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(Circulation. 1995;92:2652-2659.)
© 1995 American Heart Association, Inc.
Articles |
Postextrasystolic Mechanical Restitution in Closed-Chest Dogs
Effect of Heart Failure
From the Department of Medicine, University of Texas Health Science Center at San Antonio, and the Audie Murphy Memorial Veterans Hospital, San Antonio, Tex.
Correspondence to Sumanth D. Prabhu, MD, Department of Medicine/Cardiology, University of Texas Health Science Center, 7703 Floyd Curl Dr, San Antonio, TX 78284-7872.
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Abstract |
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 Top Abstract IntroductionMethods Results Discussion References |
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Background Postextrasystolic mechanical restitution (MRPES) is thought to be an expression of intracellular Ca2+ handling by cardiac sarcoplasmic reticulum (SR). Since congestive heart failure is characterized by abnormal intracellular Ca2+ homeostasis, we sought to delineate MRPES behavior before and after the production of heart failure to obtain insights into the relation between altered mechanical performance and Ca2+ handling.
Methods and Results Ten dogs instrumented with left ventricular (LV) micromanometers and piezoelectric dimension crystals were studied under control conditions; 6 dogs also were studied after tachycardia heart failure (THF) produced by rapid LV pacing for 4 weeks. After priming at a basic cycle length of 375 ms, test pulses were delivered at fixed extrasystolic intervals (ESIs; 300, 375, or 450 ms) and graded postextrasystolic intervals (PESIs). Postextrasystolic mechanical response was assessed using single-beat elastance. MRPES curves were constructed by expressing normalized mechanical response as a function of the PESI. Control MRPES was a monoexponential function whose time constant (TC) and PESI–axis intercept (PESI0) increased significantly (P<.01) with increases in the antecedent ESI. THF significantly slowed MRPES kinetics at each antecedent ESI (P<.025), increased normalized maximal contractile response (CRmax, P<.01), and shortened PESI0 (P<.025). Increases in the TC and CRmax were most pronounced with the smallest antecedent ESI (percent control postextrasystolic TC 363.7±60.5%, ESI of 300 ms versus 139.0±15.1%, ESI of 450 ms, P<.005; percent control CRmax 128.6±4.9%, ESI of 300 ms versus 104.9±1.0%, ESI of 450 ms; P<.005).
Conclusions MRPES is much less dynamic in THF: The failing heart operates at lower levels of contractile performance after higher stimulation frequencies and cannot increase its speed of contractile recovery to compensate for higher heart rate. Prolongation of MRPES kinetics is consistent with depression of SR Ca2+ release mechanisms in THF and implicates this site in the loss of the capacity of the failing heart to maintain mechanical performance with tachycardia.
Key Words: tachycardia • heart failure • mechanics • contractility • systole
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Introduction |
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TopAbstractIntroductionMethods Results Discussion References |
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Force-interval behavior describes the relation between myocardial contractile performance and the rate and pattern of stimulation.1 One manifestation of this relation is MR, time-dependent recovery of the contractile response of extrasystoles after a depolarization. MRPES is a related process that describes the contractile recovery of postextrasystoles after a beat occurring at a fixed ESI. While MR is a mechanical expression of the negative inotropic effect of early activation, MRPES offers additional insights into the mechanisms of functional recovery after abrupt changes in stimulation pattern. Both MR and MRPES can be characterized by monoexponential functions relating mechanical response to either the ESI or PESI and quantified by specific TCs.2 3 4 The force-interval relation is a fundamental property of the myocardium and has been studied in a variety of preparations, including isolated muscle,5 6 isolated hearts,3 4 and intact animals.2 7 8 A prior study6 revealed that the variability in contractile response is related linearly to intracellular Ca2+ concentration and that these events are manifestations of the circulation kinetics of activator Ca2+ within the cell. Studies with ryanodine, an inhibitor of Ca2+ release from the SR, have established a central role for this organelle in governing force-interval behavior.6 9 10 11
Prior studies from this laboratory2 7 8 have shown that (1) MR can be quantified accurately in the intact animal within the pressure-volume framework, (2) MR kinetics are much faster in intact animals than in isolated hearts or muscle strips, (3) active relaxation also follows a biphasic pattern of restitution (an initial rapid recovery paralleling MR kinetics followed by late slowing), and (4) both MR and early relaxation restitution behavior are predicted by a "recirculating" compartmental model of Ca2+ handling put forth by several investigators.4 6 10 12 13 14 15 These studies suggested that MR and early relaxation restitution are direct reflections of SR behavior resulting primarily from recovery of SR Ca2+ release mechanisms and Ca2+ uptake capacity, respectively,7 8 and consequently are convenient windows on SR function in the intact animal.
