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Cardiovascular Research 1999 43(2):354-363; doi:10.1016/S0008-6363(99)00102-9
© 1999 by European Society of Cardiology
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Copyright © 1999, European Society of Cardiology

Load sensitivity of left ventricular relaxation in normal and failing hearts: evidence of a nonlinear biphasic response

Sumanth D. Prabhua,b,*

aDepartment of Medicine, University of Texas Health Science Center, 7703 Floyd Curl Drive, San Antonio, TX 78284, USA
bAudie Murphy Memorial Veterans Hospital, San Antonio, TX 78284, USA

* Tel.: +1-210-567-4600; fax: +1-210-567-6960 prabhu{at}uthscsa.edu

Received 18 September 1998; accepted 4 February 1999


   Abstract
Top
 Abstract
1 Introduction
 2 Methods
 3 Results
 4 Discussion
 References
 
Objective: This investigation sought to define the effect of heart failure (HF) on the load sensitivity of left ventricular (LV) relaxation and to correlate alterations in load sensitivity with the variables of ejection timing, systolic load profile and elastic recoil. Methods: Nine dogs instrumented with LV micromanometers and piezoelectric crystals were studied before and after HF produced by prolonged rapid LV pacing. After pharmacologic autonomic blockade and atrial pacing at 160 bpm, hemodynamic measurements were recorded at steady-state and during vena caval occlusion. LV relaxation for individual beats during caval occlusion was assessed using tau, the monoexponential time constant, and systolic load was estimated using end-systolic circumferential force (ESF). Results: The tau–ESF relation was nonlinear and biphasic, with an initial decrease in tau followed by a delayed increase, and was described by a parabolic equation with a curvilinearity coefficient a. Examination of ejection variables and systolic load profile indicated that the initial acceleration of relaxation reflected the influence of increased elastic recoil, whereas the late slowing reflected the influence of earlier end-ejection and delayed systolic loading. HF produced significant baseline prolongations of tau (P<0.005), time to relaxation onset (P<0.001) and time to peak force (P<0.015) compared to control. The curvilinearity coefficient of the tau–ESF relation was significantly increased (18.1±20.1·10–5 vs. 3.99±2.89·10–5 g–2, P=0.048), indicating increased load sensitivity of relaxation. This increased load sensitivity correlated with delayed onset but increased overall magnitude of the effects of earlier end-ejection and late systolic loading on relaxation. Conclusions: The tau–ESF relationship during transient load reduction is nonlinear and biphasic with an initial acceleration of relaxation, reflecting the impact of elastic recoil, and delayed slowing, reflecting changes in ejection timing and systolic loading sequence. This relation is more curvilinear in the failing heart, indicating increased load sensitivity of LV relaxation. These changes primarily occur due to alterations in the impact of ejection timing and systolic load profile rather than increased elastic recoil.

KEYWORDS Heart failure; Ventricular function; Cardiomyopathy; Contractile function; Hemodynamics


   1 Introduction
Top
 Abstract
 1 Introduction
2 Methods
 3 Results
 4 Discussion
 References
 
The failing heart is characterized by marked abnormalities in left ventricular (LV) diastolic function, including increases in myocardial stiffness and prolongation of the time constant of LV relaxation, tau [1,2]. Theoretically, alterations in LV relaxation can be secondary to reduced intrinsic myocardial lusitropy (dependent on cytoplasmic Ca2+ reuptake, myofilament Ca2+ sensitivity, and crossbridge inactivation), changes in the magnitude, temporal sequence, and uniformity of systolic load, or alterations in the end-systolic muscle length or volume, which influence the degree of elastic recoil [3–9]. Investigations using the pacing tachycardia model of heart failure (HF) have demonstrated that steady-state alterations in tau and myocardial stiffness are largely the result of increased load and can be normalized by reducing load to baseline levels [2]. Additionally, the failing human left ventricle displays enhanced sensitivity of relaxation to steady-state changes in systolic load [10], suggesting intrinsic changes in the load response of inactivation in HF.

Although the influence of steady-state load alterations on LV relaxation has been well studied, the effect of acute, transient alterations in load on LV relaxation in failing hearts is much less clear. Precise definition of this behavior is important given that many experimental studies of HF require measurement of LV relaxation under dynamic conditions. Furthermore, transient load alterations minimize the confounding effects of long-term loading history and length-dependent myofilament activation, which occur with steady-state changes [4,11–13], and thereby provide complementary insights into the relationship between load and myocardial relaxation. Thus, the purpose of this study was to test a two-fold hypothesis: (1) failing hearts demonstrate increased load sensitivity of LV relaxation in response to transient alterations in systolic load and (2) the heightened load sensitivity in HF is secondary to a combination of alterations in the distinct influences of elastic recoil, systolic loading sequence and ejection timing on LV relaxation.


