRADY, L. BUSH, W. MCBRIDE, L. M. BUJA, AND J. T. WILLERSON. Differences in myocardial
alpha- and beta-adrenergic
receptor numbers in different species.
Am. J. Physiol. 245 (Heart Circ. Physiol. 14): H957-H961, 1983. 23. MYHRE, E. S. P., A. JOHANSEN, J. BJORNSTAD, AND H. PIENE.
The effect of contractility and preload on matching between the canine left ventricle and afterload. Circulation 73: 161-171, 1986. 24. NOZAWA, T., Y. YASUMURA, AND H. SUGA. Efficiency of
S.FUTAKI,
N. TANAKA,
M. UENISHI,
energy transfer from pressure-volume area to external mechanical work increases with contractile state and decreases with afterload in the left ventricle of the anesthetized closed-chest dog. Circulation 77: 1116-l 124, 1988. 25. O’ROURKE, M. F. Steady and pulsatile energy losses in the systemic circulation under normal conditions and in simulated arterial disease. Cardiovasc. Res. 1: 313-326, 1967. 26. PIENE, H., AND T. SUND. Does normal pulmonary impedance constitute the optimum load for the right ventricle? Am. J. Physiol. 242 (Heart Circ. Physiol. 11): H154-H160, 1982. 27. SEITELBERGER, R., B. D. GUTH, J. D. LEE, K. KATAYAMA, G. HEUSCH, AND J. ROSS, JR. Alpha 1 and alpha 2 receptor stimula-
tion in conscious dogs increase coronary resistance but not myocardial function (Abstract). J. Am. Coil. Cardiol. 7, Suppl. A: 8lA, 1986. SODUMS, AND R.
M. T.,
R. F. BADKE,
M. R. STARLING,
W. C. LITTLE,
A. O’ROURKE. Evaluation of left ventricular contractile performance utilizing end-systolic pressure-volume relationships in conscious dogs. Circ. Res. 54: 731-739, 1984. 29. SUGA, H., T. HAYASHI, AND M. SHIRAHATA. Ventricular systolic pressure-volume area as predictor of cardiac oxygen consumption. Am. J. Physiol. 240 (Heart Circ. Physiol. 9): H39-H44, 1981. 30. SUGA, H., T. HAYASHI, S. SUEHIRO, R. HISANO, M. SHIRAHATA, AND I. NINOMIYA. Equal oxygen consumption rates of isovolumic
and ejecting contractions with equal systolic pressure-volume areas in canine left ventricle. Circ. Res. 49: 1082-1091, 1981. 31. SUGA, H., R. HISANO, Y. GOTO, 0. YAMADA, AND Y. IGARASHI. Effect of positive inotropic agents on the relation between oxygen consumption and systolic pressure-volume area in canine left ventricle. Circ. Res. 53: 306-318, 1983. 32. SUGA, H., AND N. NISHIURA. Dissociation of end-ejection from end-systole of ventricle. Jpn. Heart J. 22: 117, 1981. 33. SUNAGAWA, K., W. L. MAUGHAN, D. BURKHOFF, AND K. SAGAWA. Left ventricular interaction with arterial load studied in isolated canine ventricle. Am. J. Physiol. 245 (Heart Circ. Physiol. 14): H773-H780,1983. 34. SUNAGAWA,
K., W. L. MAUGHAN, AND K. SAGAWA. Optimal arterial resistance for the maximal stroke work studied in isolated canine left ventricle. Circ. Res. 56: 586-595, 1985. 35. SUNAGAWA, K., W. L. MAUGHAN, AND K. SAGAWA. Stroke volume effect of changing arterial input impedance over selected frequency ranges. Am. J. Physiol. 248 (Heart Circ. Physiol. 17): H477-H484, 1985. 36. TOOROP, G. P., G. J. VAN DEN HORN, WESTERHOF. Matching between feline left
G.
ELZINGA,
AND
N.
ventricle and arterial
load: optimal external power or efficiency. Am. J. Physiol. 254 (Heart Circ. Physiol. 23): H279-H285, 1988. 37. VAN DEN HORN, G. J., N. WESTERHOF, AND G. ELZINGA. Interaction of heart and arterial system. Ann. Biomed. Engr. 12: l51162,1984. 38. VAN DEN HORN,
G. J., N. WESTERHOF, AND G. ELZINGA. Optimal power generation by the left ventricle: a study in the anesthetized open thorax cat. Circ. Res. 56: 252-261, 1985. D. E. L., A. A. CHARLIER, J. I. E. HOFFMAN, AND A. 39. WILCKEN, GUZ. Effects of alterations in aortic impedance on the performance of the ventricles. Circ. Res. 14: 283-293, 1964.
Downloaded from www.physiology.org/journal/ajpheart by ${individualUser.givenNames} ${individualUser.surname} (130.056.064.029) on December 13, 2018.
