(Circulation. 1995;91:176-185.)
© 1995 American Heart Association, Inc.
Effect of Tachycardia Heart Failure on the Restitution of Left Ventricular Function in Closed-Chest Dogs
From the Department of Medicine, University of Texas Health Science Center at San Antonio, and 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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Background Cardiac mechanical restitution and relaxation restitution are thought to be physiological correlates of the recovery kinetics of Ca2+ release mechanisms and sequestration capacity of the sarcoplasmic reticulum (SR). Since congestive heart failure is characterized by abnormal intracellular Ca2+ handling, we sought to delineate changes in mechanical and relaxation restitution produced by heart failure.
Methods and Results Six dogs instrumented with left ventricular (LV) micromanometers and piezoelectric dimension crystals were studied under control conditions and after tachycardia heart failure (THF) produced by rapid LV pacing for 3 to 4 weeks. After priming at a basic cycle length of 375 ms, test pulses were delivered at graded extrasystolic intervals (ESIs). Mechanical response was assessed from single-beat elastance. Relaxation was assessed from the time constant of isovolumic relaxation (tau), the average rate of pressure fall during isovolumic relaxation (Ravg), and peak negative dP/dt, the first derivative of LV pressure. Normalized mechanical and relaxation responses plotted against ESI produced monoexponential curves of mechanical and relaxation restitution. THF depressed baseline contractile and relaxation parameters compared with control (end-systolic elastance, 4.7±0.4 versus 7.1±0.5 mm Hg/mL, P<.005; tau, 34.8±2.2 versus 26.7±1.2 ms, P<.05; all values mean±SEM). THF slowed mechanical restitution and delayed development of peak contractile response, with the time constant of mechanical restitution increasing from 61.8±6.9 to 100.2±9.6 ms, P<.01. THF abolished the biphasic behavior of relaxation restitution, and this relation was approximated by a single monoexponential function. There was no difference in the time constants of the first phase of relaxation restitution at control and after THF (TCR1, normalized 1/Ravg, 44.3±5.6 versus 42.0±8.5 ms, P=NS; TCR1, normalized (dP/dtmin)-1, 42.2±6.3 versus 36.7±4.3 ms, P=NS).
Conclusions These results indicate that THF alters the recovery kinetics of SR Ca2+ release to a significantly greater extent than those of SR Ca2+ sequestration and that the abnormal time course of Ca2+ availability to the myofilaments is the rate-limiting step in the recovery of cardiac function after a depolarization.
Key Words: mechanics • calcium • myocardial contraction • heart failure
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Introduction |
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Congestive heart failure (CHF) is marked by multiple structural and functional derangements of the myocardium. Many investigators have suggested that altered intracellular Ca2+ handling plays an important role in producing the myocardial functional abnormalities in CHF.1 2 3 4 5 6 Such abnormal Ca2+ handling could occur in any one of several sites, including the sarcolemma, the sarcoplasmic reticulum (SR), and the contractile apparatus. Studies of myocardium from humans with CHF and from animals modeled to have heart failure have demonstrated associated alterations of SR function. Myocardial calcium transients (dependent in part on SR function) measured with aequorin or fura-2 are consistently prolonged in heart failure.1 2 3 4 5 6 Human studies have reported higher end-diastolic levels of intracellular Ca2+ (Ca2+i)1 2 3 4 5 and either normal1 2 or decreased5 peak Ca2+i levels. Studies of gene expression7 have revealed that the mRNA for both the SR Ca2+ release channel and Ca2+ ATPase pump is reduced in heart failure and that the greatest reduction occurs in advanced disease.
Mechanical restitution and relaxation restitution of cardiac muscle are the time-dependent processes by which the capacity to contract and the ability to relax return after a stimulation. Mechanical restitution can be described by a monoexponential function relating mechanical response to the extrasystolic interval (ESI)8 and has been described in intact animals9 10 as well as isolated hearts11 12 and isolated muscle preparations.13 14 Wier and Yue14 have shown that the contractile response generated has a linear correlation with intracellular Ca2+ concentration, with a central role for Ca2+ handling by the SR in restoring contractile performance.
