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(Circulation. 1997;96:3665-3671.)
© 1997 American Heart Association, Inc.

Articles

Stabilization of Chronic Remodeling by Asynchronous Cardiomyoplasty in Dilated Cardiomyopathy

Effects of a Conditioned Muscle Wrap

Himanshu J. Patel, MD; David J. Polidori, MD; James J. Pilla, PhD; Theodore Plappert, CVT; David Kass, MD; Martin St John Sutton, FRCP; Edward B. Lankford, MD, PhD; ; Michael A. Acker, MD

From the Divisions of Cardiothoracic Surgery (H.J.P., D.J.P., J.J.P., M.A.A.) and Cardiology (T.P., M.S.S., E.B.L.), Departments of Surgery and Medicine, University of Pennsylvania School of Medicine, Philadelphia, and the Department of Medicine (D.K.), The Johns Hopkins School of Medicine, Baltimore, Md.

Correspondence to Michael A. Acker, MD, Division of Cardiothoracic Surgery, Silverstein 4, Hospital of the University of Pennsylvania, 34th and Spruce Streets, Philadelphia, PA 19104.

	Abstract

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Background Dynamic cardiomyoplasty is a promising new therapy for dilated cardiomyopathy. The girdling effects of a conditioned muscle wrap alone have recently been postulated to partly explain its mechanism. We investigated this effect in a canine model of chronic dilated cardiomyopathy.

Methods and Results Twenty dogs underwent rapid ventricular pacing (RVP) for 4 weeks to create a model of dilated cardiomyopathy. Seven dogs were then randomly selected to undergo subsequent cardiomyoplasty, and all dogs had 6 weeks of additional RVP. The cardiomyoplasty group also received 6 weeks of concurrent skeletal muscle stimulation consisting of single twitches delivered asynchronously at 2 Hz to transform the wrap without active assistance. All dogs were studied by pressure-volume analysis and echocardiography at baseline and after 4 and 10 weeks of pacing. Systolic indices, including ejection fraction (EF), end-systolic elastance (Ees), and preload-recruitable stroke work (PRSW) were all increased at 10 weeks in the wrap versus controls (EF, 34.0 versus 27.1, P=.008; Ees, 1.65 versus 1.26, P=.09; PRSW, 35.9 versus 25.5, P=.001). Ventricular volumes, diastolic relaxation, and left ventricular end-diastolic pressures stabilized in the cardiomyoplasty group but continued to deteriorate in controls. Both the end-systolic and end-diastolic pressure-volume relationships shifted farther rightward in controls but remained stable in the cardiomyoplasty group.

Conclusions In addition to potential benefits from active systolic assistance, benefits from dynamic cardiomyoplasty appear to be partially accounted for by the presence of a conditioned muscle wrap alone. This conditioned wrap stabilizes the remodeling process of heart failure, arresting progressive deterioration of systolic and diastolic function.

Key Words: cardiomyopathy • electrical stimulation • heart failure • mechanics • remodeling • surgery

	Introduction

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Dynamic cardiomyoplasty, in which the latissimus dorsi is wrapped around the heart and stimulated to contract in synchrony with the heart, is a promising but poorly understood alternative surgical therapy for the treatment of CHF. Recent studies have shown its effects on patient functional status and survival,^1–5 but its precise mechanism of action has not yet been elucidated. Some studies have documented objective evidence of improved cardiac function and hemody-namic parameters.^5,6 Others, however, have shown no change in ventricular function.^7,8 Experimental studies using both normal and cardiomyopathic hearts and both conditioned and unconditioned skeletal muscle have similarly yielded conflicting results.^8–13 Several investigators have postulated a role for the direct active synchronous assistance of the wrap,^2,5,11–18 whereas others have suggested that the primary action is a girdling mechanism whereby the muscle acts to prevent further dilation of the ventricle.^19–21 A recent study using PV analysis in three patients suggested that CMP may act as an elastic constraint to the epicardial surface and allow reverse remodeling of the LV chamber to occur.²⁰

The discordant results of various studies may have several explanations. Some studies have been performed with short-term, unconditioned wraps or have performed CMP on normal hearts. Neither of these situations is clinically relevant, because skeletal muscle transformation results in significant changes with respect to function and structure. Furthermore, it is hard to improve on the function of a normal heart, and analysis may require load-independent measures to discern slight differences in function. Frequently, the modalities used to study cardiac function either were load sensitive or relied on traditional imaging methods that do not follow the translational motion out of the imaging plane that occurs with dynamic CMP.¹⁵ Those studies that used load-independent measures of function were performed in either normal hearts^11,12 or untrained muscle¹² and showed augmentation of function with dynamic compression.

