(Circulation. 1995;92:3560-3567.)
© 1995 American Heart Association, Inc.
Articles |
Loading Sequence Plays an Important Role in Enhanced Load Sensitivity of Left Ventricular Relaxation in Conscious Dogs With Tachycardia-Induced Cardiomyopathy
From the Second Department of Internal Medicine, Toyama Medical and Pharmaceutical University, Toyama, Japan.
Correspondence to Hidetsugu Asanoi, MD, The Second Department of Internal Medicine, Toyama Medical and Pharmaceutical University, 2630 Sugitani, Toyama 930-01, Japan.
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Abstract |
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Background Left ventricular relaxation rate in the failing heart depends more on the systolic load than in the normal heart. To elucidate the mechanisms for the enhanced load sensitivity of left ventricular relaxation in heart failure, we examined the relative contributions of changes in end-systolic volume and loading sequence to the left ventricular relaxation rate.
Methods and Results In seven conscious dogs, the time constant (Td) of left ventricular pressure decay, end-systolic volume, systolic circumferential force, and time to peak force during caval occlusion were compared before and after development of tachycardia-induced heart failure. Rapid ventricular pacing decreased the slope of the end-systolic pressure-volume relation from 4.5 to 2.8 mm Hg/mL (P<.01) and prolonged Td from 33 to 49 ms (P<.01). In normal conditions, caval occlusion reduced end-systolic force (-580 g, P<.01) and end-systolic volume (-7 mL, P<.01) but did not change Td or time to peak force. In heart failure, however, caval occlusion shortened Td (-11 ms, P<.01), with a concomitant decrease in the time to peak force (-30 ms, P<.01), while end-systolic volume and force declined slightly. Consequently, for a comparable reduction in end-systolic force, Td decreased more in heart failure than in normal hearts, suggesting enhanced load sensitivity. Moreover, changes in Td correlated well with those in the time to peak force (r=.79, P<.01) but not with those in end-systolic volume.
Conclusions Loading sequence rather than elastic recoil seems to play the predominant role in the enhanced load sensitivity of left ventricular relaxation in heart failure.
Key Words: heart failure • conduction • catheters • pressure
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Introduction |
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TopAbstractIntroductionMethods Results Discussion References |
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The rate of left ventricular isovolumic pressure decay (Td) depends both on the myocardial deactivation process and on the prevailing loading conditions. The prolongation of left ventricular relaxation in the failing heart is attributed to abnormalities of intracellular calcium handling in myocytes and/or to an increased load in the failing heart. Recently, Komamura et al1 reported that an increase in load is largely responsible for the prolonged relaxation of the depressed left ventricle produced by rapid ventricular pacing in the dog and that diastolic dysfunction in the failing heart could be reversed by load reduction. Load dependence of left ventricular relaxation was first demonstrated by Parmley and Sonnenblick2 in papillary muscle and then systematically analyzed by Brutsaert et al3 in isolated cardiac muscle. Blaustein and Gaasch4 showed in the open-chest dog heart that the relaxation rate becomes more sensitive to left ventricular end-systolic pressure when cardiac contractility is decreased with propranolol. Eichhorn et al5 also reported in humans that as contractility worsened, the slope of the relation of time constant of isovolumic pressure decay as a function of end-systolic pressure became steeper, indicating enhanced load sensitivity of relaxation in depressed hearts. These data suggest that a baseline inotropic state modifies the load sensitivity of left ventricular relaxation. A given load reduction results in a greater reduction in end-systolic volume in the failing heart than in the normal heart because volume shifts by a greater extent on the depressed left ventricular end-systolic pressure-volume relation. This augments restoring forces (elastic recoil), which accelerate the speed of the left ventricular isovolumic pressure fall.6 Another possible mechanism for enhanced load sensitivity of relaxation in the failing left ventricle involves a change in the loading sequence during systole, because left ventricular relaxation is influenced not only by the magnitude of afterload but also by the systolic load profile.7 8 9 10 In this study, we took account of changes in end-systolic volume or systolic loading sequence to explain the mechanism of the enhanced load sensitivity of relaxation in the failing heart.
