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.
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.
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.
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:
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:
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:
All monoexponential function analysis and TC derivations were performed according to standard nonlinear techniques.
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.
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.
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.
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.
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).
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.
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.
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.
Selected Abbreviations and Acronyms
|APD||=||action potential duration|
|CRmax||=||maximum (plateau) value of contractile response|
|LV||=||left ventricle, left ventricular|
|LVP||=||left ventricular pressure|
|MRPES||=||postextrasystolic mechanical restitution|
|PESI0||=||smallest postextrasystolic interval that produces a mechanical response (initial postextrasytsolic interval); postextrasystolic interval–axis intercept|
|THF||=||tachycardia heart failure|
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.
- Copyright © 1995 by American Heart Association
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