The purpose of this study was to test the influence of a chronically conditioned but nontetanic (single twitches delivered asynchronously at 2 Hz) skeletal muscle wrap on the evolution of cardiac failure in a model of DCM. Because burst or tetanic contractions were not used, the possibility of active beat-to-beat assistance (squeeze) was eliminated. We used the canine model of RVP, which displays many of the mechanical and biochemical features of DCM.^22–27 PV analysis and 2D echocardiography were used to derive load-sensitive and load-independent assessments of ventricular function.

	Methods

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All animals used in this study received care in compliance with the Guide for the Care and Use of Laboratory Animals published by the National Institutes of Health (NIH publication 86–23, revised 1985), and the investigation was approved by the Institutional Animal Care and Use Committee.

Design of the Study
Twenty heartworm-free adult male mongrel dogs (22 to 30 kg) underwent the protocol shown schematically in Fig 1. All dogs underwent baseline 2D echocardiography and PV analysis as described below. After pacemaker implantation, the dogs were subjected to RVP at 215 bpm for 4 weeks to ensure development of CHF. Studies were repeated to confirm deterioration of cardiac function before randomization of 7 dogs into the CMP group. All 20 dogs continued the RVP protocol for an additional 6 weeks. The 7 dogs that had CMP also underwent a concurrent asynchronously delivered (2-Hz) single-twitch muscle conditioning protocol during the ensuing 6 weeks of RVP. At the end of the 10-week RVP period, hemodynamics were again assessed in all animals. All dogs were maintained on medical therapy consisting of daily digoxin (0.125 mg) and furosemide (20 mg) along with thrice-weekly aspirin (80 mg) for the last 9 weeks of the rapid pacing period.

View larger version (21K): [in this window] [in a new window]   Figure 1. Experimental design of protocol. All dogs underwent pacer implantation at baseline followed by 10 weeks of RVP at 215 bpm. Studies at baseline and at 4 and 10 weeks of RVP consisted of 2D echocardiography (echo) and PV analysis. Seven of 20 dogs were randomly selected to undergo CMP after 4-week study. "Muscle on" indicates muscle conditioning by asynchronously delivered (2-Hz) single-twitch electrical stimuli.

Anesthesia
One hour before surgery, each animal was premedicated with acepromazine (0.1 mg/kg IM) and glycopyrrolate (0.001 mg/kg IM). General anesthesia was induced with ketamine (10 mg/kg IV) and diazepam (0.5 mg/kg IV) and maintained after endotracheal intubation with inhaled oxygen (3 L/min) and isoflurane (1% to 2%). Cefazolin (25 mg/kg IV) was administered prophylactically before the skin incision and again just before the termination of all procedures.

Instrumentation and Data Collection
Standard 2D transthoracic echocardiograms with an Acuson 128XP were obtained before each PV analysis with the dogs awake. Both short-axis and apical four-chamber and long-axis views were obtained and stored for later analysis.

PV analysis was conducted under anesthesia as follows. A 7F multielectrode dual-field conductance catheter (Webster Laboratories) and a 5F micromanometer-tipped catheter (Millar Instruments) were placed under fluoroscopic guidance along the long axis of the LV cavity via sterile cutdowns of the carotid and right femoral arteries. Similarly, 20-mL occlusion catheters (Applied Vascular) were placed at the junction of the superior and inferior venae cavae with the right atrium via the right jugular and right femoral veins. A balloon-tipped pulmonary artery catheter was placed via the left jugular vein.

Volume measurements were obtained by the conductance catheter technique.^28–32 Briefly, an electrical field is generated along the LV long-axis chamber, and the time-varying potential is measured at several locations along the catheter. These potential gradients are related to the conductance of blood, which is proportional to the amount of blood contained within the chamber. Thus, an estimate of instantaneous LV volume is made. All hemodynamic signals and the ECG tracing were processed with an analog amplifier (Gould, Inc), digitized at 250 Hz, and stored on computer disk for off-line analysis.