   2 Methods
Top
 Abstract
 1 Introduction
 2 Methods
3 Results
 4 Discussion
 References
 
2.1 Experimental protocol
All animal studies were performed in accordance with guidelines described in the NIH Guide for the Care and Use of Laboratory Animals (DHHS publication No. [NIH] 85-23, revised 1996). Nine healthy mongrel dogs of either sex were surgically instrumented for long term physiologic monitoring as described previously [14,15] Data regarding the effect of HF on hemodynamics, mechanical restitution, postextrasystolic restitution and relaxation restitution from four of the animals were reported in an earlier study [15]; data regarding the effect of acute load changes on relaxation either at baseline or after HF have not been reported previously. After administration of acepromazine and pentobarbital, endotracheal intubation was performed under 1–2% isoflurane general anesthesia. A left thoracotomy was performed under sterile conditions. Fluid-filled 16-gauge catheters were placed in the descending aorta and the left atrium (LA). A high fidelity micromanometer (Konigsberg Instruments) and a fluid-filled catheter for calibration were implanted across the LV apex. Three sets of piezoelectric crystals (5 mm diameter, 5 MHz frequency) were implanted in the LV endocardium along the anterior–posterior (DAP), septal–lateral (DSL) and long axis (DLA) diameters. Pacing electrodes were sutured to the epicardium of the LA and LV. Balloon occluder cuffs were placed around the inferior and superior vena cavae. The chest was closed in multiple layers and all wires and tubes were tunneled subcutaneously to exit from the back of the neck. The animals recovered a minimum of two weeks prior to experimentation.

All experiments were performed with the animal lying in a sling on its right side. The dogs were anesthetized with a combination of thiopental sodium (25–30 mg/kg), droperidol (1.5–3.0 mg/kg), and fentanyl (0.03–0.06 mg/kg). Respiration was supported with endotracheal intubation and mechanical ventilation with room air. Under baseline conditions, the following parameters were recorded on an eight-channel forced ink oscillograph (Beckman Instruments): LV pressure (P), the first derivative of the LVP with respect to time (dP/dt), ECG, aortic pressure, and the three LV dimensions. The analog signals were simultaneously digitized at a sampling rate of 500 Hz using an IBM PC. All hemodynamic data were collected during 10 s periods of apnea to avoid the effects of respiration on measured parameters. After recording baseline hemodynamics, autonomic blockade was produced by the administration of intravenous atropine (2 mg) and hexamethonium (20–25 mg/kg). Steady-state hemodynamic measurements were then repeated. The atria were then paced at a heart rate (HR) of 160 beats per minute (bpm). After achievement of a hemodynamic steady-state, data were collected at baseline and during rapid caval occlusions to acutely alter LVP and volume (V) and produce variably loaded beats. Runs that did not display at least a 20-mmHg drop in peak systolic LVP were discarded.

The animals were allowed to recover from the initial experiments for at least two days. To produce HF, rapid ventricular pacing (RVP) was then instituted at a HR of 210 bpm for two weeks and 240 bpm for two–three more weeks (mean, 28±7 days total pacing) using customized pacemakers as described previously [16]. Mechanical measurements were performed at weekly intervals. HF was considered to be present when there was LV dilatation (≥50% increase in end-diastolic and/or end-systolic volume), contractile dysfunction (≥33% reduction in dP/dtMAX and/or end-systolic elastance), and elevated filling pressure (end-diastolic pressure ≥18). The above protocol was then repeated.

2.2 Data analysis
The digitized data were analyzed using custom-developed computer software. The LV was assumed to be an ellipse and VLV was calculated using the equation:

Formula
dP/dt was calculated from instantaneous LVP using a running five point Lagrangian fit. For caval occlusion runs, end-systole was defined as occurring at the upper left corner of the P–V loop, and the end-systolic pressure–volume (PES–VES) relation was determined by least squares linear regression using the equation:

Formula
where EES is the slope of the relation and V0 is its volume intercept [17].

For precise analysis of individual beats during caval occlusion, end-systole was considered to occur at maximal time-varying elastance for the beat [18] defined as the maximal ratio of LVP to corrected VLV (the absolute volume minus V0 determined from caval occlusion). End-diastole was defined as occurring at the peak of the QRS complex. TES, the time to end-systole, was defined as the time interval from end-diastole to end-systole. Since, in the physiologically afterloaded LV, end-systole (as defined above) occurs very close to end-ejection [18], TES was used as an index of the time to end-ejection. TT, the total time for the beat, was defined as the time interval from end-diastole to the end of isovolumic relaxation. TRO, the time of onset of isovolumic relaxation, was defined as the time interval from end-diastole to peak negative dP/dt. Instantaneous circumferential force (CF, g) was determined from the method of Suga and Sagawa [19] using the equation:

Formula
and end-systolic force (ESF) was used as an index of systolic load.