As mechanical corollaries of SR function, restitution parameters can be used to identify abnormalities in Ca2+ handling that occur as a result of cardiac pathology. Congestive heart failure is characterized by altered intracellular Ca2+ homeostasis at many levels, evidenced by prolongation of myocardial Ca2+ transients measured with fluorescent indicator dyes,16 17 18 increased end-diastolic and reduced peak intracellular Ca2+ levels,17 and reduced expression of mRNA encoding for the Ca2+ release channel and Ca2+-ATPase pump of cardiac SR.19 Recently, we have shown that heart failure produced by prolonged rapid ventricular pacing (THF) in closed-chest dogs slows MR without affecting early relaxation restitution despite marked depression of both baseline contraction and relaxation.8 This indicated in the intact animal that the recovery kinetics of SR Ca2+ release are altered to a significantly greater extent than SR Ca2+ sequestration and that the former is the rate-limiting step in the restitution of cardiac function in the failing heart.
The purpose of the present study was to extend our prior work by examining MRPES behavior in closed-chest dogs before and after THF to obtain further insights on the relation between mechanical performance and altered Ca2+ handling in normal and failing intact hearts. Additionally, we hypothesized that delineating patterns of postextrasystolic mechanical recovery would help define mechanisms of contractile regulation in normal and failing hearts during abrupt changes in heart rate. THF has been used extensively as an experimental model of heart failure, and in the canine model,18 20 21 rapid cardiac pacing produces ventricular dilatation without excessive fibrosis, hypertrophy, or ischemia.
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Methods |
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TopAbstractIntroductionMethods Results Discussion References |
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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 NIH 85-23, revised 1985). Ten healthy mongrel dogs of either sex were surgically instrumented for long-term physiological monitoring as previously described.7 8 22 Data regarding the effect of THF on hemodynamics, MR, and relaxation restitution from 5 of the dogs were previously reported8 ; MRPES data from these dogs either at baseline or after THF have not been reported previously. After premedication with acepromazine and induction with pentobarbital, endotracheal intubation was performed under 1% to 2% isoflurane general anesthesia. Under sterile conditions, a left thoracotomy was performed. Fluid-filled polyvinyl 16-gauge catheters were placed in the descending aorta and the left atrium. For calibration, a high-fidelity micromanometer (Konigsberg Instruments, Inc) and a fluid-filled catheter were implanted across the apex of the LV. Three sets of piezoelectric crystals with 5-mm diameter and 5-MHz frequency were implanted in the LV endocardium along the anteroposterior, septal-lateral, and long-axis diameters. Pacing electrodes were sutured to the epicardium of the left atrium and LV. Balloon-occluder cuffs were placed around the inferior vena cava. The chest was closed in multiple layers, and all wires and tubes were tunneled subcutaneously to exit from the back of the neck. The dogs recovered a minimum of 2 weeks before experimentation.