coupling
in conscious dogs
WILLIAM C. LITTLE AND CHE-PING CHENG Section of Cardiology, Department of Medicine, Bowman Gray School of Medicine, Wake Forest University, Winston-Salem, North Carolina 27103
LITTLE, WILLIAM C., AND CHE-PING CHENG. Left uentricular-arterial coupling in conscious dogs. Am. J. Physiol. 261 (Heart Circ. Physiol. 30): H70-H76, 1991.-We investigated the criteria for the coupling of the left ventricle (LV) and the arterial system to maximize LV stroke work (SW) and the transformation of LV pressure-volume area (PVA) to SW. We studied eight conscious dogs that were instrumented to measure LV pressure and determine LV volume from three ultrasonically determined dimensions. The LV end-systolic pressure (P&-volume (V& relation was determined by caval occlusion. Its slope (EES) was compared with the arterial elastance ( EA) and determined as PEs per stroke volume. At rest, with intact reflexes, EES/EA was 0.96 k 0.20. EEs/EA was varied over a wide range (0X-2.59) by the infusion of graded doses of phenylephrine and nitroprusside before and during administration of dobutamine. Maximum LV SW, at constant inotropic state and end-diastolic volume (V&, occurred when E&E* equaled 0.99 t 0.15. At constant V EI1 and contractile state, SW was within 20% of its maximum value when EES/EA was between 0.56 and 2.29. The conversion of LV PVA to SW increased as EES/EA increased. The shape of the observed relations of the SW to EEs/EA and SW/PVA to E&E A was similar to that predicted by the theoretical consideration of LV PEs-VEs and arterial PEs-stroke volume relations. We conclude that the LV and arterial system produce maximum SW at constant VEI) when EES and EA are equal; however, the relation of SW to EEs/EA has a broad plateau. Only when EA greatly exceeds EES does the SW fall substantially. However, the conversion of PVA to SW increases as EES/EA increases. These observations support the utility of analyzing LV-arterial coupling in the pressurevolume plane.
PV loop is assumed to be flat and the end-diastolic pressure is negligible, this analysis predicts that the stroke work (SW) (or the area of the PV loop) should be maximized when EA = EES (3, 34). Data obtained from the isolated canine LV ejecting into a windkessel model of the arterial system were consistent with these predictions (34). However, this concept has not been evaluated in the intact cardiovascular system. Sunagawa et al. (34) recognized the difficulty in directly extrapolating their results in isolated hearts to the intact cardiovascular system and stated: “Any hypothesis concerning physiological matching of cardiac performance with arterial load must eventually be tested and validated in an intact animal under various physiologic conditions.” The function of the cardiovascular system is to provide for the perfusion of the tissues. This requires that the LV produce both flow (stroke volume) and perfusion pressure (arterial pressure). The LV SW integrates both these parameters; thus, it provides a simple means of quantitating the performance of the cardiovascular system (34). The interaction of the LV and the arterial system, in addition to determining SW, also importantly influences. the determinants of myocardial oxygen demand (MVo2) (3). Accordingly, this study was undertaken to evaluate, in conscious animals, the effect of alterations of the coupling between the LV and arterial system on LV SW and pressure-volume area (PVA).
stroke work; pressure-volume
Instrumentation. Eight healthy mongrel dogs (28.1 t 1.5 kg body wt) were instrumented as we have previously described (15). A micromanometer pressure transducer
area; elastance
of the cardiovascular system depends on the interaction of its components. The left ventricle (LV) pumps the stroke volume into the arterial system that delivers the flow to the tissues. Thus optimal cardiovascular function requires appropriate coupling of the LV and arterial system. Functional analysis of this interaction requires that the LV and arterial system be described in similar terms. Sunagawa et al. (33-35), and Burkhoff and Sagawa (3) proposed that LV-arterial coupling be analyzed in the pressure-volume (PV) plane. They suggested that the intersection of the LV end-systolic pressure (PEs)-volume (V,s) relation and the arterial PEs-stroke volume relation would predict the stroke volume. The slope of the PEs-VEs relation is the end-systolic elastance (&s) of the LV, whereas the slope of the arterial PEs-stroke volume relation represents the effective arterial endsystolic elastance (EJ. If the ejection portion of the LV THE PERFORMANCE
H70
0363-6135/91
$1.50 Copyright
METHODS
and a polyvinyl catheter for transducer calibration were inserted through a LV apical stab wound. Three pairs of ultrasonic crystals (5 MHz) were implanted in the endocardium of the LV to measure the anterior-posterior (DA& septal-lateral (DSL), and long-axis (base-apex) (DLA) dimensions of the LV. Inflatable hydraulic occluder cuffs were placed around the inferior and superior venae cavae to alter loading conditions. The tubes and wires were tunneled subcutaneously to the base of the neck and then exteriorized. The thoracotomy was closed, and the animals were allowed to recover for 1-Z wk. Data collection. Studies were performed with the dogs conscious, lying quietly on their right side in a sling. The LV catheter was connected to a Statham P23 DB pressure transducer calibrated with a mercury manometer, using the vertebral column as the zero reference point. The LV pressure signal from the micromanometer was adjusted to match the fluid-filled catheter. The transit