The period of isovolumic relaxation was defined as occurring between the time of peak negative dP/dt to the time when pressure had fallen to 5 mmHg above beat starting pressure. The time constant of LV relaxation, tau, was determined by nonlinear regression analysis of the pressure and time data during isovolumic relaxation using the monoexponential function:

Formula
where P0 (mmHg) is an estimate of the pressure at peak negative dP/dt, t is the time (ms), {tau} is the time constant of relaxation (ms) and PB (mmHg) is the floating pressure asymptote as t approaches infinity [20].

The relaxation–load relation during caval occlusion was assessed by plotting tau as a function of ESF. As the relation appeared to be parabolic in form, the data were fit using the least-squares technique to the quadratic equation:

Formula
where the coefficient a (g–2) quantifies the degree of curvilinearity of the tau–ESF relation (larger values of a indicating greater curvilinearity), b (g–1) is a second constant, and Tau0 (ms) is the tau axis intercept. Positive values of a indicate convexity to the ESF axis and negative values indicate concavity to the ESF axis. The tau–ESF relation defined a U-shaped curve (see below) with a minimum (nadir) for tau at an ESF value unique to each relation, termed ESFMIN. The parameter TauMAX was defined as the extrapolated tau value at an ESF that was twice that of ESFMIN (i.e. akin to Tau0 but on the right side of the tau–ESF curve).

2.2.1 Statistical analysis
Comparisons of hemodynamics, steady-state beat timing, mechanical parameters. and relaxation–load relations prior to and after the development of HF were made using the paired t-test. A P value <0.05 was considered to be significant. Comparisons of beat timing, systolic load profile, and ESV of individual beats during caval occlusion were made using a paired t-test with Bonferroni correction. Since three comparisons were made for each condition, a P value <0.0167 was considered to be significant. All group data are expressed as the mean±SD.


   3 Results
Top
 Abstract
 1 Introduction
 2 Methods
 3 Results
4 Discussion
 References
 
3.1 Steady-state hemodynamic and mechanical effects of prolonged RVP
Analog tracings prior to autonomic blockade from a representative animal before and after HF are shown in Fig. 1. Note the reductions of LVP and dP/dtMAX, increases in LVEDP, and increases in the AP, SL, and LA dimensions after prolonged RVP. Table 1 summarizes group hemodynamic data under control conditions and after HF. To control for the influence of variable heart rate, relaxation parameters and variables determined from the PES–VES relation were recorded after autonomic blockade and atrial pacing at a HR of 160 bpm. The remaining variables were recorded during baseline conditions without autonomic blockade or atrial pacing. Prolonged rapid ventricular pacing produced significant reductions in the parameters of contractility dP/dtMAX (P=0.005) and EES (P=0.004), significant increases in LV filling pressure (EDP, P=0.002), chamber size (EDV, P<0.001), and systolic load (ESF, P=0.01), a significant rightward shift of the PES–VES relation (V0, P=0.004), and significant prolongation of the rate of LV relaxation (tau, P=0.003).


Figure 1
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  		Fig. 1 Analog tracings from a representative animal showing steady-state measurements before and after heart failure. Note the increase in left ventricular (LV) end-diastolic pressure, reduction in the maximal value of dP/dt, the first derivative of LV pressure, and increases in the anterior–posterior (AP), septal–lateral (SL), and long axis (LA) diameters. ECG, electrocardiogram.

 

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  		Table 1 Hemodynamics and mechanical parameters before and after heart failurea

 
Table 2 lists parameters of systolic (ejection) timing, relaxation onset and duration, total beat duration, and timing of peak systolic force (PSF) before and after HF. These variables were recorded during steady-state conditions after autonomic blockade at a HR of 160 bpm. In the failing heart, the onset of relaxation was significantly prolonged (TRO, P=0.01) with a trend towards prolongation of total beat duration (TT, P=0.07), without significant differences in the duration of systole (TES) or relaxation (TR). Additionally, peak systolic load occurred significantly later during contraction (TPSF, P<0.001). Thus, compared to control, the failing heart was characterized by prolonged contraction (delayed inactivation), depression of the relaxation rate, and redistribution of peak systolic load to the latter half of systole.