All experiments were performed with the dog lying on its right side in a sling. The dogs were anesthetized with a combination of thiopental sodium (25 to 30 mg/kg), droperidol (1.5 to 3.0 mg/kg), and fentanyl (0.03 to 0.06 mg/kg). Respiration was supported with endotracheal intubation and mechanical ventilation with room air. Autonomic blockade was produced by the administration of atropine (2 mg IV) and hexamethonium (20 to 25 mg/kg IV). All hemodynamic data were collected during 10-second periods of apnea to avoid the effects of respiration on measured parameters. The following parameters were recorded on an eight-channel forced-ink oscillograph (Beckman Instruments Inc): LVP, the first derivative of the LVP with respect to time (dP/dt), ECG, aortic pressure, and the three LV dimensions. The analog signals were digitized simultaneously at a sampling rate of 500 Hz by use of an IBM personal computer.
The atria were paced at a basic cycle length of 375 ms (160 beats per minute). After a hemodynamic steady state was achieved, data were collected at baseline and during rapid caval occlusions to acutely alter LVP and LV volume. Runs that did not display at least a 20-mm Hg drop in peak-systolic LVP were discarded. After caval occlusions were performed, MRPES was assessed. After an initial series of beats at the basic cycle length, two atrial extrastimuli were introduced with a programmable stimulator (Bloom Instruments). The first extrastimulus was delivered at a fixed ESI of 300, 375, or 450 ms. The second extrastimulus was delivered over a range of PESIs. The initial PESI was timed to be within the absolute refractory period of the atrioventricular node. The PESI was then increased at 20-ms intervals, resulting in beats with progressively increasing cycle length. The process was terminated when an intrinsic sinus beat captured the ventricle before the paced beat.
The dogs were allowed to recover from the initial experiments for 2 days. At this point, rapid ventricular pacing was instituted in six dogs at a heart rate of 210 beats per minute for 2 to 3 weeks and 240 beats per minute for 1 to 2 more weeks. Hemodynamic measurements were performed at weekly intervals. When there was clear LV chamber dilation and hemodynamic evidence for heart failure, the above restitution protocol was repeated. After the full study was completed, the dogs were euthanatized by lethal injection under general anesthesia.
Data Analysis
The digitized data were analyzed by use of
computer
software developed in our laboratory. The LV chamber was assumed to be
an ellipse, and LV volume (VLV) was calculated from the
three orthogonal dimensions with the following equation:
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where DAP, DSL, and DLA are anteroposterior, septal-lateral, and long-axis diameters, respectively. Calculated dP/dt was derived from instantaneous LVP with a running five-point lagrangian fit. For caval occlusion runs, end systole was deemed to occur at the upper left corner of the LV pressure-volume loop, and the end-systolic pressure-volume (Pes-Ves) relation was determined by use of the iterative approach of Kono et al.23 The data were fitted to the following equation:
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by the least-squares linear regression technique, where Ees is the slope of the relation.
For postextrasystolic beats, maximal time-varying elastance (SBE) was defined as the maximal ratio of LVP to corrected VLV (calculated volume minus V0 determined from the caval occlusions) and used as a measure of contractile response.24 For MRPES analyses, calculated SBE for the postextrasystolic beat was normalized to the SBE from the last preceding beat at the basic cycle length and expressed as a percent. MRPES curves were generated by plotting normalized SBE (SBEn) versus the corresponding PESI. The curves were fit to the following monoexponential function:
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All monoexponential function analysis and TC derivations were performed according to standard nonlinear techniques.
Statistical Analyses
Comparisons between MRPES
parameters
within each experimental condition corresponding to different ESIs were
made by paired t test with the Bonferroni correction.
Because three comparisons were made under each condition (control and
THF), a value of P<.0167 was considered significant.
Comparisons between hemodynamic and restitution
parameters before and after the development of THF were
made by paired t test. A value of P<.05 was
considered significant. All group data are expressed as the
mean±SEM.
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Results |
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TopAbstractIntroductionMethods Results Discussion References |
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Postextrasystolic MR in the Normal Intact Heart
Analog tracings from a representative animal before and after the production of THF are shown in Fig 1
.