We produced chronic experimental heart failure by rapid cardiac pacing in conscious dogs instrumented with a left ventricular micromanometer and conductance catheter that allowed continuous and reproducible measurements of ventricular pressure and volume simultaneously11 and analyzed the mechanisms for the load sensitivity of left ventricular relaxation. Many investigators have documented that this model is characterized by progressive impairment of left ventricular contractility and relaxation with an increase in pacing period.12 13 14 However, the mechanism for enhanced load sensitivity of left ventricular relaxation has not been examined in this model.
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Methods |
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TopAbstractIntroductionMethods Results Discussion References |
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Instrumentation
The surgical procedure used has been described in detail elsewhere (Fig 1
,
left).11 15 16 Briefly,
seven mongrel dogs underwent thoracotomy in the left fifth intercostal
space under anesthesia with 1% halothane after induction
with pentobarbital sodium (25 mg/kg IV). The pericardium was opened
wide. A high-fidelity micromanometer
(Konigsberg P-7) was inserted into the left ventricular
chamber through an apical stab incision. The
micromanometer was calibrated by comparison with
pressures obtained through a fluid-filled catheter connected to a
Statham P23Db (Gould) transducer. A conductance catheter was also
advanced from the apex so that its tip passed through the aortic valve.
The position of the most distal electrode was verified by
two-dimensional echocardiography (Toshiba
SSH-40A) together with monitoring of segmental volume signals. Another
polyvinyl catheter was placed in the pulmonary artery for
infusion of hypertonic saline to determine parallel conductance by
decreasing the resistivity of the left ventricular chamber
blood pool.17 18 Pacing electrodes were sutured to
the
left ventricular epicardial surface to pace the ventricle
at a high rate and to induce heart failure. Pneumatic cuff occluders
were placed around the superior and inferior venae cavae,
and the chest was closed. All the wires and tubes were exteriorized to
the backs of the dogs, and experiments were carried out at least 10
days after surgery, when the dogs had recovered completely.
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The animals used in this study were maintained in accordance with the guidelines of the Committee on Animal Care of Toyama Medical and Pharmaceutical University.
Volume Determination From the Conductance Catheter
The
catheter system used in this study consisted of a 4F
polyethylene catheter with eight ring electrodes mounted equidistantly
at its tip and providing an electric field distribution similar to that
from catheters conventionally inserted retrogradely from the ascending
aorta. We used catheters with a distance of either 5, 6, or 7 cm
between the first and the last electrodes, depending on the size of the
left ventricle of the dog under study.11 To serially
determine the instantaneous ventricular volume, we modified
the original conductance catheter introduced by Baan's
group17 so that it could be implanted for a long period.
An alternating current (20 kHz, 0.07 mA) was passed between the driving
electrodes in the apex and at the base by use of a signal
conditioner–processor (Leycom Model Sigma-5). The five potential
differences generated between each sensing electrode spanning the left
ventricular cavity were measured continuously. Dividing the
current by each of the potential differences gave five conductances,
and the sum of these five segmental conductances, G(t), was linearly
related to the ventricular volume, V(t), by the following
equation17 :
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where
represents the conductivity of blood
surrounding the catheter in the ventricular cavity,
Vc is the parallel conductance formed by tissues
surrounding the left ventricular cavity
(myocardium, right ventricle, etc), 
is an empirical
slope coefficient for the V(t)-G(t) relationship (the value was assumed
to be 1.0 in all the experiments),19 20 and L is the
distance between electrodes 1 and 8.
