Loading Sequence Plays an Important Role in Enhanced Load Sensitivity of Left Ventricular Relaxation in Conscious Dogs With Tachycardia-Induced Cardiomyopathy
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.
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.
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.
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 :
where ρ 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), α 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 α 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).
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.
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
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.
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.
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).
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.
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±6.5×10−3 versus 20.4±10.6×10−3 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).
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.
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.
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 α. 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 α 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 α for different sizes of canine hearts in comparison with Fick flow output16 and found that α was 0.95±0.11. Therefore, we used a value of α=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.
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.
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.
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.
- Copyright © 1995 by American Heart Association
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