Analogous to the restitution of generated force, the ability of the myocardium to relax also recovers in an exponential fashion after a stimulus. We have previously shown15 that relaxation restitution proceeds in two phases: an initial recovery of relaxation occurring from small ESIs until the basic cycle length and a late slowing of relaxation occurring with ESIs greater than the basic cycle length. Each phase can be described by a monoexponential function with a specific time constant of restitution. The time constant of the first phase is generally smaller than the time constant of the second phase, indicating faster initial restitution. Since dissociation of Ca2+ from troponin C, myocardial cross-bridge separation, and sarcomere force decay are dependent on active Ca2+ uptake by the SR,16 17 it follows that this organelle also plays a major role in determining the kinetics of the first phase of relaxation restitution. The late slowing of relaxation is probably not an expression of SR function but may be secondary to loading effects on relaxation evident at long cycle lengths.15
Thus, mechanical restitution and early relaxation restitution are macroscopic measures of cardiac calcium handling and may reflect physiological correlates of SR function. Since alterations of SR function may play a prominent role in the production of Ca2+ handling abnormalities in heart failure, the purpose of this study was to define changes in mechanical and relaxation restitution after the production of heart failure in dogs by prolonged rapid ventricular pacing. Tachycardia heart failure (THF) has been produced in several species, including pigs,18 dogs,19 20 and rabbits21 ; it has hemodynamic, neurohumoral, and biochemical abnormalities identical to clinical systolic heart failure.20 Our results indicate that THF significantly slows mechanical restitution without affecting early relaxation restitution, despite marked depression of baseline contractile and relaxation parameters. Additionally, THF significantly attenuated or abolished the late phase of relaxation restitution, despite similar changes in total load occurring in beats with long ESIs compared with those at the baseline cycle length.
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Methods |
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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 1985). Six healthy mongrel dogs of either sex were surgically instrumented for long-term physiological monitoring as previously described by this laboratory.22 23 After premedication with xylazine and induction with pentobarbital, endotracheal intubation was performed under 1% to 2% halothane 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. A high-fidelity micromanometer (Konigsberg Instruments, Inc) and a fluid-filled catheter for micromanometer calibration were implanted across the left ventricular (LV) apex. Three sets of piezoelectric crystals 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 left atrium and left ventricle. Balloon occluder cuffs were placed around the inferior vena cava. After the chest was closed in multiple layers, all wires and tubes were tunneled subcutaneously to exit from the back of the neck. The animals were allowed to recover a minimum of 2 weeks before 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 to 30 mg/kg), droperidol (1.5 to 3.0 mg/kg), and fentanyl (0.03 to 0.06 mg/kg). Once anesthetized, the animals were intubated and mechanically ventilated with room air. Autonomic blockade was produced by the administration of intravenous atropine (2 mg) and hexamethonium (20 to 25 mg/kg). All hemodynamic data were collected during 10- to 15-second periods of posthyperventilation apnea to avoid the effects of respiration on the measured parameters. Analog tracings were recorded on an 8-channel forced ink oscillograph (Beckman Instruments Inc). The following signals were recorded: LV pressure (P), the first derivative of the LVP with respect to time (dP/dt), ECG, aortic pressure, and the three LV dimensions. These signals were simultaneously digitized at a sampling rate of 500 Hz with an IBM PC.
For the restitution protocols, 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 volumes. Runs that did not display at least a 20 mm Hg drop in peak systolic LVP were discarded. After caval occlusions were performed, mechanical and relaxation restitution were assessed. After an initial series of beats at the basic cycle length, a single test atrial extrastimulus was introduced with a programmable stimulator (Bloom Instruments). The first ESI was timed to be within the absolute refractory period of the AV node. The ESI 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 animals were allowed to recover from the initial experiments for 2 days. At this point, rapid ventricular pacing was instituted 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 dilatation and hemodynamic evidence for heart failure, the restitution protocol was repeated. After completion of the full study, the animals were killed humanely 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 by the equation
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For the caval occlusion runs, end systole was defined as occurring at the upper left corner of the LVP-volume loop, and the end-systolic pressure-volume (Pes-Ves) relation was determined by the iterative approach of Kono et al.24 The data were fitted to the equation
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by least-squares linear regression technique, where Ees is the slope of the relation, and V0 is its volume intercept.