0 1991 the American
Physiological
Society
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LV-ARTERIAL
time of 5 MHz sound between the crystal pairs was determined and converted to distance, assuming a constant velocity of sound in blood of 1.55 m/ms (Triton Technology, San Diego, CA). The analog signals were digitized using an on-line analog-to-digital converter at 5ms intervals (200 Hz) using a computer system (IBM-AT) and software that we have developed and validated. The LV volume (V) was calculated from the three LV dimensions (&P, DsL, &A) using the formula V = (r/6)
l
DAp DsL DLA l
l
This is the same method we have previously described and validated in our laboratory (6, 15, 18, 19, 28). Generation of PV relation. Our studies required the evaluation of a large range of LV pressures and volumes to determine the PEs-VEs relation. This evaluation was accomplished by the transient occlusion of the inferior and superior venae cavae using the implanted hydraulic occluder cuffs. Only caval occlusions that produced at least a 30 mmHg fall in LV systolic pressure and did not produce ventricular extrasystoles were accepted for analysis. To avoid the possible influence of global LV ischemia, data were not analyzed with a LV PEs of ~40 mmHg. Protocol. The animals were studied following full recovery from the surgery (7-10 days after instrumentation). Measurements were made both under resting conditions with intact reflexes and also after autonomic blockade. First, steady-state measurements were recorded before any medications were administered, and then three transient (12 s) vena caval occlusions were performed. Autonomic blockade was then produced by administering hexamethonium (5 mg/kg iv) and atropine (0.2 mg/kg iv) to prevent reflex changes in LV contractility as arterial pressure was altered. The steady-state measurements and caval occlusions were repeated. Phenylephrine was then infused at a rate sufficient to increase mean aortic pressure by 20-25 mmHg. The steady-state measurements and caval occlusions were repeated. Phenylephrine was then infused to increase the mean aortic pressure by 40-50 mmHg and subsequently 60-70 mmHg over control, and the measurements and vena caval occlusions were repeated at each level of phenylephrine infusion. The phenylephrine was discontinued and 20 min were allowed for reequilibration. Additional atropine (0.5 mg) was administered. Nitroprusside, sufficient to decrease the baseline aortic pressure by 20-25 mmHg, was then given. The steady-state measurements and the vena caval occlusions were repeated. The protocol was repeated on a separate day after inotropic state, and EEs was increased by a continuous infusion of dobutamine (6-8 mg kg-‘. min-I). Data analysis. The 12-s recordings during the steadystate periods with each intervention were used to generate an average beat by aligning each beat in end diastole using software developed in our laboratory. For each condition, the EA was determined as PEs/SV. End diastole was defined as the peak of the R wave of electrocardiographic lead II. End systole was defined as the upper left-hand corner of the LV PV loop, identified using the iterative method described by Kono et al. (13). SW was l
H71
COUPLING
calculated as the integral (PdV) of each beat’s PV loop. The data from the caval occlusions were fit to the following equation P ES = EES'[VES - VO] (1) using least-squares technique. Since V0 is an extrapolated value (11, 16, 17), we quantitated the position of the PEsVEs relation by calculating the volume (V& associated with a PEs of 100 mmHg V 100 = VO + lOO/EES (2) We have previously evaluated this method of quantitating the position of the P ES’VES relation (15). we quantitated the dependence of SW on VEn by fitting the data to SW = M[VEn - Vi] (3) where M is the slope of the SW-VEn relation, and Vi is the volume axis intercept (9). Although the theoretical consideration of LV-arterial coupling predicts a more complex, nonlinear relation of SW and VEn (see Eq. 6 below), the linear relation provides a reasonable approximation of the response of SW to VEn under most physiological conditions (9,16). We used the VEn-SW relation to compare the SW produced at constant VEn under the various experimental conditions. The comparison was made at a VEn that was in the middle of the range of steady-state V En occurring during the interventions. We calculated the total PVA as defined by Suga et al. (29). The SW was calculated as the integral of the PV loop. The remaining PVA (potential work PVA) was calculated as potential work PVA = PEs* [VEs - Vo]/2 (4) The total PVA was calculated as PVA = SW + potential work PVA (5) The conversion of PVA to SW was calculated as SW/ PVA (24). To correct for the effect of changes in VED, SW/PVA were compared at constant VED for each intervention using the same strategy as for SW. The coupling of the LV and arterial system was quantitated as E&E*. We chose to use this ratio, since the theoretical analysis proposed by Sunagawa et al. (33-35) and Burkhoff and Sagawa (3) predicts that at constant EES and VED, SW, and SW/PVA are determined by this ratio. We compared our results to the predictions of this model. As derived by Burkhoff and Sagawa (3) SW = EEs(VED - VO)"*(EA/EES)/(l + EA/EEd2 (6) Since, according to this model, SW is maximal when EA = EES, normalized SW (SW,) (SW/maximum SW) at constant VED and EES can be predicted as SW, = 4*(EA/EES)/(1 + &I/EEd2 (7) Similarly, from the work of Burkhoff and Sagawa (3), PVA is predicted to be PVA = EEs(VED - Vo)2