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  		Table 2 Steady-state beat timing before and after heart failurea

 
3.2 Effect of acute variations in load on LV relaxation in normal and failing hearts
Fig. 2 shows group data regarding the effect of caval occlusion on tau under control conditions. Tau (mean±SD) is plotted against selected beats during the course of caval occlusion. With a HR of 160 bpm and a 10-s recording period, one run typically consisted of 25 beats, and in Fig. 2, data from every fourth beat is shown. Upon initiation of caval occlusion, tau initially decreased, indicating faster relaxation, but was followed by a late increase in tau with continued occlusion. In Fig. 3, tau is plotted against systolic load (ESF) for similarly selected beats from two successive caval occlusions in a representative animal (larger ESF values correspond to beats occurring earlier during occlusion). The relationship between tau and load was nonlinear and biphasic, with an initial reduction in tau with reduction in load (phase 1), followed by a late increase despite continued load reduction (phase 2). The data shown corresponded to a parabolic function with a curvilinearity coefficient a of 1.16x10–5 g–2. Fig. 4 shows the effect of HF on this relationship in the same animal. After HF, the tau–ESF relation remained nonlinear and biphasic but was shifted upward and to the right with more curvilinearity, a increasing to 3.00x10–5 g–2.


Figure 2
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  		Fig. 2 Plot of the change in tau during the course of vena caval occlusion (VCO) for the group during control conditions. Data (mean±SD) from every fourth beat are shown. Note that tau initially decreases, indicating faster relaxation, but increases again late in the occlusion to near baseline levels.

 

Figure 3
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  		Fig. 3 Tau plotted against the end-systolic force (ESF) of beats from two successive caval occlusion runs from a representative animal. The tau–ESF relation is nonlinear and biphasic, comprised an initial decrease in tau with initial load reduction (phase 1) followed by a delayed increase with continued load reduction (phase 2). The curvilinearity coefficient a describing this relation is 1.16·10–5 g–2.

 

Figure 4
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  		Fig. 4 Tau–end-systolic force (ESF) relations before and after heart failure (HF) from the same animal depicted in Fig. 3. After HF, the relation is shifted upward and to the right with increased curvilinearity, indicating increased load sensitivity of relaxation. The curvilinearity coefficient in this animal increased from 1.16·10–5 g–2 at baseline to 3.00·10–5 g–2 after HF.

 
Table 3 lists the parameters a, b, Tau0, and TauMAX of the parabolic tau–ESF relation before and after HF for each animal. The curvilinearity coefficient was significantly increased after HF (a, P=0.048), indicating increased load sensitivity of relaxation in the failing heart and resultant increased convexity of the curve toward the ESF axis. The parameters b and Tau0 were also significantly increased after HF (P=0.04 and 0.023, respectively). To determine the relative contribution of each phase of the nonlinear tau–ESF relation to the increased curvilinearity, the percentage change in Tau0 and TauMAX after HF were also calculated. As seen in Table 3, both Tau0 and TauMAX increased by nearly equivalent amounts (Tau0, 288.3% vs. TauMAX, 284.8%; P=NS), indicating a proportionate increase in curvilinearity of both phases of the tau–ESF relation after HF.


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  		Table 3 Tau–ESF relation before and after heart failurea

 
3.3 Effect of acute variations in load on beat timing, systolic loading sequence and end-systolic volume in normal and failing hearts
To determine the influence of ejection timing, relaxation onset, systolic load profile and elastic recoil on tau during caval occlusion, individual beats corresponding to the start of occlusion (BS), end of occlusion (BE), and point of inflection from phase 1 to phase 2 of the tau–ESF relation (BI) were analyzed. As seen in Table 4, under control conditions, when compared to the initial beat (BS) of phase 1, BI displayed significant reductions in TES (P=0.006), TRO (P<0.001) and ESV (P=0.003), significant increases in TPSF (P<0.001), and no significant change in TR. Upon comparison of BI to the last beat of phase 2 (BE), there was a continued significant increase in TPSF (P<0.001), continued significant reduction in ESV (P=0.015), and no significant change in either TES, TRO or TR. As indicated by the highly significant (P<0.001) and proportional reductions of PSF throughout caval occlusion, there were comparable degrees of systolic load reduction during both phases. Overall, when comparing the last beat (BE) with the first beat (BS) of caval occlusion, TES (P=0.012) and ESV (P=0.001) were significantly reduced, TPSF was significantly increased (P<0.001), and the remaining variables were unchanged. Thus, in the normal LV, the reduction in tau during phase 1 of the tau–ESF relation was associated with: (1) earlier onset of end-systole and relaxation, (2) delayed occurrence of peak systolic load, and (3) marked reductions in ESV. The subsequent phase 2 increase in tau was associated with: (1) persistent reductions in the onset of end-systole, (2) further delay in the occurrence of peak systolic load, and (3) further, though smaller, reductions in ESV.