For the mechanical restitution experiments, end
systole was considered
to occur at the point of maximal time-varying elastance
(Emax) for the beat, as previously described by
Sagawa et al (see Reference 25 for review). This was defined as the
maximal ratio of LVP to corrected LV volume (the absolute volume minus
V0 determined from the caval occlusions). End diastole was
defined as occurring at the peak of the QRS complex. For purposes of
analysis, dP/dt was calculated from the instantaneous LVP by use of
a running five-point linear fit. The period of isovolumic relaxation
was defined as occurring between the time of peak negative dP/dt and
the time when pressure had fallen to 5 mm Hg above the
end-diastolic pressure for that beat. The time constant of
LV relaxation, 
, was determined by nonlinear regression analysis
of the pressure and time data during isovolumic relaxation by use of a
monoexponential function of the form
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where
P0 (mm Hg) is an estimate of the pressure at
peak negative dP/dt, t is the time (ms), is the time constant of
relaxation (ms), and Pb (mm Hg) is the floating pressure
asymptote as t approaches infinity. The computer algorithm used the
method described by Hartley.26 The average rate of
pressure fall during isovolumic relaxation, Ravg
(mm Hg/ms), was defined as the total pressure fall during this period
divided by its duration in milliseconds.15 27
To evaluate systolic and diastolic restitution, the following
parameters were used. We have previously shown15 that
relaxation restitution can be accurately defined by use of the inverse
of Ravg or the inverse of
dP/dtmin, both model-independent relaxation
parameters, in an equivalent manner to analysis using . These
model-independent parameters were used to define relaxation restitution
(see below). Emax for each beat (single-beat elastance,
SBE) was determined as described above and used as a measure of
contractile response. For mechanical restitution analyses, calculated
SBE was normalized to the peak absolute SBE achieved for each
restitution curve and expressed as a percentage. For relaxation
restitution analyses, the relaxation parameter (ie, inverse of
Ravg or inverse of dP/dtmin) calculated
for the extrasystolic beat was normalized to the value from the control
beat immediately preceding the extrasystole and expressed as a
percentage.
Mechanical restitution was described by an elastance-based construct10 15 and fitted to the monoexponential function
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where SBEn is normalized SBE, CRmax is the maximal (plateau) value of contractile response, ESI0 is the smallest ESI that produces a mechanical response ("initial" ESI), and TCM is the time constant of mechanical restitution. Relaxation restitution was described by two monoexponential functions corresponding to the early and late phases of restitution.15 The early-phase data (up to the basic cycle length) were fitted to the equation
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where Rn is the normalized relaxation parameter of interest, ESI0 is the smallest ESI that produces a mechanical response ("initial" ESI), K0 is an estimate of Rn at ESI0, Ka is the plateau asymptote during the first phase of restitution, and TCR1 is the time constant of the first phase of relaxation restitution. When possible, the late-phase data were fitted to the equation
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where Kb is the plateau, or asymptote, and TCR2 is the time constant of the second phase of relaxation restitution. All monoexponential function analyses and time constant derivations were performed according to standard nonlinear techniques.
To evaluate the effect of load during the second phase of
relaxation
restitution, wall stress (
) was estimated for onset of ejection
(OEJ) and end ejection (EEJ) at the basic cycle length (375 ms) and at
an arbitrarily chosen ESI of 500 ms before and after THF. OEJ was
considered to occur at the upper right corner of the pressure-volume
loop and EEJ at end systole. For the purposes of these approximations,
the LV was assumed to be spherical, and was estimated by use of the
Laplace relation,
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where R is DAP/2 and H is the LV wall thickness. H at OEJ, 375 ms before THF, was considered to be one arbitrary unit. Given that the myocardium is incompressible, H was calculated for the other time points before THF by the principle of conservation of LV wall volume (WVLV). WVLV was determined in the following manner:
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where
Ri is the radius to the endocardium
(DAP/2 or chamber radius). Keeping WVLV
constant and assuming H at OEJ, 375 ms, to be 1, relative wall
thickness was calculated for the other time points before THF. Since
studies of THF in the canine model have revealed that there is no
change in LV mass after THF,19 relative wall thickness for
each time point after THF was also calculated by use of the principle
of conservation of LV wall volume. Relative wall stress for each animal
was subsequently calculated; values for at OEJ and EEJ with an ESI
of 500 ms were normalized to at OEJ and EEJ with an ESI of 375 ms
for each experimental condition and expressed as a percentage.
Statistical Analysis
Comparisons between hemodynamic
parameters, relative changes in
wall stress, and restitution time constants before and after the
development of heart failure were made with the paired t
test. A value of P<.05 was considered significant. All
group data are expressed as the mean±SEM.