l [(&/EES)/(1
+
&4/EEd2]
l [I
(8) +
WAIEES)I~I
Thus SW/PVA
= l/( 1 + o.h!?~/&s)
(9)
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H72
LV-ARTERIAL
COUPLING
Our data were grouped by &S/E* ratios, and the SW, and SW/PVA at each E&E* were compared with the predictions of the P-V model. Statistical methods. We summarized the data as means t SD. Comparisons were performed by analysis of variance. If a significant effect was present, intergroup comparisons were performed using the Student-NewmanKeuls test or paired Bonferroni t tests (8). RESULTS
The data before and after autonomic blockade are shown in Table 1. An example of variably loaded PV loops acquired before autonomic blockade and the resulting PES-Vb:s relation and the steady-state PV loop are shown in Fig. 1. For the group, before autonomic blockade, EES (7.2 t 2.7 mmHg/ml) and EA (6.9 t 3.1 mmHg/ml) were nearly equal. After autonomic blockade, EES increased in response to dobutamine and was not significantly altered by the infusion of phenylephrine or nitroprusside (both before and after dobutamine). During phenylephrine infusion, V,0,1tended to decrease, indicating a leftward shift of the PES-VESrelation. This change reached statistical significance at the highest dose of phenylephrine both before and after dobutamine. In response to vasodilation with nitroprusside, V 100tended to increase, indicating an opposite rightward shift. As expected, EA increased in response to phenylephrine and was decreased by nitroprusside. This resulted in a range of mean E&E* from 1.93 t 0.40 (d ob ut amine and nitroprusside) to 0.43 t 0.06 (high-dose phenylephrine). Individual values of E& EA ranged from 0.18 to 2.59. Figure 2 shows the relations between SW and VED, while loading conditions were altered. While inotropic state was held constant, the SW-VEII relation was shifted progressively toward the right (i.e., smaller SW at conTABLE
DISCUSSION
In this study, we examined the criteria for the coupling of the LV and arterial system of the conscious dog to maximize SW and SW/PVA. It is important to recognize that SW is strongly influenced by both LV VED and the contractile state. This can be quantitated as the SW-VED relation (9, 16, 21). In our study, we compared SW at constant V ED, while contractile state was held constant. We found that SW is maximized when the LV EES and EA are equal (i.e., E&E* = 1). However, there is a broad plateau to the relation of SW to E&E*. SW was within 95% of its maximum value when E&E* was between 0.74 and 1.20. When EES further exceeded EA, the SW remained high, still being approximately 83% of its maximum with an E&E* equal to 2.2. Only when EA markedly exceeded EES (i.e., E&E* < 0.56) was SW substan-
1. Data before and after blockade
Unblocked Blocked Phenyl
stant VED) as E&E* deviated from 1.0. The relation of SW (at constant V& to E&E* is shown in Fig. 3, and the relation of SW/PVA to E&E* is shown in Fig. 4. The maximum SW at constant VED occurred at E&E* of 0.99 t 0.15. This is similar to the E&E* of 0.96 t 0.20 (P = NS) observed in the absence of autonomic blockade. There was a broad plateau to the relation between SW and V ED. For example, SW was within 5% of its maximum value (i.e., normalized SW > 0.95) when E&E* was between 0.74 and 1.20 and was within 20% of its maximum value when E&E* was ~0.56. SW declined rapidly when E&E* was reduced to lower values. In contrast to the relation of SW to E&E*, SW/ PVA increased steadily over the range of E&E* studied (0.18-2.59). The responses of SW and SW/PVA to varying E&E* are similar in shape to that predicted by Sunagawa et al. (34) and Burkhoff and Sagawa (3) (Fig. 4). However, SW and SW/PVA were consistently less than predicted.
1
Pheny12 Pheny13 NTP Dobutamine Dob + Phenyl Dob + Pheny12 Dob + Pheny13 Dob + NTP
1
Heart Rate, beats/min
PEI,, mmHg
P ES, mmHg
V ED, ml
111* t16 148 +18 135 +7 1:3* +10 137 +17 145 +12 145 +24 140 +36 744 -+33 143 +33 742 +14
6.2 k5.1 9.7 +6.5 16.5 k9.1 20.5” +6.7 ;2.6* +8.3 -6.0 +4.2 -8.4
126 t8 117 AI9 140* t8 165* k9 177* +31 -94* k12 143* +23 151t t22 17ot k16 184t t29 941 +18
55.4 t16.0 49.3 k22.1 54.9* k20.5 58.2* 222.2 58.4* t20.2 41.9* t18.0 49.5 t19.0 51.0 219.0 53.8 k22.4 55.5 t22.8 43.6 k18.2
+8.5 11.1 k6.8 18.2t +7.8
i3.74 k9.7 5.2 -+8.1
V KS, ml 36.2 t12.7 35.9 t18.9 41.1” k17.3 45.6* t19.6 45.6* t15.3 31.4 t14.8 34.0 t16.6 35.8 k14.9 37.8 t17.8 39.8 t16.5 31.3 t14.0
Data are means t SD of 8 animals. Blocked, after administration progressively increasing doses); NTP, nitroprusside; Dob, dobutamine. vs. dobutamine.
sv, ml 19.2* k5.9 13.4 +4.9 13.8 +3.3 12.5 +4.1 12.8 +5.1 13.4 +7.5 17.4* 25.0 16.2 k6.2 15.8 +4.8 16.8 k9.3 14.2 k6.4
E ES, mmHg/ml 7.2 +2.7 -9.0 +4.3 -7.5 t3.8 6.9 +3.8 -6.8 22.9 10.7 k5.0 13.1* k7.2 11.0 +4.8 il.7 26.0 10.5 t5.6 15.0 k8.8
of hexamethonium Other abbreviations
V 10th ml
mmHg/ml
33.6 k10.8 34.2 +16.1 -34.5 k15.4 33.2 t14.3 32.3* t13.7 35.5 t17.6 31.0* t15.7 30.7 t15.6 29.ot k14.5 29.ot t15.7 34.8 t14.7
6.9* t3.1 10.5 +6.2 10.7* t3.0 14.4* t4.6 16.7” t9.0 8.5* t3.6 8.8 +3.0 I1.2t t6.6 12.ot +4.8 14.2t t7.8 8.2 t4.9
and atropine; are defined
EA,
phenyl, in text.