The value of the parallel
conductance was determined in each experiment
by injecting 3 mL of 6 mol/L hypertonic saline through the catheter in
the pulmonary artery. The accuracy of volume measurement by
this method has been validated by Burkoff et al.18 We have
also evaluated the accuracy of our conductance volumetry in another
group of six dogs.16 The difference in stroke volume
between conductance volumetry and the Fick method was only
-0.8±1.4 mL, and was 0.95±0.11. Therefore, we did
not
determine the slope coefficient in each animal and instead used the
value 1.0 for all dogs in the present study. Serial reproducibility
of this system was also examined by repeated measurements on separate
days (1 to 14 days apart) in the same dog.11 The mean
differences in left ventricular
end-diastolic and end-systolic volumes were
3±2 and 3±2 mL, respectively (not significant).
Study Protocol
Baseline recordings of hemodynamic data
and conductance volume were performed during spontaneous sinus rhythm
in the unanesthetized animal lying quietly on its left
side. After these recordings, changes in
hemodynamic parameters during load
reduction by caval occlusion were determined (Fig 1
, right).
The
occlusion was applied to interrupt venous return, with a subsequent
fall in left ventricular systolic pressure of 10 to
30 mm Hg.
After these recordings in the control state, the dogs were
paced for 2 or 3 weeks (17±3 days, mean±SD) at a rate of 260
beats
per minute with an external pacemaker (Biotonic EDP20). Rapid pacing
was continued until the animals developed congestive symptoms,
including ascites, respiratory distress, or anorexia, and left
ventricular end-diastolic pressure rose
above 20 mm Hg. Then, the same recordings as in the control
state were repeated both at baseline and during load reduction. All
these measures were obtained starting 
1 hour after temporary
cessation of the rapid pacing. This period was adequate to evaluate the
hemodynamic condition during sinus rhythm in the
failing heart, because a stable heart rate continued for at least 3 or
4 hours starting 10 minutes after the cessation of rapid
ventricular pacing.
Data Analysis
Micromanometer pressure and conductance
catheter volume were digitized by an on-line
analog-to-digital converter (ANALOG-PRO I, Canopus) at 333 Hz
and were stored on a floppy disk memory system by use of a computer
system (PC-9801 RX, NEC), and pressure-volume loops were obtained
on a beat-to-beat basis. The left ventricular
contractile state was assessed by the slope of the left
ventricular end-systolic pressure-volume
relation, Ees. Preload reduction by caval occlusion
influenced the shape of the initial portion of the
end-systolic pressure-volume relation through a right
ventricular unloading artifact.19 The initial
shallow portion of the relation from the calculation of the linear
end-systolic pressure-volume relation was therefore
excluded from the analysis. The time constant of isovolumic
pressure decay was calculated by the method of Weiss et
al21 and by the derivative method of Raff and
Glantz22 : Td=-1/slope of a linear fit of
the negative dP/dt versus the left ventricular pressure
over the same interval. This method allows for a nonzero pressure
asymptote. As an index of afterload, the
end-systolic total circumferential force was calculated
from23
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where ESF is end-systolic force, ESP is end-systolic pressure, and ESV is end-systolic volume. The time to peak force, ie, the time from end diastole to the peak of the force as an index of loading pattern, and ESV as a determinant of the relaxation rate through elastic elements of the left ventricle were determined. End systole was defined as the time to the peak instantaneous ratio of left ventricular pressure to volume.
After completion of the study, the animals were killed with an overdose of pentobarbital, and the hearts were examined to confirm that the instrumentation was properly positioned. There were no fibrin clots around the conductance catheter and no stenosis of inferior and superior venae cavae where cuff occluders were placed.
Statistical Analysis
Group data are summarized as
mean±SD. The differences in
hemodynamic variables between normal and failing
hearts and between before and after load reduction were tested by
repeated-measures ANOVA. If a significant effect was present,
intergroup comparisons were performed with Scheffé's test.
Percentage changes from baseline values were tested by the paired
t test. A probability level less than .05 was considered
significant.
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Results |
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TopAbstractIntroductionMethods Results Discussion References |
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Development of Heart Failure
The hemodynamic and conductance volume data before and after development of heart failure are summarized in the Table
. In the failing heart, the heart rate increased
from 85±13 to 117±20 beats per minute (P<.01).