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Hemodynamic Effects of Prolonged Rapid Ventricular Pacing
Analog tracings from a representative animal before and after the production of THF are shown in Fig 1
. Beats
with identical ESIs are shown under both conditions. After prolonged
ventricular pacing, there is a reduction of LVP and
dP/dtmax and increases in the AP, SL, and LA
dimensions, indicating chamber dilation. There is no respiratory
variation in the recorded parameters. Table 1 summarizes
group hemodynamic and relaxation data under control conditions and
after THF (mean±SEM). To control for the influence of variable heart
rate, , Ravg, dP/dtmin,
and Ees were 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 in parameters of contractility
(dP/dtmax, 1684±77 versus 2726±188
mm Hg/s, P<.01; Ees, 4.7±0.4 versus
7.1±0.5 mm Hg/mL, P<.005), significant increases in LV
filling pressure and chamber size (EDP, 18±2 versus 8±1 mm Hg,
P<.005; EDV, 62±8 versus 46±6 mL,
P<.005),
and significant prolongation of relaxation (, 34.8±2.2 versus
26.7±1.2 ms, P<.05; Ravg, 0.937±0.037
versus 1.174±0.074 mm Hg/ms, P<.05;
dP/dtmin, -1449±85 versus -2113±137
mm Hg/s, P<.01). The hemodynamic and geometric changes are
consistent with the production of dilated cardiomyopathy.
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Effect of THF on Mechanical Restitution
Fig 2
shows the mechanical restitution curves from
a representative animal under control conditions and after THF. Fig
2A relates absolute SBE to the ESI under each condition. The
reduction of peak contractile response after THF production is evident.
In Fig 2B, the restitution curves from the same animal have
been
normalized to the peak response generated under each experimental
condition. THF produces significant slowing of mechanical restitution,
with the time constant increasing from 46.8 to 88.1 ms. Because of
slower restitution kinetics in THF, achievement of maximal contractile
response is shifted to the right, with significantly less percentage
recovery of mechanical function at the basic cycle length of 375 ms.
Fig 3 shows group data for the relation between
normalized elastance and ESI before and after THF. Mean responses
(±SEM) are shown; error bars for many data points were very small
relative to the axis scales used and consequently may not be seen.
Group behavior was identical to that shown in Fig 2B, with
heart
failure producing significant slowing of mechanical restitution and
delayed recovery of peak contractile response. Table 2
lists the TCM for each animal under control conditions and
after THF. Heart failure consistently resulted in slowing of mechanical
restitution in each animal, producing a significant increase in mean
TCM (100.2±9.6 versus 61.8±6.9 ms at control,
P<.01).
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Effect of THF on Relaxation Restitution
We have previously
shown15 that restitution of LV
relaxation can be described using either model-dependent parameters
(normalized ) or model-independent parameters (the inverse of either
normalized Ravg or normalized dP/dtmin).
Relaxation restitution is delineated similarly regardless of which
parameter is used. The production of THF, however, slowed baseline
relaxation as quantified by , and early extrasystolic beats (ie,
beats with small ESIs) would usually display pressure decays during
isovolumic relaxation that were small and linear and not well
approximated by a monoexponential descriptor. As a result, use of
normalized to quantify relaxation restitution yielded fewer data
points with which to describe the restitution curve after THF
production. This was not the case if model-independent parameters were
used. Given the increased descriptive power of 1/Ravg and
(dP/dtmin)-1, we used these
normalized parameters to define relaxation restitution before and after
THF.
Fig 4A displays the relation between normalized
relaxation (assessed by use of 1/Ravg) and ESI under
control conditions and after THF in a representative animal. Fig
4B
shows the same relation in the same animal by use of the normalized
inverse of dP/dtmin. Regardless of the parameter
used, the data points are approximated by the same relation under both
conditions. Relaxation restitution curves before and after THF are
constructed with group data (±SEM) for both normalized relaxation
parameters in Figs 5 and 6. Figs
5A and 6A demonstrate relaxation restitution
under control conditions using
normalized 1/Ravg and normalized
(dP/dtmin)-1, respectively. As we have
described previously,15 relaxation restitution occurs in
two phases described by two concatenated monoexponential curves with a
breakpoint near the basic cycle length. The early phase exhibits faster
kinetics (TCR1, 1/Ravg=45.1 ms;
TCR1,
(dP/dtmin)-1=45.6 ms) than the slower
late phase (TCR2, 1/Ravg=58.4 ms;
TCR2,
(dP/dtmin)-1=76.7 ms). Figs
5B and 6B
show group data for relaxation restitution after the production
of THF. Regardless of parameter used, the data are best described by a
single monoexponential function with a time constant that is virtually
the same as TCR1 under control conditions
(TCR, 1/Ravg=42.6 ms;
TCR,
(dP/dtmin)-1=47.2 ms). There is no
discernible late phase of relaxation restitution.