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  		Table 4 Beat timing parameters during VCO before and after heart failurea

 
After HF, vena caval occlusion also produced highly significant and proportional reductions in systolic load (PSF, P<0.006) during both phases of the tau–ESF relation (Table 4). After HF, when compared to the initial beat (BS) of phase 1, BI displayed significant reductions in TR (P=0.015) and ESV (P=0.012), significant increases in TPSF (P=0.004) but no significant changes in either TRO or TES. Comparison of BI to BE during phase 2 revealed continued significant reductions in ESV (P=0.006) but no significant further changes in TR, TES, TRO or TPSF. As in the control state, when the last beat (BE) and first beat (BS) of caval occlusion were compared, TES (P=0.007) and ESV (P=0.005) were significantly reduced, TPSF was significantly increased (P<0.001), and the remaining variables were unchanged. Thus, similar to control conditions, caval occlusion in the failing heart resulted in earlier onset of end-systole, delayed occurrence of peak systolic load and significant reductions in ESV. However, the temporal course of these changes in TES and TPSF were markedly altered from control, with reductions in TES being more pronounced later and increases in TPSF being more prominent earlier during the caval occlusion. As a consequence, although the phase 1 reduction in tau was accompanied by significantly delayed TPSF and reduced ESV, there were no significant changes in systolic (ejection) timing or relaxation onset. Additionally, the phase 2 increase in tau was only associated with further reductions in ESV, without change in the timing variables.


   4 Discussion
Top
 Abstract
 1 Introduction
 2 Methods
 3 Results
 4 Discussion
References
 
This study provides a comprehensive evaluation of the load sensitivity of LV relaxation in the intact animal before and after HF. The major new findings are: (1) the relationship between LV relaxation and systolic load during transient load reduction is nonlinear and biphasic, resembling a U-shaped curve comprising an initial acceleration of relaxation followed by delayed slowing, (2) the initial acceleration of relaxation correlates with increased elastic recoil, whereas the delayed slowing correlates with alterations in ejection timing and systolic loading sequence, (3) in HF, the relaxation–load relation is more curvilinear, which is indicative of increased load sensitivity of LV relaxation in the failing heart and (4) the increased load sensitivity is correlated with delayed onset but increased magnitude of the impact of changes in ejection timing and systolic loading sequence.

4.1 Load sensitivity of LV relaxation in normal hearts
LV relaxation is an important determinant of LV early diastolic filling and overall LV diastolic function [21,22)] and is fundamentally regulated by myofilament inactivation (dependent on properties of both the contractile proteins and the sarcoplasmic reticulum), loading conditions, and spatial and temporal nonuniformity of these variables [3–6,23]. In the intact ejecting LV, relaxation is dependent on both the magnitude and timing of systolic load. In general, increases in systolic load in the physiological range slow the rate of relaxation, with a more pronounced effect if the load increase occurs later in ejection [5,6,24]. Additionally, early systolic loads delay whereas late systolic loads shorten the onset of relaxation [5,24]. Nonuniformity of function also slows the rate of intact LV relaxation via underlying mechanisms distinct from that of changes in global loading conditions [23]. Lastly, the ejection variables of end-systolic muscle length (or its correlate, ESV) [6,8,9] and time to end-ejection [7] are also important determinants of the LV relaxation rate. The smaller the ESV, the greater the degree of compression of myocardial elastic elements [8] and, consequently, the greater the degree of elastic recoil and restoring forces, which accelerate relaxation. Hori et al. [7] showed that delays in end-ejection independently accelerate relaxation rate in the ejecting LV, possibly indicating the influence of beat contraction history on the crossbridge detachment during relaxation. Thus, in the intact left ventricle, in addition to alterations in intrinsic deactivation properties, changes in systolic load profile, ejection timing, end-systolic volume and nonuniformity must be individually considered when evaluating mechanisms underlying alterations of relaxation.

Most prior studies assessing the effect of load in the intact LV have been performed with steady-state maneuvers such as volume loading, methoxamine, phenylephrine, nitroprusside, or aortic clamping [6,21,23–25]. Steady-state changes in afterload have complicated effects on LV function due to long-term loading history [4] and changes in contractile state due to length-dependent activation [11–13]. Additionally, neurohumoral reflex effects occur, which can change inotropic state and relaxation rates [25,26]. Single beat alterations in load [5] avoid these confounding variables but provide little insight into the effect of short term contraction history. In this study, neurohumoral reflex effects were abolished by pharmacologic autonomic blockade, and transient alterations in load with vena caval occlusion provided a window on the effect of short term contraction history without significant changes in contractile state. In addition, changes in global loading conditions were accomplished via a reduction in venous return and preload, a maneuver that does not produce significant nonuniformity [23]. Thus, these results permit selective examination of the interaction between transient changes in ejection variables and systolic load profile on LV relaxation and provide useful insights into the mechanisms underlying beat-to-beat variations in relaxation behavior.