Identical stimulation patterns (extrasystoles at ESIs
of either 300 or 450 ms followed by postextrasystoles at a PESI of 280
ms) are shown under both conditions. There was no respiratory variation
in the recorded parameters. Note that under both
conditions, the mechanical response of the postextrasystole was smaller
after beats with the larger ESI of 450 ms. Fig 2 shows
control MRPES curves from another dog at the three
different ESIs. After an increase in the antecedent ESI, the
MRPES curves displayed slower kinetics (TC increased
sequentially from 13.7 ms at an ESI of 300 ms to 55.3 ms at an ESI of
450 ms) and a rightward shift (PESI0 increased sequentially
from 251 ms at an ESI of 300 ms to 277 ms at an ESI of 450 ms).
Additionally, this dog displayed a slight decrease in normalized
CRmax with increasing ESI (CRmax decreased
sequentially from 107.9% at an ESI of 300 ms to 101.2% at an ESI of
450 ms). Control MRPES parameters corresponding
to each ESI are shown in Table 1. MRPES was
strongly dependent on the interval of the preceding
extrasystolic beat. Both the TC and the PESI0
increased significantly with a corresponding increase in the preceding
ESI (P<.01 for the change in either parameter
when compared at an ESI). There was no significant difference in
normalized CRmax achieved at any given antecedent ESI.
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Hemodynamic Effects of Prolonged Rapid
Ventricular Pacing
As seen in Fig 1
, there were
reductions of LVP and maximum dP/dt
and increases in the anteroposterior, septal-lateral, and
long-axis dimensions after prolonged rapid ventricular
pacing. Table 2 summarizes group
hemodynamic data under control conditions and after THF
(mean±SEM). To control for the influence of variable heart rate,
Ees was recorded after autonomic blockade with atropine
and hexamethonium and with atrial pacing at a cycle
length of 375 ms. The remaining variables were recorded during
baseline conditions without autonomic blockade or atrial pacing. THF
produced significant reductions (P<.005) in
parameters of contractility
(dP/dtmax and Ees) and significant
increases (P<.015) in LV filling pressure and chamber size.
The hemodynamic and geometric changes were
consistent with the production of dilated
cardiomyopathy.
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Effect of THF on MRPES
Fig 3 shows
the MRPES curves
corresponding to an ESI of 300 ms from a representative
dog before and after THF. Absolute SBE is plotted as a function of the
PESI. The reduction of peak contractile response after THF
production is evident. Fig 4 shows normalized
MRPES curves from the same dog corresponding to three
different ESIs: 300 (Fig 4A), 375 (Fig 4B), and
450 ms (Fig 4C).
Regardless of the antecedent ESI, THF produced (1) significant slowing
of MRPES kinetics evidenced by prolongation of the TC, (2)
significant increases in normalized CRmax despite marked
reductions in absolute contractility, and (3)
significant reductions in PESI0 (PESI0,
170 versus 250 ms for an ESI of 300 ms, 218 versus 238 ms for an ESI of
375 ms, and 215 versus 251 ms for an ESI of 450 ms). These effects
resulted in reduced concavity of the MRPES curve with
respect to the PESI axis and delayed achievement of CRmax.
Additionally, changes in all of these parameters were most
pronounced at the smallest ESI of 300 ms.
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MRPES parameters
corresponding to each ESI
before and after THF are shown in Table 3. Regardless of
the antecedent ESI, heart failure consistently and
significantly increased the postextrasystolic TC
and CRmax and shortened PESI0
(P<.025 for the change in any parameter after
THF). When the effect of the ESI on MRPES
parameters after THF is examined, two differences from
control are apparent. First, although the MRPES TC
generally increased with increasing ESI, the magnitude of change was
much smaller than that of control (1.3-fold versus 3.3-fold increase in
TC from an ESI of 300 to 450 ms) and did not reach strict statistical
significance over the range of ESIs tested (ESI of 300 ms versus ESI of
450 ms, P=.0214). Second, normalized CRmax
increased significantly when the antecedent ESI was shortened (ESI of
300 ms versus ESI of 450 ms, P<.001). The effect of the ESI
on PESI0 after THF was similar to control;
PESI0 decreased significantly with decreasing ESI (ESI of
300 ms versus ESI of 450 ms, P<.005).