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Relaxation
restitution time constants from individual dogs, along
with mean values and SEMs, are presented in Tables 3 and
4 with normalized 1/Ravg and normalized
(dP/dtmin)-1, respectively. There is no
significant difference in mean TCR1 under control
conditions and after the production of THF (1/Ravg,
44.3±5.6 versus 42.0±8.5 ms, P=NS;
(dP/dtmin)-1, 42.2±6.3 versus
36.7±4.3 ms, P=NS). TCR2 at baseline was
55.6±7.0 ms for 1/Ravg and 61.8±9.9 ms for
(dP/dtmin)-1. After THF, relaxation
restitution did not consistently demonstrate biphasic behavior;
consequently, TCR2 after THF is not reported. The control
value for TCR2 reported here is somewhat smaller than
reported in our previous study (75.94±10.65 ms) but is within the
range of SEM. Thus, heart failure does not affect the kinetics of the
early phase of relaxation restitution despite baseline prolongation of
relaxation (see Table 1
) and abolishes the late phase in this
range of
ESIs.
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To evaluate the effect of load on the second phase of relaxation
restitution before and after THF, changes in wall stress occurring at
long cycle lengths were assessed. Fig 7 plots
pressure-volume loops at the basic cycle length of 375 ms (solid lines)
and at a longer cycle length of 500 ms (dotted lines) at control and
after THF in one animal. After THF there is LV dilation, with failing
hearts operating at significantly greater volumes than during control
conditions. This results in increased wall stress during all parts of
the cardiac cycle in THF compared with control. Lengthening the ESI in
either experimental condition results in higher chamber volume and
pressure at OEJ and lower chamber volume and pressure at EEJ. As a
result, early systolic wall stress (contraction load) is higher and
end-systolic wall stress (relaxation load) is lower for beats at an ESI
of 500 ms.
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Fig 8 shows the difference in wall stress at
an ESI of
500 ms (500) at OEJ and EEJ compared with the same time
points at an ESI of 375 ms for each experimental condition. Despite the
generalized increase in absolute wall stress in THF, there is no
difference in test pulse interval–induced percent changes in
contraction load (8.7±2.4% versus 9.1±3.1%,
P=NS) and
relaxation load (-2.3±1.3% versus -1.5±1.2%,
P=NS) for
the longer ESI before and after THF. Thus, after THF there is
attenuation or disappearance of the second phase of relaxation
restitution despite similar relative changes in load during this
portion of the curve.
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Discussion |
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The results of these studies demonstrate that despite generalized depression of both systolic and diastolic performance, THF produces differential effects on systolic mechanical and relaxation restitution of the intact canine heart. THF selectively slows the kinetics of mechanical restitution without affecting those of early relaxation restitution. THF also significantly attenuates or abolishes the late phase of relaxation restitution, despite similar changes in load during this phase compared with control. From these findings, it can be inferred that THF alters the recovery kinetics of SR Ca2+ release to a significantly greater extent than those of SR Ca2+ sequestration and that the abnormal time course of Ca2+ availability to the myofilaments is the rate-limiting step in the time-dependent recovery of cardiac function after depolarization.
Studies by Yue et al12 and Wier and Yue14
have shown that mechanical restitution and postextrasystolic
potentiation can be described by monoexponential functions with a
common time constant. Their studies with ryanodine and aequorin have
established that the amount and time course of SR
Ca2+ release to the myoplasm is the major
determinant of mechanical restitution. On the basis of these studies,
these investigators proposed a model of SR Ca2+
handling (Fig 9) to explain mechanical restitution. The
SR is composed of a Ca2+ uptake pool and release
pool. Ca2+ uptake occurs mainly during the
Ca2+ transient (predominantly from internally
released stores and a smaller amount from transsarcolemmal flux), and
sequestered Ca2+ is only gradually available for
release for the subsequent beat. The time course of availability of
releasable Ca2+ is responsible for mechanical
restitution kinetics. The mechanism of this gradual return of
releasable Ca2+ can be secondary to either
time-dependent transfer (K2) between distinct uptake and release pools
or time-dependent recovery of the SR Ca2+ release
channel from a closed to an open state. The latter mechanism has more
experimental support, given that (1) ultrastructural studies have not
demonstrated anatomic membrane boundaries within the SR,28
(2) transfer of sequestered Ca2+ to the release pool
by diffusion should occur rapidly (on the order of a few
milliseconds29 ), and (3) recovery of SR
Ca2+ release channel activity has a time constant
(700 to 800 ms30 ) similar to the TCM reported
in ferret papillary muscles by Wier and Yue.14 Thus, as
suggested by Bers,29 recovery of the SR
Ca2+ release channel may be the cellular mechanism
governing mechanical restitution.