As seen in Figs. 2–4GoGo, the response of LV relaxation to transient systolic load reduction was nonlinear and biphasic, with an initial acceleration of relaxation rate followed by a late slowing with continued reductions in load. This biphasic relationship between tau and load has not been reported previously. Examination of ejection variables and systolic load profile during this time revealed that the phase 1 acceleration of relaxation was associated with reduced ESV, TES, and delayed systolic timing of PSF (Table 4). Of these factors, only reduced ESV and attendant increased elastic recoil would result in faster relaxation [6,8,9]. Both earlier end-ejection [7] and delayed systolic timing of peak load [5,24] would be expected to slow relaxation. Similarly, examination of the phase 2 increase in tau reveals that late slowing of relaxation was associated with persistent reductions in TES, further delay in TPSF, and continued (though smaller) reductions in ESV. These directional changes in the beat timing variables (earlier end-ejection and delayed PSF) would indeed slow relaxation during this phase (see above), whereas further reductions in ESV would have the opposite effect. Thus, in the normal intact left ventricle, phase 1 of the tau–ESF relation appears to be an indicator of the influence of elastic recoil on LV relaxation, whereas phase 2 appears to be an indicator of the effect of changes in ejection timing and loading sequence. The results indicate that these timing variables exert a delayed effect on tau in this model of transient load reduction, whereas the effect of elastic recoil and restoring forces manifest more quickly.

4.2 Load sensitivity of LV relaxation in failing hearts
As seen in Tables 1 and 2Go, HF resulted in prolongation of tau, delayed onset of relaxation, suggesting delayed myofilament inactivation, and a change in systolic loading sequence such that PSF occurred during the latter half of systole, compared to the first half of systole under control conditions. These abnormalities occurred in the face of increased operative systolic load (higher ESF). During vena caval occlusion, the nonlinear relationship between tau and ESF was preserved in the failing heart. However, as seen in Fig. 3 and Table 3, the relationship became significantly more curvilinear after HF, indicative of increased load sensitivity of LV relaxation. Furthermore, the degree of increased curvilinearity was manifested equally in both phases of the tau–ESF relation, indicating a generalized increase in load sensitivity. As seen in Table 4, although the overall directional changes in the opposing influences of reductions in TES and increases in TPSF on one hand and reductions of ESV on the other during caval occlusion in the failing heart were similar to control, the temporal course of these effects was significantly altered. Whereas ESV decreased significantly during both phases of the tau–ESF relation, the reduction in TES was delayed, not becoming apparent until phase 2, and the increase in TPSF occurred earlier, with significant reductions only during phase 1. This would suggest that the increased curvilinearity of the tau–ESF relation and, hence, the increased load sensitivity of LV relaxation, occurs primarily due to a delay in onset and an increase in the overall magnitude of the effects of earlier end-ejection and late systolic loading on relaxation. These alterations would magnify the accelerative effect of increased elastic recoil (reduced ESV) on tau during phase 1, and augment the depressive effect of earlier end-ejection and late systolic loading on tau during phase 2. Delayed influence of these timing variables may be due in part to the alterations in loading sequence and relaxation onset already present at baseline in the failing ventricle.

Eichhorn et al. [10] described increased sensitivity of LV relaxation to steady-state changes in afterload in failing hearts compared to control, and observed that the degree of load-dependency increased with greater degrees of impairment of systolic function. Little [27] postulated that this increased load sensitivity of relaxation was secondary to larger reductions in ESV and greater degrees of elastic recoil, with comparable reductions in LV pressure in failing hearts compared to control. In the current study, increased load sensitivity was evident despite similar absolute reductions in ESV both before and after HF, implying that mechanisms other than increased elastic recoil were operative. The results presented would support the contention that alterations in the impact of ejection timing and systolic load profile and not increased elastic recoil are responsible for the heightened load sensitivity of LV relaxation in HF.