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Fig 5
expresses each MRPES
parameter after THF as a percentage of that under control
conditions (before THF) at each of the three ESIs. The greatest degrees
of prolongation of MRPES kinetics and increases in
CRmax were seen at the smallest ESI (percent control TC,
363.7±60.5% for an ESI of 300 ms versus 139.0±15.1% for an ESI
of
450 ms, P<.005; percent control CRmax,
128.6±4.9% for an ESI of 300 ms versus 104.9±1.0% for an ESI of
450
ms, P<.005). Reductions in PESI0 were
comparable at each ESI (percent control PESI0,
82.7±5.1% for an ESI of 300 ms versus 87.2±3.6% for an ESI of
450
ms; P=NS). Thus, THF resulted in (1) generalized but
disproportionate slowing of MRPES kinetics with the
greatest changes corresponding to smaller antecedent ESIs, (2)
increased normalized CRmax with disproportionately greater
changes again corresponding to smaller antecedent ESIs, and (3)
proportional reductions in the time of onset of MRPES.
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Discussion |
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TopAbstractIntroductionMethods Results Discussion References |
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This study provides, for the first time, a systematic assessment of MRPES in closed-chest dogs before and after heart failure. The results demonstrate that the dependence of postextrasystolic contractile strength on the preceding stimulus interval in the intact dog without heart failure has the following properties: (1) MRPES is a monoexponential function for which TC increases (ie, slower kinetics) with increases in the preceding ESI; (2) PESI0, the extrapolated time of onset of MRPES, increases along with the preceding ESI; and (3) CRmax is invariant despite changes in the preceding ESI. Heart failure alters this relation in several ways: (1) THF significantly slows MRPES kinetics, (2) THF significantly increases normalized CRmax, and (3) THF significantly decreases PESI0. The increases in the MRPES TC and CRmax were greatest with the smallest preceding ESI, whereas the reductions in PESI0 were similar regardless of the ESI. As a result, MRPES behavior in the failing heart was characterized by significantly less variability of the TC with changes in the preceding ESI and a novel dependence of CRmax on previous beat contraction history. The dependence of PESI0 on the preceding stimulus interval in THF was similar to control.
We will focus the discussion on three areas: (1) implications of these findings on mechanical performance of normal, intact hearts and the relation of our data to prior studies of MRPES; (2) implications of these findings on the mechanical performance of failing hearts and possible explanations for differences in MRPES behavior between the intact animal and the isolated heart; and (3) the prediction of MRPES behavior before and after THF using compartmental models of myocardial Ca2+ handling.
Insights on Mechanical Performance of Normal Intact
Hearts
MRPES has been studied in the isolated muscle
preparation,25 26 27 the isolated
heart,4 and to
a very limited extent in intact animals.2 26
Objective
comparisons to early studies by Johnson et al,25 Anderson
et al,26 and Wohlfart27 are difficult because
the MRPES curves reported, while qualitatively appearing
monoexponential, were not fitted to simple
monoexponential functions. However, leftward shifts of
the MRPES curve with reductions in the preceding ESI were
described by both Johnson et al and Wohlfart. Yue et al4
were the first group to quantify MRPES in isolated perfused
hearts obtained from normal dogs. They reported MRPES TCs
that were significantly longer than in the present study (182±44
ms) and that were independent of the preceding ESI. Additionally,
decreases in the ESI were associated with decreases in
PESI0 and increases in CRmax (range in
CRmax, 129% to 258%). The reduction in
PESI0 was correlated to shortened monophasic APD of the
extrasystolic beat. Shortening of APD with increasing
stimulation frequency also has been confirmed in the in situ canine
heart28 and in isolated muscle fiber
studies.16
Examination of our data in the normal intact
dog (Fig 2 and Table 1)
reveals differences in behavior from the isolated heart preparation.
