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Ann Thorac Surg 2000;70:2102-2106
© 2000 The Society of Thoracic Surgeons

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Original article: cardiovascular

Ventricular remodeling after cardiomyoplasty in heart failure sheep: passive and dynamic effects

^a Cardiac Technology Centre, Department of Cardiology, Royal North Shore Hospital, Sydney, Australia
^b Department of Cardiothoracic Surgery, Royal North Shore Hospital, Sydney, Australia
^c Department of Cardiothoracic Surgery, Nagoya University of Medicine, Nagoya, Japan

Accepted for publication May 3, 2000.

Address reprint requests to Dr Shirota, c/o Prof Stephen Hunyor, Cardiac Technology Centre, Block 4, Level 3, Royal North Shore Hospital, St. Leonards, Sydney, NSW, 2065, Australia
e-mail: stephenh{at}med.usyd.edu.au

	Abstract

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 
Background. Recent reports claim that cardiomyoplasty (CMP) has a girdling effect on the left ventricle, to prevent dilatation and functional deterioration, but the mechanism of its long-term effects on the native heart is not known. We compared the relative role of CMP’s active squeezing and passive girdling in chronically failing hearts.

Methods. After induction of stable heart failure (left ventricular ejection fraction = 27% ± 7%) by staged coronary microembolization, CMP was performed in 11 of 18 sheep. After 8 weeks pacing training of the latissimus dorsi muscle (LDM), cardiac assist was begun with 1:2 synchronous bursts in 6 sheep (d-CMP, n = 6), and the LDM in the passive group (p-CMP, n = 5) remained unstimulated. Four (base line) and 30 weeks after induction of heart failure, the pressure-volume relationship was derived.

Results. After 30 weeks in d-CMP the slope (E_max) of the end-systolic pressure-volume relationship increased by 66% ± 55% (p < 0.05) and external work efficiency by 48% ± 41% (p < 0.01). In the passive CMP and control groups, slope and external work efficiency were unchanged. Conversely, left ventricular end-diastolic volume decreased (-14% ± 12%, p < 0.05) in the dynamic CMP group compared with a static course in the passive CMP group (3% ± 10%, p > 0.05) and an increase (18% ± 15%, p < 0.05) in controls.

Conclusions. Dynamic CMP improved native heart’s contractility and external work efficiency. In addition, whereas passive CMP has simply a girdling effect, dynamic CMP also induces reverse left ventricular chamber remodeling.

	Introduction

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 
Dynamic cardiomyoplasty (CMP) has been used to treat patients with dilated heart failure [1–5]. It has the potential outstanding advantage of supporting the circulation with a native power source and avoiding blood contact. Its mechanism and mode of action can also provide useful insights for developing a new generation of direct cardiac compression and restraining devices [6]. Despite the nonphysiologic geometry of wrapped latissimus dorsi muscle cardiac compression, CMP has been assumed to assist the failing heart by augmenting systolic ejection through circumferential squeezing of the ventricles. Although subjective clinical improvement has been noted in clinical trials, evidence for active systolic assist has been inconsistent [2–5, 7]. Recently it was reported that the girdling effect of a nonstimulated muscle wrap also contributes to clinical improvement [8–10]. However, such an effect has been explored only in short-term studies using a rapid-pacing heart failure model, which is known to provide an unstable substrate when pacing is ceased [8, 10].

We used sheep with chronic heart failure induced by staged coronary microembolization. This model provides stable left ventricular dysfunction with progressive left ventricular dilatation and simulates the remodeling process seen in heart failure [11].

In addition, because improvement in patients’ symptoms resulting from CMP might relate to altered myocardial energetics, we also examined this possibility by examining the behavior of the pressure-volume area (PVA). which has a linear relationship to myocardial oxygen consumption under steady-state contractile conditions [12]. In this study we conducted a long-term evaluation of the controlled effect of both dynamic and passive CMP on the native heart, using sheep with chronic ischemic heart failure.

	Material and methods

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 
We used 18 Merino-Wether sheep (54 ± 4 kg) in this study. They received humane care in compliance with the "Principles of Laboratory Animal Care" formulated by the National Society for Medical Research and the "Guide for the Care and Use of Laboratory Animals" prepared by the Institute of Laboratory Animals Research and published by the National Institutes of Health (National Institutes of Health Publication no.86-23, revised 1985).

For each assessment procedure, the animals were anesthetized with 20 mg/kg of thiopental sodium as induction, intubated, and ventilated with 1.5 L/min of oxygen, 2 L/min of nitrogen dioxide, and isoflurane (1.5% to 1.8%) through a respirator (Bird model 8; Bird Australia, Pty, Ltd., Chatswood, NSW, Australia). Maintenance fluid was provided through peripheral venous access with Hartmann solution. Electrocardiography was monitored with electrodes clipped to the extremities. All procedures were started 30 minutes after intubation, allowing for stabilization of the heart rate.