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All animals demonstrated significant cardiac dysfunction 2 or 3 weeks after pacing. Peak positive dP/dt was reduced by 52% (P<.01). Left ventricular end-diastolic pressure was elevated from 12.9 to 29.3 mm Hg. Although the left ventricular filling period was shortened by an increase in heart rate, left ventricular end-diastolic and end-systolic volumes were increased, with a significant reduction in the ejection fraction, from 49±8% to 30±9% (P<.01). Diastolic function was also impaired, as evidenced by a 26% decrease in peak negative dP/dt and prolonged isovolumic pressure decay; that is, the time constant calculated by Weiss's method (Tw , 20.2 to 34.7 ms) and that by the derivative method (Td, 32.9 to 48.7 ms) became greater.
Effects of Load Reduction on Left Ventricular
Relaxation
Changes in hemodynamic data after preload
reduction with caval occlusion are shown in the Table and Fig
2. The heart rate was not altered after reduction of
preload in either the normal or failing heart. In normal hearts, left
ventricular end-systolic pressure and volume
fell by 18% and 35%, respectively. End-systolic force
decreased by 39%, while the time to peak force remained unaltered.
Although peak negative dP/dt was significantly decreased, by 13%,
there was no change in Td with a reduction in preload.
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) in left
ventricular relaxation rate (
In
the failing heart, caval occlusion resulted in a smaller
reduction in left ventricular end-systolic
pressure (-7%), volume (-12%), and force (-15%),
whereas Td and the time to peak force were markedly
shortened by caval occlusion (-22% and -17%,
respectively). Consequently, for a comparable reduction in
end-systolic volume or force, Td in failing
hearts decreased more than that in normal hearts. Fig 3
shows the relations between end-systolic force and the left
ventricular relaxation rate during caval occlusion in each
dog. The slope of this relation was considerably greater in the failing
heart than in the normal heart
(2.3±6.5x10-3 versus
20.4±10.6x10-3 ms/g,
P<.01), suggesting that load sensitivity of left
ventricular relaxation was enhanced in the failing heart.
Fig 4 illustrates the systolic load sequence
before and after caval occlusion. The left ventricular
loading profile in the normal heart remained essentially similar,
peaking early during systole. In the failing heart, however, the
loading sequence changed, with its peak shifting from late to mid
systole. Fig 5 shows serial diastolic
pressure-volume loops obtained during caval occlusion. There were
no changes in the shape of the early diastolic
pressure-volume loops in the normal heart (Fig 5, top). The
baseline loop in the failing heart exhibited a marked distortion in
early diastole, suggesting impaired relaxation of the left
ventricle. This abnormal pressure-volume loop was gradually
restored toward the normal shape as the end-systolic volume
decreased by caval occlusion (Fig 5, bottom).
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indicates normal
heart; 
, failing heart; and Td, time constant of left
ventricular pressure decay calculated from a negative dP/dt
vs left ventricular pressure.
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Although
there was no significant relation between Td and
end-systolic volume, changes in Td correlated
well with changes in the time to peak force (r=.79,
P<.01, Fig 6) in both normal and failing
hearts. Some dogs in Fig 6 showed twofold or threefold
differences in
changes in Td for a similar reduction in the time to peak
force. This variation was derived from the disparate magnitudes of
the reduction in end-systolic force during caval
occlusion.
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Discussion |
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TopAbstractIntroductionMethods Results Discussion References |
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Ventricular relaxation depends not only on the magnitude of afterload changes but also on the pressure waveform during ejection. The present study demonstrated that in the failing heart, abrupt reduction in preload by caval occlusion produced a significant shortening of the time constant of isovolumic left ventricular pressure decay with fewer changes in afterload compared with the normal heart. The improvement in the relaxation rate of the failing heart was parallel to a reduction in the time to left ventricular peak force rather than changes in end-systolic force or volume. This finding could not directly indicate that the time to peak force affected only the time constant of the left ventricle in the failing heart, because there was large variation in the reduction in Td for the same change in the time to peak force (Fig 6
). Nevertheless, these data
suggested
that changes in systolic load sequence play a predominant role
in enhanced load sensitivity of the failing heart.