First, MRPES TCs are much smaller (ie, faster kinetics) and
highly dependent on the antecedent ESI. Second, normalized
CRmax is also significantly smaller and invariant,
regardless of the preceding ESI. Conversely, PESI0 behavior
is very similar to the isolated heart. This indicates that (1) at the
basic cycle length we tested, the intact heart operates close to its
CRmax (resulting in smaller normalized values of
CRmax) even at higher stimulation frequencies
(smaller ESIs) and (2) restitution behavior is rapid and dynamic in the
intact heart, adapting to perturbations in stimulation pattern. Thus,
in response to increases in stimulation frequency, the intact heart
speeds its recovery of mechanical capacity such that it can maintain
its level of performance near the optimal range, thereby
minimizing any detrimental effects of tachycardia on
contractile performance.
Insights on Mechanical Performance of Failing Intact
Hearts
We previously reported that THF slowed MR kinetics and
prolonged
the time required for achievement of CRmax such that
significantly less contractile recovery occurred at the basic cycle
length.8 Similarly, the basic abnormality in
MRPES behavior after THF is slowing of restitution kinetics
reflected by significant increases in the TC regardless of the
preceding ESI (Fig 4). Concurrently, the failing heart displays
earlier
onset of MRPES (smaller PESI0), perhaps to
compensate for slower kinetics. Additionally, achievement of
CRmax was delayed owing to slower recovery of mechanical
performance, and THF hearts (unlike normal hearts) did not
operate at maximal capacity at the heart rates used. This was
manifested by increases in normalized CRmax plateau values
after establishment of THF at each ESI used. As seen in Fig 5,
the
changes in MRPES TC and CRmax were
disproportionate and the greatest degree of change occurred with the
smallest ESI. This asymmetric effect resulted in relative independence
of the TC and a strong dependence of CRmax on the preceding
ESI after THF production. Thus, in the failing heart,
restitution is much less dynamic, as evidenced by the inability of the
heart to increase its speed of mechanical recovery with reductions in
stimulation frequency. The heart is unable to maintain mechanical
performance in the face of tachycardia and operates
at increasingly lower levels of performance at higher heart
rates. Conversely, slower heart rates allow the heart enough time to
operate near its CRmax plateau. These results are
consistent with attenuation or reversal of the normal
augmentation in contractility effected by increasing
heart rate (ie, force-frequency effect), which has previously been
reported in isolated myopathic
muscle,16 29 30
closed-chest dogs with THF,31 32 and patients with
dilated cardiomyopathy.33
These alterations in MRPES behavior, prolongation of the TC, increases in CRmax with reductions in ESI, and relative independence of the TC on the ESI, are akin to MRPES behavior in isolated hearts obtained from normal animals.4 This suggests that there is a significant degree of myodepression intrinsic to the isolated heart preparation that reconciles the differences in restitution behavior seen between that preparation and the intact state. This observation also has important implications in the interpretation of other mechanical data obtained from the isolated heart and suggests that myocardial depression inherent to the preparation may affect the results of performance reported to represent normal function.
Interestingly, our dogs displayed a consistent reduction in PESI0 after THF, regardless of the antecedent ESI, which may compensate for slower overall MRPES kinetics. As mentioned above, Yue et al4 correlated reduction in PESI0 to shortening of the extrasystolic monophasic APD and hypothesized that the two may be casually related. Arlock et al34 showed that MR starts at the time of repolarization and is a function of cell membrane potential. Because of limits posed by atrioventricular nodal conduction time and refractory period, PESI0 is an extrapolated, rather than measured, variable in the intact state. Nonetheless, the shortened time to onset of MRPES would suggest shortening of APD and abbreviated repolarization in THF at the stimulation frequencies used. Electrophysiological studies in the canine THF model by Li et al35 revealed variable effects on APD with increased APD of ventricular muscle and shortened APD of Purkinje fibers (frequency of stimulation, 1 Hz). Resting membrane potential was uniformly decreased (less negative), regardless of site. Studies of ventricular trabeculae from patients with dilated and ischemic cardiomyopathy16 have revealed prolongation of APD at low stimulation frequencies (0.33 Hz) but no difference from control at higher stimulation frequencies (1 Hz). Interestingly, studies of doxorubicin-induced cardiomyopathy have revealed shortening of ventricular repolarization.36 These microelectrode studies suggest that APD is variable in the failing heart depending on site of measurement, stimulation frequency, and model used. One can speculate that at the relatively high stimulation frequencies used in our studies, APD may have been shorter after THF than in the control state. Alternatively, after THF, PESI0 may be less dependent on APD and more a function of other electrophysiological variables, such as membrane potential and altered depolarization thresholds. Since we did not assess APD specifically, further studies are required to define the mechanisms underlying the leftward shift of PESI0 after THF.