VI, J%s/EA
0.96 to.20 0.91 to.32 0.61” to.17 0.48* to.20 0.43” to.06 1.27” to.36 1.33* kO.57 1.04 to.41 0.89 t to.27 0.76t kO.28 1.93t kO.40 *
M’ mmHg
ml
84.6 k7.2 82.0 k16.1 77.0 k11.4 75.0 k19.4 61.9* t11.9 71.7* t18.8 106.0* t25.6 102.3 k34.6 104.8 231.5 105.8 t34.5 94.4t t24.5
31.8 klO.6 30.4 k14.9 30.6 t12.5 30.4 t11.6 29.8 t13.3 31.6 t15.4 28.6 k15.2 30.2 k15.3 27.2 k14.5 28.1 t15.0 33.0 k13.5
phenylephrine (1, 2, 3, indicates P < 0.05 vs. blocked; t P < 0.05
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LV-ARTERIAL
COUPLING
H73
A160
sures (4,10,17). However, over a 30- to 60-mmHg range, as evaluated in this study, the PEs-VEs relation is closely approximated by a straight line (17). The theoretical -120 analysis assumed that the LV PEs-VEs relation is independent of the mode of ejection. In contrast, we found I” 100 E that arterial vasoconstriction tended to shift the PEs-VEs E 60 relation to the left (decreased VloO), whereas vasodilation i! tended to shift the PEs-VEs relation toward the right 3 60 co (increased V&. This is consistent with previous obserxi 40 vations in isolated dog hearts (20) and intact animals (7, k 2 20 14,28). However, despite marked changes in the arterial system, the slope of the PES-VESrelation is relatively unchanged. The afterload-dependent shifts of the PEsVEs relation help preserve SW as EA increases (5). In addition, the theoretical analysis of Sunagawa et al. (34) LV Volume (ml) and Burkhoff and Sagawa (3) assumed that mean ejection pressure was closely approximated by PEs, and diaB160 stolic LV pressures were zero. Despite some inaccuracy *\\\ in these simplifying assumptions, we found that the \ 140 shape of the SW-E&E* relation (Fig. 3), as directly EEs/EA=I -08 determined in the intact cardiovascular system of conscious animals, was very similar to the model’s predic\\ \\\ tion. However, the SW at each E&E* was consistently \\\ \\ less than predicted by the theoretical PV analysis. This \\\ \\\ lower than predicted SW may at least partially be due to \\\ the nonzero diastolic pressures and deviation of mean \\\ \\ ejection pressure from PEs. With this quantitatively \\\ \\ small exception, our results are consistent with the pre\\ dictions of the PV analysis and suggest it provides an \\ accurate approximation of LV-arterial coupling in conscious animals. 0 10 20 30 40 50 60 The coupling of the LV and arterial system also influences the determinants of myocardial oxygen demand LV Volume (ml) (MOON). Suga and colleagues (29, 30, 31) have demonL I I I I 1 50 40 30 20 10 0 strated that MOON, at constant contractile state, is linearly related to the total LV pressure-volume area. SW/ Stroke Volume (ml) PVA indicates how much of the PVA produces useful FIG. 1. A: variably loaded left ventricular (LV) pressure-volume work. If the contractile state is unchanged, and thus the loops produced by transient caval occlusion in a conscious dog at rest in absence of autonomic blockade. Top left-hand corner of loops MVO~-PVA relation is constant, an increase in SW/PVA indicates LV end-systolic pressure-volume relation. B: steady-state LV indicates that the ratio of SW to MVO~ will be higher. pressure-volume loop is superimposed on end-systolic pressure-volume Thus more of the MVO~ will be utilized to generate useful line from A. Arterial end-systolic pressure-stroke volume relation is external work or SW. We found that as E&E* increased, shown in dotted line. End-systolic point of pressure-volume loop occurs SW/PVA increased over the entire range of E&E* that at intersection of LV and arterial end-systolic lines. In this animal, at rest with intact reflexes, LV end-systolic elastance (&s) and arterial we studied. This is in agreement with the observations elastance (EA) are almost equal. of Nozawa and Suga (24) in anesthetized dogs. The relation we observed between SW/PVA and E&E* is tially (~20%) reduced. Our data indicate the cardiovassimilar, although slightly and consistently lower than cular system of the resting, conscious dog with intact predicted from the analysis of Burkhoff and Sagawa (3). autonomic reflexes operates near the center of the pla- Again, this is probably a consequence of their assumption teau with nearly equal E Es and EA. Thus, during most that the LV end-diastolic P was negligible, and the physiological perturbations in EES and EA, it appears ejection portion of the PV loop is flat. These findings that the LV would still operate on the plateau of the indicate that the EA that produces maximal SW at a SW-E&E* relation, where the LV and arterial system given EES is higher than the EA that results in maximum interact to produce nearly maximal SW. transformation of PVA to SW. Burkhoff and Sagawa (3) The relation between SW and E&E* that we observed also predicted the efficiency of the LV (MVOJPVA). is similar to that predicted by Sunagawa et al. (34) and When they plotted efficiency vs. EA, efficiency rose to a maximum at a point where EA was less than EES and Burkhoff and Sagawa (3). They modeled LV arterial coupling in the PV plane, using linear PEs-VEs and PEs- then declined. Since we did not measure Mi’02 in our SV relations to describe the LV and the arterial system. study, we cannot evaluate this prediction. We found that in conscious animals with intact reTheir analysis includes several assumptions that are not completely correct. For example, the PEs-VEs relation is flexes, the LV and arterial system operated in the range not perfectly linear, instead it is concave toward the that maximizes SW. Several other observations also volume axis when evaluated over a wide range of pres- suggest that at rest the LV and arterial system may I
I
L
1
1
I
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H74
LV-ARTERIAL
COUPLING
B
2500
2000
2500
2000
1500
1500
SW mmHg-ml
SW
mmHg-ml loo0
1000 Ees/Ea=0.8
500
0 40
50
60
70
80
60
Ved (ml)
C
80
Ved (ml)
2500
D
2500
2000
1500
1500
SW mmHg-ml
SW
mmHg-ml 1000
1000
500
500
0
0 40
50
60
70
80
40
50
60
70
80
Ved (ml)
E
2500
2000
FIG. 2. Left ventricular stroke work (SW)-end-diastolic volume (V& relation determined by transient caval occlusion in a conscious dog after autonomic blockade. Ratio of slopes of LV end-systolic pressure-volume relation and arterial end-systolic pressure-stroke volume relation (&s/&J was close to 1.0. SW-VED relations, produced after incremental doses of phenylephrine (23, C, and D) and nitroprusside (E), are compared with control SW-VEh relation. As E&EA is progressively decreased (B, C, and D), SW-VED relation is progressively shifted toward the right so that a smaller SW is associated with each V ED.Similarly, as E&E* is increased (E), SW-VED is also shifted toward the right.