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This model also provides a conceptual basis for predicting early relaxation restitution behavior.15 The major determinant of myocardial relaxation is the active reuptake of Ca2+ by the SR.17 Direct studies of SR have revealed that SR Ca2+ sequestration capacity is not unlimited but rather displays saturation to a steady-state level.31 This plateau level is achieved within 200 ms of initiation,32 at which time internal binding sites are saturated, raising free intraluminal Ca2+ and inhibiting further uptake. This time course would suggest that at the basic cycle length of 375 ms, SR Ca2+ uptake is near the saturation plateau. With short ESIs, less Ca2+ is released from the SR and more Ca2+ remains bound to intraluminal sites. As a result, SR Ca2+ sequestration operates at a point closer to the saturation plateau, and Ca2+ uptake rates are slower. This would be reflected mechanically as slower rates of relaxation. With prolongation of the ESI, SR uptake rates would normalize incrementally to the level of the basic cycle length; the time course of this normalization is delineated by the relaxation restitution curve. Thus, mechanical and early relaxation restitution are direct reflections of SR behavior that result primarily from recovery of SR Ca2+ release channel function and SR Ca2+ uptake capacity, respectively.
Since beat-to-beat Ca2+ handling is the result of
interdependent functions of the SR integrated in a closed loop, it is
intriguing that THF produces divergent effects on mechanical and early
relaxation restitution kinetics. As seen in Figs 2 and
3 and Table 2,
THF slows mechanical restitution kinetics significantly. Given the
cellular correlates of mechanical restitution in normal hearts, this
probably reflects a reduction in SR Ca2+ release
channel function. There are many lines of evidence supporting this
contention, including (1) prolonged Ca2+ transients
measured with aequorin in
human1 2 3 4 and
canine6 myopathic papillary muscle, (2) reduced peak
systolic Ca2+ (measured with fura-2) in human
myopathic isolated myocytes,5 and (3) reduced expression
of the mRNA coding for the SR Ca2+ release channel
in human heart failure.7 Given the widespread alterations
of myocardial function in heart failure, however, mechanisms distal to
SR Ca2+ release must also be considered.
Theoretically, altered kinetics of Ca2+ binding to
troponin C (ie, myofilament Ca2+ sensitivity) could
affect mechanical restitution. However, since cardiac muscles from dogs
with THF do not show altered myofilament Ca2+
sensitivity compared with controls,6 this mechanism is
unlikely.
The effect of THF on relaxation and relaxation restitution is somewhat
more complex. THF slows ventricular relaxation rates significantly over
control (Table 1), suggesting depression of SR
Ca2+
uptake mechanisms. Indeed, biochemical and functional studies have
revealed (1) significant reductions in SR Ca2+
ATPase pump activity and SR Ca2+ transport in the
canine THF model,20 (2) a 50% reduction of SR
Ca2+ uptake in homogenates of cardiac biopsies from
humans with dilated cardiomyopathy,33 and (3)
reduced expression of the mRNA coding for the SR
Ca2+ ATPase pump7 34 and the SR
Ca2+ pump regulatory protein
phospholamban7 in human heart failure.