Although Ishizaka et al. [28] also reported that loading sequence rather than elastic recoil is the predominant variable underlying the increased load sensitivity of relaxation in the failing left ventricle, the results presented here are in conflict with their data. These investigators similarly examined the effect of transient load alterations produced by vena caval occlusion on LV relaxation, but did not report a biphasic relationship between tau and load in normal or failing hearts. Additionally, they reported no change in loading sequence during caval occlusion under normal conditions and a reduction in TPSF in HF, whereas the results of this study indicated a delay in TPSF with caval occlusion under both conditions. Significant differences in the experimental design probably account for these discrepancies. First, Ishizaka and colleagues did not control for HR, which varied between control and after HF as well as during the course of caval occlusion. As HR can significantly influence both tau and timing variables [20,29], changes in this parameter may have impacted upon the results obtained. Second, neurohumoral reflex effects were probably present in their study as significant changes in HR were induced during caval occlusion, and since autonomic blockade was not performed. Lastly, the degree of LV pressure drop achieved was less than in the current study, and greater reductions in load may be required to fully delineate the biphasic effect described here. In this study, confounding variables of HR and neurohumoral reflexes were carefully controlled in an effort to selectively examine myocardial properties.

4.3 Study limitations
This study must be examined in light of possible sources of error. First, although prior studies have shown that changes in volume load do not produce changes in LV nonuniformity indexes [23], this variable was not measured directly and the influence of subtle alterations in the uniformity on tau cannot be excluded. Second, as the exact moment of end-ejection could not be measured in this study, time to end-systole was used as a surrogate marker and a small degree of error may have been introduced. However, as delineated by Sagawa et al. [18], in the intact left ventricle contracting against physiologic levels of afterload, the end of LV ejection occurs very close in time to end-systole as defined by maximal elastance, and the difference can be disregarded without introducing significant error. Third, the influence of reduced coronary blood flow during caval occlusion must be considered. Although coronary blood flow was not measured in this study, data were not analyzed from beats with peak systolic pressures below 50 mmHg. Given that myocardial oxygen demand decreases during caval occlusion due to reduced wall stress, this level should provide adequate oxygen delivery for the transient period of caval occlusion.

In summary, I have shown that the relationship between LV relaxation and systolic load during transient load reduction is nonlinear and biphasic, with an initial acceleration of relaxation followed by delayed slowing. The initial acceleration of relaxation reflects the impact of increased elastic recoil, whereas the delayed slowing reflects the influence of earlier end-ejection and delayed systolic loading. The relaxation–load relation is more curvilinear in the failing heart, which is indicative of increased load sensitivity of LV relaxation. The increased load sensitivity of relaxation correlates with alterations in the impact of ejection timing and systolic load profile rather than increased elastic recoil. This dynamic and complex interaction between elastic recoil, timing of ejection, and systolic load profile should be carefully considered when assessing LV relaxation during transient changes in load under normal conditions and in cardiac pathologic states.

Time for primary review 31 days.


   Acknowledgements
 
This work was supported by a Grant-in-Aid from the American Heart Association, a VISN-17 Grant from the Research Service of the Department of Veterans Affairs, a grant from the South Texas Health Research Center, and a grant from the San Antonio Area Foundation. The author gratefully acknowledges the excellent technical assistance of Danny Escobedo, Cindy Ramirez and Arshia Azimi. Dr. Prabhu is an Established Investigator of the American Heart Association.


   References
Top
 Abstract
 1 Introduction
 2 Methods
 3 Results
 4 Discussion
 References
 