1500 SW
mmHg-ml 1000
500
0
t 1: 40
60
70
80
Ved (ml)
operate close to the point that results in maximal SW (23,26,36-39). For example, Wilcken et al. (39) observed that LV SW in conscious dogs fell following a sudden, marked increase or decrease in aortic impedance. Similarly, van den Horn et al. (37) found that maximum mean stroke power of ventricles of anesthetized cats occurred when loaded with “normal” arterial impedances. In contrast, Piene and Sund (26) found in the cat right ventricle that maximum pump efficiency, not SW, occurred with a normal pulmonary artery impedance. However, Myhre et al. (23) observed that anesthetized openchest dogs operated close to the point of maximum SW, not mechanical efficiency. Similarly, Toorop et al. (36) found in anesthetized open-chest cats that the physio-
logical load on the heart produced maximal SW. Thus it appears that the LV and arterial system are coupled so that SW is maximized in both anesthetized preparations and conscious animals. This is probably due to the plateau of the SW-&s/EA relation, in which SW is near maximal over a broad range of &s/EA. Asanoi et al. (1) recently reported that &s/EA was approximately two in normal human subjects. This is a higher value than we observed in instrumented animals with intact reflexes but still in the range in which SW is near maximum. The differences in our results may, at least partially, be due to the different method employed by Asanoi et al. to determine &s. They assess LV endsystolic volume with M mode echocardiography and used
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LV-ARTERIAL 1.1
1 Predicted
0.8-
0.3
1 1
0.2
0.6
1.0
1.4 EEsE
1.8
2.2
2.6
A
at constant end-diastolic 3. Plot of stroke work (S W) occurring SW produced at each contractile state volume normalized by maximum and vs. ratio (EEs/EA) of slopes of LV end-systolic pressure-volume SW arterial end-systolic pressure-stroke volume relation. Maximum by theoretical model proposed occurs when E&EA = 1. SW predicted by Sunagawa et al. (3, 4) and Burkhoff and Sagawa (7) is also shown. Data are shown as group means & SE. FIG.
0.2
0.6
1.o
1.4
1.8
2.2
2.6
EESE A to format of Fig. 3, ratio of LV stroke work (SW) to total pressure-volume area (PVA) is shown as a function of E&E*. SW/PVA increases as EEs/EA increases. Line shows predictions of theoretical model. FIG.
H75
COUPLING
4. Similar
the dicrotic notch of the brachial arterial pressure as an approximation of LV PEs. Graded infusions of phenylephrine and nitroprusside were used to generate a variety of points. These interventions may both shift the PEsVEs relation (7,14,20) and also alter the relation between dichrotic notch arterial pressure and PEs (32). Connecting points generated in this manner result in a steeper PEs-VEsrelation (7,20) than produced by caval occlusion,
as utilized in our study. In addition, the instrumentation used in our study may have resulted in some depression of &s. These factors may partially explain the higher value for &s/& observed by Asanoi et al. (1) in patients than observed in unblocked conscious dogs in our study. The description of the arterial system by EA ignores the contribution of the higher frequency components of arterial impedance to LV-arterial coupling. Under normal circumstances, these components of arterial impedance account for only about 10% of the energy loss; however, their importance may be increased with slower heart rates, increased vascular tone, or other conditions (25). Our results and the observations of Sunagawa et al. (34) in isolated hearts suggest that, under most circumstances, considering the arterial system in terms of EA provides a framework for understanding LV-arterial coupling. Analysis of the dynamic coupling throughout the period of LV ejection will require consideration of the higher frequency components of arterial impedance. Our methods of varying EES and EA should be considered. We held contractile state constant by autonomically blocking the animals while varying EA by infusing vasoconstrictors or vasodilators. Then contractile state was augmented by infusing dobutamine at a constant rate while EA was again altered. While at constant inotropic state, E Es did not significantly vary. We used phenylephrine to increase EA, which may augment contractile state (2). However, this effect is probably minimal in the dog (22, 27), and we observed no increase in EES to indicate an increase in contractile state. Our observations may have clinical implications. In the normal operating range, SW is insensitive to changes in EA. This is reflected in insensitivity of the SW-VEn relation to afterload changes in the physiological range (9, 12, 16). This is not the case when EA greatly exceeds EES, as may occur in many patients with heart failure in whom EES is reduced and EA increased. In this situation, SW is very sensitive to changes in EA, and both SW and SW/PVA would be improved by a reduction in EA, as would be produced by a vasodilator. In conclusion, this study indicates that LV SW is maximal when EES and EA are equal (i.e., E&E* = 1). The conversion of PVA to SW (SW/PVA) increases as E&E* increases. There is a broad range of E&E* over which SW is only minimally reduced from its maximal level. The arterial system and LV of the intact conscious dog, with intact reflexes, operates in this range where SW is maximized. Only when EA greatly exceeds EES does SW fall substantially. We are grateful for Mary Ann Hayner’s expert secretarial assistance, the technical assistance of Todd A. Hall, Donald C. Bengtson, and Robert Rhode, and to Drs. Sidney Klopfenstein and Yuichiro Igarashi for review of the manuscript and suggestions. This study was supported in part by National Heart, Lung, and Blood Institute Grants HL-37324 and HL-42364 and a grant-in-aid from the American Heart Association. W. C. Little is an Established Investigator of the American Heart Association. Address for reprint requests: W. C. Little, Section of Cardiology, Bowman Gray School of Medicine, 300 South Hawthorne Rd., Winston-Salem, NC 27103. Received
7 December
1990; accepted
in final
form
12 March
1991.