Relationship of MRPES Behavior to Intracellular
Ca2+ Handling
Several
investigators4 6 10 12 13 14 15
have proposed a
"recirculating" model of cellular activator
Ca2+ to explain force-interval behavior.
According to this model, Ca2+ sequestered by the SR
during the Ca2+ transient (predominantly from
internally released stores and a smaller amount from transsarcolemmal
flux) is only gradually available for release on the subsequent beat.
The time course of availability of releasable Ca2+
is responsible for MR kinetics. Since there is no anatomic evidence for
the presence of distinct uptake and release structures within the
SR,37 the mechanism for this gradual return of releasable
Ca2+ is likely to be due to time-dependent
recovery of the SR Ca2+ release
channel.38 Moreover, diffusion of sequestered
Ca2+ to SR Ca2+ release sites is
thought to occur too rapidly to affect restitution
kinetics.38
This model provides a basis for
conceptualizing MRPES
behavior and the changes produced by heart failure. In the normal
heart, introduction of a beat with a short ESI would result in less SR
Ca2+ release due to incomplete recovery of the
release channel. Simultaneously, additional loading of the
SR would occur during the Ca2+ transient of the
early beat. This would result in a greater amount of SR
Ca2+ available for release on the subsequent
postextrasystolic beat, with the result of larger
mechanical responses and faster restitution kinetics. This effect would
be most pronounced with very short ESIs and would decrease in magnitude
as the ESI lengthens. Predictably, our data show the greatest relative
increase in control MRPES TC values after the ESI is
increased from 300 to 375 ms (2.3-fold increase versus 1.4-fold
increase seen after the ESI is increased from 375 to 450 ms, Table
1).
It is likely that if larger ESIs were tested, the increases in the
MRPES time constant would have incrementally decreased.
In
failing hearts, concomitant effects of the underlying pathology must
be taken into account. Multiple lines of evidence attest to generalized
alterations of both SR Ca2+ release and uptake
properties in CHF, resulting in altered Ca2+
homeostasis.16 17 18 19 39
Vatner et al40 showed
that ryanodine receptor binding (ie, SR Ca2+ release
channel binding) is significantly reduced, with attendant depression of
MR after rapid ventricular pacing for just 1 day,
suggesting a primary role for this site in the pathogenesis of THF. We
have previously shown that despite generalized depression of both
contractile function and active relaxation, THF selectively slows MR
kinetics without affecting early relaxation restitution kinetics,
incriminating abnormal SR Ca2+ release channel
recovery as the rate-limiting step in cardiac
restitution.8 Reduced SR Ca2+ release
channel function would also be expected to slow MRPES
kinetics, regardless of the preceding ESI (Fig 4 and Table
3).
Abnormalities at this site can also explain the
divergent effects of
changing the preceding stimulus interval on MRPES behavior
in failing hearts compared with control hearts. Just as in the control
state, decreasing the preceding ESI would result in additional
Ca2+ loading of the SR before the postextrasystole.
Unlike the control state, however, depression of SR
Ca2+ release mechanisms would delay availability of
this additional Ca2+ until longer PESIs are reached.