  1. Tomita M., Spinale F.G., Crawford F.A., Zile M.R. Changes in left ventricular volume, mass, and function during development and regression of supraventricular tachycardia-induced cardiomyopathy: disparities between recovery of systolic versus diastolic function. Circulation (1991) 83:635–644.[Abstract/Free Full Text]
  2. Komamura K., Shannon R.P., Pasipoularides A., et al. Alterations in left ventricular diastolic function in conscious dogs with pacing-induced heart failure. J Clin Invest (1992) 89:1825–1838.[Web of Science][Medline]
  3. Brutsaert D.L., Housmans P.R., Goethals M.A. Dual control of relaxation: its role in the ventricular function in the mammalian heart. Circ Res (1980) 47:637–652.[Free Full Text]
  4. Brutsaert D.L., Sys S.U. Relaxation and diastole of the heart. Physiol Rev (1989) 69:1228–1315.[Abstract/Free Full Text]
  5. Gillebert T.C., Lew W.Y.W. Influence of systolic pressure profile on rate of left ventricular pressure fall. Am J Physiol (1991) 261:H805–H813.[Web of Science][Medline]
  6. Gaasch W.H., Blaustein A.S., Andrias C.W., Donahue R.P., Avitall B. Myocardial relaxation. II. Hemodynamic determinants of rate of left ventricular isovolumic pressure decline. Am J Physiol (1980) 239:H1–H6.[Web of Science][Medline]
  7. Hori M., Kitakaze M., Ishida Y., et al. Delayed end ejection increases isovolumic relaxation rate in isolated perfused canine hearts. Circ Res (1991) 68:300–308.[Abstract/Free Full Text]
  8. Nikolic S., Yellin E.L., Tamura K., et al. Passive properties of the canine left ventricle: diastolic stiffness and restoring forces. Circ Res (1988) 62:1210–1222.[Abstract/Free Full Text]
  9. Sys S.U., Brutsaert D.L. Determinants of force decline during relaxation in isolated cardiac muscle. Am J Physiol (1989) 257:H1490–H1497.[Web of Science][Medline]
  10. Eichhorn E.J., Willard J.E., Alvarez L., et al. Are contraction and relaxation coupled in patients with and without congestive heart failure? Circulation (1992) 85:2132–2139.[Abstract/Free Full Text]
  11. Lew W.Y.W. Time-dependent increase in left ventricular contractility following acute volume loading in the dog. Circ Res (1988) 63:635–647.[Abstract/Free Full Text]
  12. Sugiura S., Hunter W.C., Sagawa K. Long-term versus intrabeat history of ejection as determinants of canine ventricular end-systolic pressure. Circ Res (1989) 64:255–264.[Abstract/Free Full Text]
  13. Freeman G.L. Effects of increased afterload on left ventricular function in closed-chest dogs. Am J Physiol. (1990) 259:H619–H625.[Web of Science][Medline]
  14. Sodums M.T., Badke F.R., Starling M.R., Little W.C., O’Rourke R.A. Evaluation of left ventricular contractile performance utilizing end-systolic pressure–volume relationships in conscious dogs. Circ Res (1984) 54:732–739.
  15. Prabhu S.D., Freeman G.L. Postextrasystolic mechanical restitution in closed-chest dogs: effect of heart failure. Circulation (1995) 92:2652–2659.[Abstract/Free Full Text]
  16. Freeman G.L., Colston J.T. Simple circuit for pacing hearts of experimental animals. Am J Physiol (1992) 262:H1939–H1940.[Web of Science][Medline]
  17. Kono A., Maughan W.L., Sunagawa K., et al. The use of left ventricular end-ejection pressure and peak pressure in the estimation of the end-systolic pressure–volume relationship. Circulation (1984) 70:1057–1065.[Abstract/Free Full Text]
  18. Sagawa K., Maughan L., Suga H., Sunagawa K. Cardiac contraction and the pressure–volume relationship. (1988) New York: Elsevier Science. 34–41.
  19. Suga H., Sagawa K. Graphical estimation of ventricular wall force and stress from pressure–volume diagram. Am J Physiol (1979) 236:H787–H789.[Web of Science][Medline]
  20. Prabhu S.D., Freeman G.L. Kinetics of restitution of left ventricular relaxation. Circ Res (1992) 70:29–38.[Abstract/Free Full Text]
  21. Cheng C.P., Freeman G.L., Santamore W.P., Constantinescu M.S., Little W.C. Effect of loading conditions, contractile state, and heart rate on early diastolic left ventricular filling in conscious dogs. Circ Res (1990) 66:814–823.[Abstract/Free Full Text]
  22. Gilbert J.C., Glantz S.A. Determinants of left ventricular filling and of the diastolic pressure–volume relation. Circ Res (1989) 64:827–852.[Free Full Text]
  23. Gillebert T.C., Lew W.Y.W. Nonuniformity and volume loading independently influence isovolumic relaxation rates. Am J Physiol (1989) 257:H1927–H1935.[Web of Science][Medline]
  24. Hori M., Inoue M., Kitakaze M., et al. Loading sequence is a major determinant of afterload-dependent relaxation in intact canine heart. Am J Physiol (1985) 249:H747–H754.[Web of Science][Medline]
  25. Karliner J.S., LeWinter M.M., Mahler F., Engler R., O’Rourke R.A. Pharmacologic and hemodynamic influences on the rate of isovolumic left ventricular relaxation in the normal conscious dog. J Clin Invest (1977) 60:511–521.[Web of Science][Medline]
  26. Blaustein A.S., Gaasch W.H. Myocardial relaxation. VI Effects of β-adrenergic tone and asynchrony on LV relaxation rate. Am J Physiol (1983) 244:H417–H422.[Web of Science][Medline]
  27. Little W.C. Enhanced load dependence of relaxation in heart failure: clinical implications. Circulation (1992) 85:2326–2328.[Free Full Text]
  28. Ishizaka S., Asanoi H., Wada O., Kameyama T., Inoue H. Loading sequence plays an important role in enhanced load sensitivity of left ventricular relaxation in conscious dogs with tachycardia-induced cardiomyopathy. Circulation (1995) 92:3560–3567.[Abstract/Free Full Text]
  29. Freeman G.L., Little W.C., O’Rourke R.A. Influence of heart rate on left ventricular performance in conscious dogs. Circ Res (1987) 61:455–464.[Abstract/Free Full Text]

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