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H76
LV-ARTERIAL
COUPLING 20. MAUGHAN,
REFERENCES
H., S. SASAYAMA, AND T. KAMEYAMA. Ventriculoarterial coupling in normal and failing heart in humans. Circ. Res. 65: 483-
1. ASANOI,
493,1989. 2. BRUCKNER, R., W. MEYER, A. MUGGE, W. SCHMITZ, SCHOLZ. Alpha-adrenoceptor-mediated positive inotropic
phenylephrine
AND H.
effect of in isolated human ventricular myocardium. Eur. J.
Pharmacol. 3. BURKHOFF,
99: 345-347, 1984. D., AND K. SAGAWA. Ventricular efficiency predicted by an analytical model. Am. J. Physiol. 250 (Regulatory Integrative Comp. Physiol. 19): R1021-R1027, 1986. 4. BURKHOFF, D., S. SUGIURA, D. T. YUE, AND K. SAGAWA. Contrac-
tility-dependent curvilinearity of end-systolic pressure-volume relations. Am. J. Physiol. 252 (Heart Circ. Physiol. 21): H1218H1227,1987. 5. FREEMAN, G. Effects of increased afterload on left ventricular function in closed-chest dogs. Am. J. Physiol. 259 (Heart Circ. Physiol. 28): H619-H625, 1990. 6. FREEMAN, G. L., W. C. LITTLE, AND R. A. O’ROURKE. Influence of heart rate of the left ventricular performance in conscious dogs. Circ. Res. 61: 455-464, 7. FREEMAN, G. L., W.
1987.
C. LITTLE, AND R. A. O’ROURKE. Effect of vasoactive agents on the left ventricular end-systolic pressurevolume relation in closed-chest dogs. Circulation 74: 1107-l 113, 1986. 8. GLANTZ, S. A. Primer of Biostatistics. New York: McGraw-Hill, 1981. 9. GLOWER, D. D., J. A. SPRATT, N. D. SNOW, J. S. KABAS, J. W. DAVIS, C. 0. OLSEN, G. S. TYSON, D. C. SABISTON, AND J. S. RANKIN. Linearity of the Frank-Starling relationship in the intact heart: the concept of preload recruitable stroke work. Circulation 71: 994-1009, 1985. 10. KASS, D. A., R. BEYAR, E. LANKFORD, MAUGHAN, AND K. SAGAWA. Influence
curvilinearity
M.
HEARD,
W.
L.
of contractile state on of in situ end-systolic pressure-volume relations.
Circulation 79: 167-178, 1989. 11. KASS, D. A., AND W. L. MAUGHAN. From “Emax” to pressurevolume relations: a broader view. Circulation 77: 1203-1212, 1988. 12. KASS, D. A., W. L. MAUGHAN, Z. M. Guo, A. KONO, K. SUNAGAWA, AND K. SAGAWA. Comparative influence of load versus
inotropic states on indexes of ventricular contractility: experimental and theoretical analysis based on pressure-volume relationships. Circulation 76: 1428-1436, 1987. 13. KONO, A., W. L. MAUGHAN, K. SUNAGAWA, C. KALLMAN, K. SAGAWA, AND M. L. WEISFELDT. Left ventricular end-ejection
14. 15.
16.
17.
18.
19.
pressure and peak pressure to estimate the end-systolic pressurevolume relationship. Circulation 70: 1057-1065, 1984. LITTLE, W. C. The left ventricular dP/dt,,,-end-diastolic volume relation in closed-chest dogs. Circ. Res. 56: 808-815, 1985. LITTLE, W. C., F. R. BADKE, AND R. A. O’ROURKE. Effect of right ventricular pressure on the end-diastolic left ventricular pressurevolume relationship before and after chronic right ventricular overload. Circ. Res. 54: 719-730, 1984. LITTLE, W. C., C. P. CHENG, M. MUMMA, Y. IGARASHI, J. VINTENJOHANSEN, AND W. E. JOHNSTON. Comparison of measures of left ventricular contractile performance derived from pressure-volume loops in conscious dogs. Circulation 80: 1378-1387, 1989. LITTLE, W. C., C. P. CHENG, T. PETERSON, AND J. VINTENJOHANSEN. Response of the left ventricular end-systolic pressurevolume relation in conscious dogs to a wide range of contractile states. Circulation 78: 736-745, 1988. LITTLE, W. C., R. C. PARK, AND G. L. FREEMAN. Effect of alterations on the left ventricular activation sequence on left ventricular systolic performance. In: Activation, Metabolism and Perfusion of the Heart: Simulation and Experimental Models, edited by S. Sideman, and R. Beyar. The Hague: Nijhoff, 1987. LITTLE, W. C., AND R. A. O’ROURKE. Effect of regional ischemia on the left ventricular end-systolic pressure-volume relationship in chronically instrumented dogs. J. Am. Coil. Cardiol. 5: 297-302, 1985.