Despite the prolongation of baseline relaxation, the kinetics of early
relaxation restitution remained unchanged after THF (Figs 4 through
6,
Tables 3 and 4). This apparent discrepancy can
be explained by the
model in Fig 9. As described above, the restitution of
relaxation
depends on the degree of availability of SR internal binding sites for
Ca2+ (ie, degree of saturation of the SR). The
maintenance of early relaxation restitution despite prolonged baseline
relaxation would suggest that despite slower Ca2+
uptake, the level of internal Ca2+ site saturation
achieved and recovery of intraluminal Ca2+ binding
capacity are unchanged after THF. This would require unaltered transfer
kinetics between the uptake and release pools (K2) as well as
maintenance of SR intraluminal Ca2+ binding proteins
in THF. Consistent with this last hypothesis, Takahashi et
al35 found no change in the expression of mRNA coding for
calsequestrin (the protein that determines SR Ca2+
storage capacity) in human heart failure. Thus, our results would
indicate that although both SR Ca2+ release and
uptake mechanisms are depressed in THF, recovery of
Ca2+ release channel function is the rate-limiting
step in the restitution of cardiac function after a depolarization.
The production of THF also led to disappearance of the second phase of
relaxation restitution (Figs 4 through
6), and the underlying
mechanisms for this are much less clear. In our previous
study,15 we postulated that the prolongation of relaxation
seen at ESIs greater than the basic cycle length was due to loading
effects on relaxation. As illustrated in Fig 7, beats following
long
cycle lengths tend to have higher wall stress at OEJ (higher
contraction load) and lower wall stress at EEJ (lower relaxation load)
both before and after THF. Both of these effects serve to slow
ventricular relaxation rates.36 However, as shown in Fig
8, the increases in contraction load and decreases in
relaxation load
that result from longer cycle lengths are similar before and after THF.
Given that data from other investigators have shown increased load
sensitivity of relaxation in heart failure,37 38 an
accentuation of the second phase would be expected if load were the
sole determinant of this portion of the curve. Clearly, other factors
are at play in heart failure that attenuate this late phase of
relaxation restitution. The nature of these mechanisms is unclear;
possibly, Ca2+ transport systems with slower
operating kinetics (eg, sarcolemmal Ca2+ flux
pathways) play a more prominent role in heart failure, affecting the
second phase. Further studies are required to clarify these mechanisms
in THF.
Our experimental results must be evaluated in light of possible sources of error. To determine SBE for extrasystolic beats, we used the volume intercept (V0) determined at the basic cycle length. Although steady-state increases in heart rate change V0, the effect of changes in ventricular volume on end-systolic pressure occur over several beats.39 This effect would be minimal in the transient alteration of pacing interval used to produce test beats at different ESIs. Given this and the fact that it would not be possible to perform caval occlusion at each ESI used, a common V0 was used.10 15 Second, as in many prior studies, our analysis assumes the Pes-Ves relation to be linear. In the intact animal model used in our study, Little et al40 showed a slight but consistent curvilinearity of the Pes-Ves 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 and should not significantly affect our analysis or restitution kinetics.
It must be emphasized that this is a mechanical study, which allows discussion of a phenomenological model: we did not directly measure SR Ca2+ flux or intracellular Ca2+ transients. Importantly, however, measurement of mechanical and relaxation restitution provides a convenient window on SR function while maintaining an intact physiological (or pathophysiological) state. Study of the intact animal in this manner can reflect insights that may not be evident in isolated myocyte or papillary muscle studies of Ca2+ handling. Additionally, the kinetics of force-interval behavior are much slower in isolated hearts than intact hearts10 and even slower in isolated muscles.14 Thus, the ability to study the kinetics of mechanical performance before and after development of THF in the same animal provides a unique opportunity to target and interpret studies at the cellular and biochemical level. Finally, Ca2+ transients measured by aequorin or fura-2 recover well before the corresponding mechanical events,1 2 3 4 5 6 suggesting that direct measurement of Ca2+ fluxes during portions of the cardiac cycle critical to the processes we describe may not be currently possible.
In summary, our results demonstrate that heart failure produced by rapid ventricular pacing selectively prolongs the time course of mechanical restitution without affecting the kinetics of the early phase of relaxation restitution in the intact canine heart. This occurs despite baseline depression of both contractile and relaxation parameters. THF was also associated with attenuation of the late phase of relaxation restitution, despite similar changes in load during this portion of the curve. The data suggest that after the development of THF, the principal defect in restoration of activator Ca2+ and recovery of cardiac performance after a stimulation is at the level of the SR Ca2+ release channel.
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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 the Fraternal Order of the Eagles. Dr Freeman was supported by an Established Investigatorship of the American Heart Association. The authors gratefully acknowledge the excellent technical assistance of Danny Escobedo and Cindy Ramirez and the statistical consultation of John Schoolfield.
Received May 12, 1994; accepted July 31, 1994.
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