All data were collected with the ventilator held at end expiration. For determination of the ESPVR and EDPVR and the PRSW (the slope of stroke work versus end-diastolic volume), the 20-mL balloons in the venae cavae were temporarily inflated to alter preload as described previously.³³ Each preload reduction and steady-state data run was performed a minimum of three times with at least 1 minute of recovery time between each sample collection. All incisions were then closed primarily.

Pacemaker Insertion
After a recovery period of no less than 3 days, each dog underwent placement of specially modified ventricular pacemakers (model 8342, Medtronics Inc) designed to maintain prolonged pacing rates at 215 bpm. The dogs were placed under general anesthesia. Through a right anterior thoracotomy, a 2x3-cm section of the apical pericardium was excised and a unipolar pacing lead (model 6917A, Medtronics Inc) was secured to the LV apex. The lead was then tunneled subcutaneously to a subfascial pocket under the right rectus abdominus and connected to the implantable pacemaker. A right thoracostomy tube was then placed, and all incisions were closed in layers. The tube was removed after 1 hour while the dog was under anesthesia. Animals were allowed to recover for at least 7 days, after which pacing was initiated at a rate of 215 bpm for 4 weeks.

Left Latissimus Dorsi Cardiomyoplasty
After four weeks of RVP, echocardiography and PV analysis were repeated in all but 2 controls (who had echocardiography alone). Seven of the dogs were randomly selected to undergo CMP immediately after catheterization. Through a left flank incision, the entire latissimus dorsi muscle was mobilized into a pedicle flap based entirely on the thoracodorsal neurovascular bundle. A neuromuscular cuff electrode was loosely secured to the thoracodorsal nerve just proximal to the trifurcation along the costal surface of the muscle. The mobilized muscle with its lead was then passed into the left hemithorax via a 5-cm window in the second rib, and its humeral insertion was anchored to the periosteum of the first rib. A right thoracotomy through the fifth intercostal space was performed. We then wrapped the muscle posteriorly to anteriorly around both ventricles in a clockwise fashion and anchored it to the surrounding pericardium and epicardium with interrupted pledgeted monofilament sutures. Adequate care was taken to avoid an overstretch of the muscle or tension on the neurovascular pedicle. The ventral border of the muscle was then anchored to the right ventricular epicardium with a running stitch. The lead was tunneled subcutaneously to a subfascial pocket under the left rectus abdominis muscle and connected to the implantable pulse generator (model Itrel, Medtronics, Inc). Once muscle threshold amplitudes were recorded and muscle stimulation was confirmed visually, the stimulator was turned off. A left thoracostomy tube and two subcutaneous drains were placed, and all incisions were closed. The tube was removed after at least 1 hour of suction and before the recovery from anesthesia.

After a recovery period of no more than 3 days, all dogs had resumption of RVP, and the CMP dogs started a concurrent muscle-conditioning protocol. The stimulator settings were programmed as follows: unipolar continuous mode, asynchronous delivery of one pulse at 2 Hz, pulse width of 210 ms. The pulse amplitude was initially set at twice threshold. Thereafter, the muscle was checked daily by palpation, and the pulse amplitude was increased as required. Final studies were performed after an additional 6 weeks of RVP (for a total of 10 weeks of RVP). Pacers and myostimulators were turned off for collection of hemodynamic data in all dogs.

Data Analysis
2D echocardiography LV volumes were calculated by the modified biplane Simpson's rule.³⁴ All hemodynamic data were analyzed off-line with custom-designed software. Parallel conductance from extracavitary structures was derived from saline calibration as previously described.²⁹ Volume gain was set to unity. Steady-state parameters that were obtained included heart rate, stroke volume, cardiac output, stroke work, peak and end-diastolic LV pressures, dP/dt_max and dP/dt_min, pulmonary artery pressures, and . was calculated by fitting a portion of the pressure signal to a monoexponential function with a variable pressure asymptote.³⁵ ESPVR, EDPVR, and PRSW data were generated from the caval inflow occlusion data. These curves were obtained from data taken after the initial decline seen in the LV pressure. All data in which there was a change in the heart rate of >5% were discarded to minimize the effects of cardiovascular reflexes.