W. L., K. SUNAGAWA,
D. BURKHOFF,
AND K. SAGAWA.
Effect of arterial impedance changes on the end-systolic pressurevolume relation. Circ. Res. 54: 595-602, 1984. 21. MISBACH, G. A., AND S. A. GLANTZ. Changes in the diastolic pressure-diameter relation alter ventricular function curves. Am. J. Physiol. 237 (Heart Circ. Physiol. 6): H644-H648, 1979. 22. MUKHERJEE, A., Z. HAGHANI, J. BRADY, L. BUSH, W. MCBRIDE, L. M. BUJA, AND J. T. WILLERSON. Differences in myocardial
alpha- and beta-adrenergic
receptor numbers in different species.
Am. J. Physiol. 245 (Heart Circ. Physiol. 14): H957-H961, 1983. 23. MYHRE, E. S. P., A. JOHANSEN, J. BJORNSTAD, AND H. PIENE.
The effect of contractility and preload on matching between the canine left ventricle and afterload. Circulation 73: 161-171, 1986. 24. NOZAWA, T., Y. YASUMURA, AND H. SUGA. Efficiency of
S.FUTAKI,
N. TANAKA,
M. UENISHI,
energy transfer from pressure-volume area to external mechanical work increases with contractile state and decreases with afterload in the left ventricle of the anesthetized closed-chest dog. Circulation 77: 1116-l 124, 1988. 25. O’ROURKE, M. F. Steady and pulsatile energy losses in the systemic circulation under normal conditions and in simulated arterial disease. Cardiovasc. Res. 1: 313-326, 1967. 26. PIENE, H., AND T. SUND. Does normal pulmonary impedance constitute the optimum load for the right ventricle? Am. J. Physiol. 242 (Heart Circ. Physiol. 11): H154-H160, 1982. 27. SEITELBERGER, R., B. D. GUTH, J. D. LEE, K. KATAYAMA, G. HEUSCH, AND J. ROSS, JR. Alpha 1 and alpha 2 receptor stimula-
tion in conscious dogs increase coronary resistance but not myocardial function (Abstract). J. Am. Coil. Cardiol. 7, Suppl. A: 8lA, 1986. SODUMS, AND R.
M. T.,
R. F. BADKE,
M. R. STARLING,
W. C. LITTLE,
A. O’ROURKE. Evaluation of left ventricular contractile performance utilizing end-systolic pressure-volume relationships in conscious dogs. Circ. Res. 54: 731-739, 1984. 29. SUGA, H., T. HAYASHI, AND M. SHIRAHATA. Ventricular systolic pressure-volume area as predictor of cardiac oxygen consumption. Am. J. Physiol. 240 (Heart Circ. Physiol. 9): H39-H44, 1981. 30. SUGA, H., T. HAYASHI, S. SUEHIRO, R. HISANO, M. SHIRAHATA, AND I. NINOMIYA. Equal oxygen consumption rates of isovolumic
and ejecting contractions with equal systolic pressure-volume areas in canine left ventricle. Circ. Res. 49: 1082-1091, 1981. 31. SUGA, H., R. HISANO, Y. GOTO, 0. YAMADA, AND Y. IGARASHI. Effect of positive inotropic agents on the relation between oxygen consumption and systolic pressure-volume area in canine left ventricle. Circ. Res. 53: 306-318, 1983. 32. SUGA, H., AND N. NISHIURA. Dissociation of end-ejection from end-systole of ventricle. Jpn. Heart J. 22: 117, 1981. 33. SUNAGAWA, K., W. L. MAUGHAN, D. BURKHOFF, AND K. SAGAWA. Left ventricular interaction with arterial load studied in isolated canine ventricle. Am. J. Physiol. 245 (Heart Circ. Physiol. 14): H773-H780,1983. 34. SUNAGAWA,
K., W. L. MAUGHAN, AND K. SAGAWA. Optimal arterial resistance for the maximal stroke work studied in isolated canine left ventricle. Circ. Res. 56: 586-595, 1985. 35. SUNAGAWA, K., W. L. MAUGHAN, AND K. SAGAWA. Stroke volume effect of changing arterial input impedance over selected frequency ranges. Am. J. Physiol. 248 (Heart Circ. Physiol. 17): H477-H484, 1985. 36. TOOROP, G. P., G. J. VAN DEN HORN, WESTERHOF. Matching between feline left
G.
ELZINGA,
AND
N.
ventricle and arterial
load: optimal external power or efficiency. Am. J. Physiol. 254 (Heart Circ. Physiol. 23): H279-H285, 1988. 37. VAN DEN HORN, G. J., N. WESTERHOF, AND G. ELZINGA. Interaction of heart and arterial system. Ann. Biomed. Engr. 12: l51162,1984. 38. VAN DEN HORN,
G. J., N. WESTERHOF, AND G. ELZINGA. Optimal power generation by the left ventricle: a study in the anesthetized open thorax cat. Circ. Res. 56: 252-261, 1985. D. E. L., A. A. CHARLIER, J. I. E. HOFFMAN, AND A. 39. WILCKEN, GUZ. Effects of alterations in aortic impedance on the performance of the ventricles. Circ. Res. 14: 283-293, 1964.
Downloaded from www.physiology.org/journal/ajpheart by ${individualUser.givenNames} ${individualUser.surname} (130.056.064.029) on December 13, 2018.