This altered time course would have two effects: a reduction in the
normal augmentation of mechanical response of beats at short PESIs and
an exaggeration of the mechanical response of beats at longer PESIs.
The former effect would minimize any abbreviation of MRPES
kinetics, with reductions in the antecedent ESI in failing hearts
compared with control hearts (Table 3). The latter effect would
increase normalized CRmax (compared with contractile
response at the basic cycle length), with reductions in the antecedent
ESI in failing hearts (Fig 4 and Table 3). Since
lesser degrees of SR
Ca2+ loading occur with larger antecedent ESIs, the
rise in CRmax after THF should decrease as the ESI is
lengthened (Fig 5 and Table 3). Thus,
derangement of SR
Ca2+ release mechanisms predict the effects of THF
on MRPES parameters seen in our study.
Additionally, pathology at this intracellular site would also be
responsible for the inability of the failing heart to maintain
mechanical performance with higher heart rates.
Study Limitations
SBE rather than maximum dP/dt was used as
an index of
contractility because restitution curves using the
latter parameter are significantly altered in ejecting
hearts compared with isovolumically beating hearts.3 As
shown by Burkhoff et al,3 this is secondary to preload
dependence of dP/dtmax (resulting in a steeper rise
of the early portion of the MR curve) and earlier onset of ejection in
beats with long test-pulse intervals (resulting in a late
descending limb of the curve). The use of SBE eliminates these
effects.2 As in our prior studies of cardiac restitution,
we used the V0 determined at the basic cycle length to
calculate SBE for postextrasystolic beats. Although
steady-state increases in heart rate change V0,
the effect of changes in ventricular volume on
end-systolic pressure occur over several
beats.41 This effect is minimal, with the transient
alteration of pacing interval used to produce test beats at different
ESIs and PESIs. Given this and the fact that it would not be possible
to perform caval occlusion at each PESI used, a common V0
was used.2 7 8 Second, as in many prior
studies, our
analysis assumes a linear end-systolic
pressure-volume relation. In the intact canine model, Little et
al42 showed a slight curvilinearity of the
end-systolic pressure-volume relation, with concavity
toward the volume axis regardless of inotropic state. Since similar
degrees of nonlinearity are present under each condition, the use
of a linear model may introduce a small and consistent
quantitative error but should not significantly affect our
analysis. Finally, it should be reiterated that owing to the
properties of atrioventricular nodal conduction,
PESI0 in the intact animal is necessarily extrapolated and
may be subject to some degree of inaccuracy. However, since the
monoexponential fits obtained in our dogs generally
were excellent and since directional changes in PESI0 were
remarkably consistent, this degree of error is probably
small.
In summary, our results demonstrate that MRPES in the intact animal begins earlier and proceeds more rapidly when preceded by extrasystoles at smaller stimulus intervals, reaching a common maximal contractile plateau. THF slows MRPES kinetics and increases normalized CRmax, with the greatest degrees of change corresponding to the smallest ESI. Additionally, the MRPES curve becomes less concave toward the PESI axis after THF, abbreviating the time of onset of MRPES. These results indicate a reduced capacity of the failing heart to recover contractile performance with increases in stimulation frequency and help to explain reduced performance of the failing heart in the presence of tachycardia. MRPES behavior in intact animals after THF resembles that of the isolated heart obtained from healthy animals and suggests some degree of myodepression intrinsic to the latter preparation. The properties of the MRPES curve are consistent with recirculating models of intracellular activator Ca2+. The alterations produced by THF suggest depression and delayed recovery of SR Ca2+ release mechanisms and implicate this process as the mechanism underlying the impaired systolic performance of the failing heart in the presence of tachycardia.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This work was supported by the Research Service of the Department of Veterans Affairs, Grants-in-Aid from the American Heart Association and its Texas Affiliate, and an institutional grant from the University of Texas Health Science Center. The authors gratefully acknowledge the excellent technical assistance of Danny Escobedo and Cindy Ramirez.
Received April 3, 1995; revision received May 22, 1995; accepted May 30, 1995.
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