Composite ESPVRs and EDPVRs were obtained for each group at each time point to assess chronic changes in ventricular contractile and passive properties.³⁶ The composite ESPVR was derived by averaging end-systolic volumes calculated at 5 mm Hg increments of end-systolic pressure within a preset physiological range using the volume intercept and the Ees for each dog. Similarly, an EDPVR was constructed for each group at each time point by averaging pressures at 5-mL increments over a physiological range of volumes. EDPVRs were fit to a monoexponential equation: P_ed(V)=P₀+a (e^bV+1), where a, b, and P₀ are constants obtained from each dog at each time point, e is the base of the natural logarithm, and P_ed(V) is the predicted end-diastolic pressure.

Statistical results were obtained by computer with standard computer software (SigmaStat, Jandel Scientific). All data are expressed as mean±SEM. values in the tables are the mean changes in each hemodynamic variable for each group from baseline to 4 weeks of RVP (Table 1) and from 4 to 10 weeks of RVP (Table 2). An unpaired t test was used to determine differences between control and asynchronous CMP groups and also to determine differences in the values between groups. Differences between time points within each group were assessed by ANOVA with repeated measures followed by the multiple-comparison method of Student-Newman-Keuls. Statistical significance was set at P.05.

View this table: [in this window] [in a new window]   Table 1. PV Analysis: Baseline vs 4 Weeks of Pacing

View this table: [in this window] [in a new window]   Table 2. PV Analysis: 4 Weeks vs 10 Weeks of Pacing

	Results

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Baseline PV analysis data are provided in Table 1. There was no difference in load-independent estimates of contractility by either the Ees (the slope of the ESPVR)³⁷ or PRSW (the slope of the relationship between stroke work and end-diastolic volume)³⁸ between the control and asynchronous CMP groups. Similarly, echocardiographic data (Fig 2) demonstrated no difference between groups for baseline ventricular volumes or ejection fraction. Relaxation time constants in control dogs, however, were slightly shorter (P=.05).

View larger version (37K): [in this window] [in a new window]   Figure 2. Imaging results. Echocardiographic volumes (A and B) continue to increase significantly over the 10-week RVP period, whereas echocardiographic ejection fraction (C) significantly decreases throughout that period for control group. Notably, these volumes and ejection fractions stabilize after first 4 weeks in CMP group. All probability values in figures describe differences between 4 and 10 weeks of pacing within each group. Asynch indicates asynchronous cardiomyoplasty group.

By 4 weeks of rapid pacing, all dogs displayed significant deterioration in both systolic and diastolic indices of function (Table 1, Fig 2). By random chance, the group that would undergo subsequent asynchronous CMP had a slightly lower PRSW (P=.09) and a greater decline in LV systolic pressure and dP/dt_max (the latter reached borderline significance). Other changes were similar. Chamber volumes increased (Fig 2A and 2B) and ejection fraction was diminished (Fig 2C) similarly and significantly in both groups. Thermodilution cardiac outputs were also significantly reduced in both groups between 0 and 4 weeks of RVP (controls, 4.09±0.3 to 3.07±0.4, P<.05; CMP, 4.43±0.47 to 2.78±0.24, P<.05), and there was no difference between groups.

After an additional 6 weeks of RVP (a total of 10 weeks), cardiac systolic function deteriorated further in the control group (Table 2). For example, PRSW declined further by nearly 23% and dP/dt_max by 27% (both P<.05). Diastolic indicators also worsened in controls, with further prolongation of relaxation ( and dP/dt_min, P<.05) along with an 60% additional rise in LVEDP (P<.05). Cardiac volumes also continued to increase, and there was a further decline in EF (both P<.05, Fig 2). Thermodilution cardiac outputs at 10 weeks declined (2.59±0.3) but were not significantly different from those at 4 weeks.

In contrast, animals from the asynchronous CMP group yielded very different results. Ees was unchanged from the 4-week results, whereas PRSW improved significantly (P<.05). The net difference in Ees between controls and CMP animals at 10 weeks of RVP approached significance (P=.09), whereas that for PRSW was highly significant (P=.001). Load-sensitive measures of ejection fraction, dP/dt_max, and peak LV pressures stabilized in the asynchronous group, whereas these variables declined further in controls (P<.05). The difference between groups in ejection fraction at 10 weeks was also significant (EF, 27.1±1.4 in controls versus 34.0±1.9 in CMP dogs, P=.008). Thermodilution cardiac outputs did not change significantly from 4 to 10 weeks of RVP in the CMP group (2.09±0.31 at 10 weeks). Diastolic dysfunction as measured by relaxation time constants, dP/dt_min, and end-diastolic pressure also stabilized in the asynchronous group. Most notably, the asynchronous wrap group did not demonstrate progressive chamber enlargement and remodeling, in contrast to controls (Fig 2).