Effects of Late Systolic Load on Ventricular
Relaxation Rate
The importance of load sequence in left ventricular
relaxation has been shown by several investigators. Hori et
al7 8 demonstrated that the afterload-dependent
relaxation in the in situ heart is more sensitive to changes in load
sequence than to the total load itself. Gillebert and Lew9
also showed that the time constant of isovolumic pressure decay
increased in direct proportion to the increment in peak left
ventricular pressure over a
physiological range and that these changes were
more pronounced when the pressure peaked later during left
ventricular ejection. The mechanisms by which late
systolic load delayed the ventricular relaxation
rate remain speculative. It is possible that increasing late
systolic pressure increases left ventricular
end-systolic volume and slows the rate of subsequent
pressure fall through a decrease in restoring forces within the
myocardium. These effects could be enhanced in the failing
heart, in which a depressed end-systolic
pressure-volume relationship results in a greater increase in
end-systolic volume for a given rise in
end-systolic pressure. However, this mechanism seems
unlikely to be involved in our experiment, since the pressure drop
during caval occlusion was smaller and the resultant decrease in
end-systolic volume was less in the failing hearts.
Abnormalities in intracellular calcium handling contribute to
diastolic dysfunction as well as an impairment of
systolic function. With an early increase in systolic
load, calcium availability is adequate to permit recruitment of
additional cross-bridge formation, so the resultant stress on
individual cross-bridges does not change. However, with late load
increases, the availability of calcium is reduced to limit the
formation of additional cross-bridges, so the stress on individual
cross-bridges increases, which may delay cross-bridge
interaction and slow the rate of subsequent fall in left
ventricular pressure. Finally, the possibility that late
systolic load augments asynchronous relaxation of the failing
ventricle could not be excluded. Recently, Schäfer et
al24 suggested that left ventricular
asynchrony may increase during an acute augmentation of left
ventricular afterload in anesthetized,
open-chest dogs, possibly leading to the afterload-dependent
prolongation of the left ventricular isovolumic relaxation
rate. In contrast, Gillebert and Lew9
simultaneously measured pressure and segmental wall motion
of the different regions of the left ventricle and concluded that the
synchrony of segmental isovolumetric relaxation was not affected by
either early or late pressure increase.
Alteration in Load Sequence
The ventricular systolic load is
determined by
the interaction of ventricular contractile properties with
aortic input impedance. It has been well recognized that in the normal
heart, systolic force peaks early in systole and ejection force
declines during the ejection period. When left ventricular
contractility is severely depressed, the time course of
afterload is dramatically altered; the absolute level of ejection force
remains high throughout the contraction, and the ventricle is not able
to unload itself as in the normal heart. The load sequence in systole
is also modified by arterial pressure reflections. Elzinga
and Westerhof25 demonstrated that the systolic
plateau in left ventricular pressure is influenced more by
arterial capacitance than by the resistance, and peak left
ventricular pressure is achieved late in systole, when the
left ventricle faces a stiffer peripheral system. Laskey
and Kussmaul26 demonstrated earlier wave reflection in
patients with heart failure, suggesting faster aortic wave velocity and
arterial stiffening. This early wave reflection imposes an
additional load on the left ventricle late in systole. Under these
conditions, a reduction in chamber size by venous pooling reduces the
shortening load, permitting greater shortening.27 Because
venous pooling with caval occlusion decreases arterial
pressure, with a reduced pulse wave velocity, the reflected wave
occurred later in the diastolic period, resulting in a
reduction in the additional late systolic load. Consequently,
load sequence in systole could be affected more by preload reduction in
the failing heart than in normal heart.
Limitations
The accuracy of the absolute left ventricular
volume
obtained with the conductance catheter has been tested in isolated
canine hearts with an intraventricular
balloon18 and also in open-chest dogs with an
electromagnetic flow probe17 or
sonomicrometry.20 All of these studies showed good
correlations between the volumes measured by the conductance technique
and those measured by the other methods. Some additional errors in
estimating the absolute volume may result from assumption of the slope
coefficient . Kass et al19 arrived at a mean value of
1.0 by use of thermodilution cardiac output in several closed-chest
dogs. Recently, Applegate et al20 showed that was
1.0±0.2 in dog hearts in a steady state by comparing left
ventricular volume measured with the conductance catheter
with that calculated from three-dimensional sonomicrometry. We
examined for different sizes of canine hearts in comparison with
Fick flow output16 and found that was 0.95±0.11.
Therefore, we used a value of =1.0 for all hearts in the present
study.
The pressure fall with brief caval occlusion could elicit a baroreflex-mediated increase in sympathetic tone, which might influence the rate of left ventricular isovolumetric pressure decay. Kass et al19 showed that rapid load alterations (<8 seconds) by this method minimize reflex changes of ventricular contractility and allow repeated determinations of the end-systolic pressure-volume relation in the presence of intact reflexes. In normal hearts, bicaval occlusion reduced peak left ventricular pressure by about 30 mm Hg within 5 seconds. The failing heart has an increased central blood volume,28 which allows a longer time to achieve a pressure drop with caval occlusion. Under these conditions, however, a sympathetically mediated influence on left ventricular relaxation would be negligible, because the heart rate did not change appreciably because of the impaired baroreflex sensitivity seen in heart failure.
Pericardial pressure might influence the relaxation rate of the failing heart. Frais et al29 clearly demonstrated that the time constant of left ventricular pressure decay determined by the Weiss method was modulated by pericardial pressure but was not affected when determined by the derivative method. We opened the pericardium wide and confirmed changes in the relaxation rate by these two methods. Therefore, effects of pericardial pressure on left ventricular relaxation rate could be ignored in the present study.
Clinical Implications
It is well recognized that afterload
reduction improves
systolic performance of the left ventricle more in
patients with heart failure than in normal subjects. Our data indicate
that vasodilators in the treatment of heart failure increase the rate
of ventricular relaxation not only by decreasing the level
of afterload but also by changing the afterload profile. In heart
failure, load sequence appears to be influenced more by load
manipulation than by the level of afterload itself. Therefore, even a
small decrease in afterload with a vasodilator might result in a
substantial improvement in the relaxation rate of the failing left
ventricle.
It has been demonstrated experimentally and clinically that positive inotropic agents improve relaxation more than contractility of the failing left ventricle.14 30 31 The mechanisms for the disparate responses to cardiotonic agents remain unknown. Most of these agents exert positive inotropic and lusitropic action by increasing intracellular cAMP. The resultant increase in ejection rate and peripheral vasodilatation through cAMP accumulation could change the time course of systolic load, which additionally accelerates left ventricular relaxation of the failing heart.
Conclusions
Left ventricular relaxation rate correlated well
with
left ventricular end-systolic force in both
normal and failing hearts. However, the slopes of these relations were
much steeper in the failing heart than in the normal heart, suggesting
that left ventricular relaxation turned more sensitive to
load after development of heart failure. In the failing heart, despite
a smaller reduction in afterload and end-systolic volume
with caval occlusion, systolic load sequence was markedly
changed, resulting in a greater acceleration of the
ventricular relaxation rate than in the normal heart. Thus,
loading sequence rather than elastic recoil seems to play the
predominant role in the enhanced load sensitivity of left
ventricular relaxation in the failing heart.
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Acknowledgments |
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This study was supported by a grant-in-aid for General Scientific Research (03454250) from the Ministry of Education, Science, and Culture of Japan and by a Research Grant for Cardiovascular Diseases from the Ministry of Health and Welfare of Japan. We are deeply indebted to Prof Sasayama at the University of Kyoto for his continuous encouragement and valuable suggestions. We thank Rie Takada and Kyoko Murakami for their technical assistance in the experiments.
Received June 27, 1995; revision received October 17, 1995; accepted October 20, 1995.
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