Fig 3 displays the results of composite ESPVR and EDPVR analysis for the two groups. Both relations shifted rightward from baseline after 4 weeks of RVP for both groups. This result is consistent with chamber dilation and remodeling previously reported in this experimental model.^22,25,26 By 10 weeks of RVP, the ESPVR shifted further rightward, with Ves₈₀ (the end-systolic volume for an end-systolic pressure of 80 mm Hg) increasing by 57.4% (Fig 3A, P<.05). In controls, progressive diastolic remodeling was also seen after 6 additional weeks of RVP. However, in the asynchronous CMP group, chamber remodeling was essentially arrested during the last 6 weeks of RVP (Fig 3B, Ves₈₀, P=NS). Thus, in the setting of a continued stimulus for cardiac failure (RVP), CMP prevented further functional deterioration.

View larger version (22K): [in this window] [in a new window]   Figure 3. Effects of rapid pacing and cardiomyoplasty on composite PV relations over time. A, Continued rightward shift of both ESPVR and EDPVR throughout 10-week pacing period in control dogs. This demonstrates remodeling seen in CHF caused by RVP in dogs. B, Curves for asynchronous cardiomyoplasty group over 10 weeks. There is an initial rightward shift over first 4 weeks of RVP. However, unlike control dog hearts, both ESPVR and EDPVR do not change after wrap despite presence of continuing insult imposed by RVP. This shows that cardiomyoplasty stabilizes chronic remodeling that occurs with heart failure. All probability values reflect differences in positions of ESPVRs as reflected by end-systolic volume for end-systolic pressure of 80 mm Hg.

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
The precise mechanism of cardiomyoplasty (CMP) remains speculative. Lack of consistent hemodynamic improvement seen in patients who have undergone CMP^7,8 has led some authors to postulate a passive or girdling effect as a major factor in the symptomatic improvement seen in these patients,^19–21 in addition to active systolic assistance demonstrated in some patients.^2,5,6 The present investigation provides novel data supporting a role of such a girdling influence. This study was performed in a clinically relevant model that resembles dilated cardiomyopathy morphologically, neurohormonally, and functionally.^22–27 In this study, cardiomyoplasty was performed in the setting of heart failure, and skeletal muscle transformation was then conducted during the evolution of heart failure. To specifically differentiate between the chronic and dynamic effects of synchronized CMP, the muscle wrap in the CMP group was stimulated and transformed^5,7,39 in an asynchronous fashion (2 Hz), with a single pulse twitch so as not to achieve tetanic contraction and thereby eliminate the possibility of active systolic assistance.

Girdling influences are suggested in this study when one looks at the evolution of heart failure in this model. The natural history of heart failure induced and maintained by rapid ventricular pacing is one in which systolic and diastolic dysfunction continue to progress. Remarkably, despite the presence of this continuing stimulus for cardiac failure (ie, RVP for 6 additional weeks), the asynchronous CMP group stabilized or even improved in both systolic and diastolic ventricular function. There was no further chamber remodeling in the CMP group, whereas significant progressive chamber dilation and decline in cardiac performance was observed in the control nontreated dogs.

It was initially hypothesized that the beneficial effects of CMP were secondary to acute synchronized systolic assistance by squeezing of the cardiac muscle through tetanic skeletal muscle activation.⁴⁰ At 1 year after CMP in 13 patients, Jatene et al⁵ showed that stimulator "on" data were better than those obtained with the stimulator "off." In a number of experimental studies, acute systolic assistance has also been demonstrated. Cho et al¹¹ and Aklog et al¹² demonstrated improved systolic function with assisted beats in normal hearts. Lee et al,¹³ Chen and colleagues,¹⁴ and Kawaguchi and associates^17,18 showed that myocardial wall stress is diminished with the addition of systolic compression. Finally, hemodynamic variables improved in other studies and in mathematical models in which skeletal muscle stimulation is optimally synchronized.^16,41,42

Passive girdling effects were also demonstrated in several recent studies. Carpentier et al² demonstrated a stable cardiothoracic ratio for up to 3 years after CMP in his series of 52 patients, whereas progressive dilation would otherwise be anticipated in such patients. Capouya et al¹⁹ reported that placement of an unstimulated wrap around a normal heart followed by rapid pacing attenuated LV enlargement. A small clinical study demonstrated leftward shift of the ESPVR and stabilization of the EDPVR at 6 and 12 months after CMP, suggesting a reversal of the remodeling process that contributed to overall clinical improvement.²⁰ Acute comparisons of PV loops with or without skeletal muscle contraction did not reveal any evidence of acute systolic assistance in that study.

The present study was undertaken to investigate whether the progression of heart failure could be stabilized without active systolic assistance, as suggested by the report by Kass et al.²⁰ The occurrence of the changes seen in our study in the absence of any active assistance by skeletal muscle contraction supports such beneficial effects of a transformed wrap alone in cardiomyoplasty. It is well known that skeletal muscle undergoes morphological, biochemical, and functional changes with chronic repetitive stimulation.^7,38,43–46 A reduction in both maximum force-generating capacity and muscle fiber caliber and an increase in connective tissue accompany the transformation by chronic electrical stimulation of skeletal muscle as it changes from type II to type I fibers. This transformed wrap, as it shrinks, may act as a pliable girdle around the heart that continually adapts to the volume of the heart. It does so, however, with a low elastance and hence little constriction. This is unlike pericardium, which has no elastance below its unstressed volume and a very high elastance above that volume. Hence, skeletal muscle may allow for stabilization or even reversal of both chamber dilation and the chronic remodeling process that occurs in diseased hearts, as we have seen clinically.²⁰

The stabilization of ventricular volumes seen in our study is remarkable, because our model is based on a continuing severe insult to the myocardium, in contrast to clinical CMP, in which surgery is performed long after the insult has occurred. The shrinkage of skeletal muscle fiber length that occurs with chronic electrical stimulation has been considered an undesirable consequence; however, it may be a major reason for the benefit seen clinically in dynamic cardiomyoplasty. Muscle lacking any stimulation may suffer from atrophy and will not undergo fiber-type transformation, which may limit its contribution to girdling.

As has been hypothesized by Oh et al,⁴⁷ it is likely that the mechanism by which CMP assists the failing heart is dependent on both active systolic assistance, as traditionally thought, and the chronic girdling effect demonstrated in this study. Further studies assessing the effects of a nontransformed unstimulated wrap as well as the additional contribution of active systolic effects of a synchronized burst–stimulated wrap (ie, dynamic cardiomyoplasty) are needed to allow suitable comparisons.

Given our results, it is intriguing to consider the possible use of a synthetic material to serve as a girdle, which would eliminate the need for muscle harvesting. However, it would need to display the plasticity, conformational capability, and reverse creep characteristics of transforming skeletal muscle. In addition, it would need to be nonimmunogenic and also not be a potential source of infection, unlike skeletal muscle. Such a material has not yet been developed.

In this study, we have demonstrated the beneficial effects of an asynchronously stimulated conditioned muscle wrap in a clinically relevant model of CHF. We found that traditional and relatively load-independent indices of cardiac function are either improved or stabilized by the presence of this wrap. The functional state of the heart, as gauged by its ESPVR and EDPVR, is stabilized in the asynchronous CMP group, whereas it continues to deteriorate in controls. In addition, ventricular volumes continued to increase significantly in controls but were stabilized by the wrap. The mere presence of an electrically stimulated conditioned muscle wrap alone may allow for stabilization of chamber volumes and may account for part of the benefit seen in dynamic cardiomyoplasty.

	Selected Abbreviations and Acronyms

 

CHF = congestive heart failure CMP = dynamic cardiomyoplasty 2D = two-dimensional DCM = dilated cardiomyopathy EDPVR = end-diastolic pressure-volume relation Ees = end-systolic elastance ESPVR = end-systolic pressure-volume relation LV = left ventricular PRSW = preload-recruitable stroke-work relation PV = pressure-volume RVP = rapid ventricular pacing = time constant of isovolumic pressure decay

	Acknowledgments

 
We gratefully acknowledge the excellent technical assistance of Dr Y-G Liu and Randy Rossi. In addition, we thank Medtronic, Inc, and in particular Dr Kendra Gealow and James Cox, for providing our laboratory with essential equipment.

Received April 30, 1997; revision received July 25, 1997; accepted August 5, 1997.

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