Heart failure induction
Staged coronary microembolizations were performed to induce heart failure (HF) with an ejection fraction of less than 35% [11]. Cardiac and selective coronary catheterization was done through the carotid artery exposed in the left side of the neck, followed by injection of heparin (5000 U bolus). Left ventricular (LV) ejection fraction was assessed by echocardiogram (Opus1; Ausonics Pty Ltd, Sydney, Australia). For selective coronary embolization, a 5F right Judkin coronary catheter (JR-4; Cordis Surgical Australia, Auburn, Sydney, Australia) was introduced into the left anterior descending or circumflex coronary artery, and a slow injection (total 0.1 to 0.8 mL) of polystyrene microspheres (90 µm in diameter; 2.54% solid latex by volume; Polyscience Inc, Warrington, PA) was given. To prevent ventricular arrhythmias, 25 mg of lignocaine was administered as a slow intravenous bolus before each injection of microspheres. Immediately after microsphere injection, the Judkin catheter was replaced with a catheter-tipped manometer (5F; Millar Instruments, Inc, Houston, TX) to monitor aortic pressure. Metaraminol bitartrate (INN: metaraminol [Aramine]; 0.2 to 0.5 mg bolus injection) was administered intravenously as needed to prevent critical hypotension. Coronary embolization was repeated every 2 to 3 weeks until LV ejection fraction decreased to less than 35%. On average, 4 ± 2 embolizations were required. When ejection fraction had been stable (27% ± 7%, mean ± standard deviation) for 4 weeks, 11 sheep had cardiomyoplasty (CMP). Seven other HF sheep served as a control group.

Cardiomyoplasty
Left posterior cardiocostal CMP was done through a left flank incision, with complete mobilization of the left latissimus dorsi muscle (LDM), leaving the thoracodorsal neurovascular pedicle intact. Two intramuscular pacing electrodes (model 053-003; Telectronics Pacing Systems, Inc, Englewood, CO) were placed in the proximal portion of the muscle flap 5 to 10 cm apart, and threshold and total recruitment stimulation amplitudes were ensured. The LDM was passed into the left chest cavity through a 5-cm window in the third rib, and its humeral insertion was anchored to the periosteum of the fourth rib. Through a left anterior thoracotomy (fifth intercostal space), the pericardium was opened, and an intramyocardial sensing lead (Model 033-572; Telectronics Pacing Systems, Inc) was implanted in the anterior wall of the right ventricle. The LDM was wrapped around both ventricles in a clockwise fashion, with the costal surface of the LDM in contact with the epicardium. The spinal border of the flap was fixed to the pericardium at the level of the atrioventricular groove behind the heart. The anterior edge of the muscle flap was sutured to itself. The pacing and sensing leads were passed under the skin and connected to an implantable cardiosynchronous myostimulator (Myostim, Model 722; Telectronics Pacing System, Inc.).

Muscle training protocol
For the first 2 weeks after CMP the LDM remained unstimulated to allow vascular recovery. During the following 2 weeks, the implanted myostimulator was programmed to deliver an electrical burst of 2.5 V amplitude, 100-microsecond pulse width, one pulse per burst, with a 1:2 synchronization ratio. After that period, the voltage and the number of pulses (35 Hz pulse frequency) per burst was increased every 2 weeks as follows: 2 pulses per burst (5.0 V), 4 pulses per burst (5.0 V). At 8 weeks, the muscle was considered fully trained.

In 6 of 11 CMP sheep (dynamic CMP [d-CMP]), cardiac assist was continued as a 1:2 synchronous ratio for 6 months, whereas in 5 other sheep (passive CMP [p-CMP]), only nonpaced, passive CMP was provided.

Hemodynamic assessment
Four (base line) and 30 weeks after HF had been induced, all animals had hemodynamic assessment under stable light anesthesia. The carotid artery and jugular vein were isolated through a cut-down in the left side of the neck. Millar (5F) and 12-electrode conductance (6F; CardioDynamics, Rijinsberg, The Netherlands) catheters were placed longitudinally in the LV cavity. The conductance catheter was connected to a Sigma 5 signal conditioner-processor (CardioDynamics). We corrected our volume measurement using a standard procedure involving hypertonic saline solution injection and blood resistivity measurement while the myostimulator was turned off. The jugular vein was cannulated with an inferior vena cava occlusion catheter (Fogarty 22F; Baxter International Inc, Irvine, CA). Left ventricular pressure, volume, and electrocardiographic findings were displayed and digitized at 200 Hz on a personal computer during steady-state conditions and again during transient inferior vena caval occlusion. Ventilation was held at end-expiration during the measurements. Data were stored on hard disk and analyzed offline with custom software.

Data analysis
In the setting of stimulator-off, all hemodynamic variables during steady state were calculated as the average of 5 to 6 beats. The end-systolic pressure-volume relationship was assessed from each set of pressure-volume data, including those during abrupt preload reduction using transient inferior vena caval occlusion.

Statistical analysis
Results at baseline (4 weeks) and 30 weeks results were compared by paired t test, when the data passed the normality test; otherwise the Mann-Whitney rank sum test was used. Differences among the three groups were assessed by one-way analysis of variance followed by the multiple-comparison method using the Student-Newman-Keuls test. Data are presented as mean ± standard deviation unless otherwise indicated. Statistical significance was set at p value less than or equal to 0.05.

	Results

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 
Table 1 shows the changes in hemodynamic variables based on the pressure-volume relationships at baseline and after 30 weeks of dynamic (n = 6) and passive CMP (n = 5) and in the HF control group (n = 7).

View larger version (25K): [in this window] [in a new window]   Fig 1. Representative pressure-volume loops and end-systolic pressure-volume relationship in the three groups at base line (Base) and 30 weeks (30w). The lines show the slope of the end-systolic pressure-volume relationship. d-CMP = dynamic cardiomyoplasty group; p-CMP = passive cardiomyoplasty group, Control = heart failure control group; LV = left ventricular.

View larger version (21K): [in this window] [in a new window]   Fig 2. Changes in left ventricular contractility (Emax) from baseline to 30 weeks in the three groups. *p < 0.05 compared with baseline. #p < 0.05 compared with control. Abbreviations as in Figure 1.

View larger version (23K): [in this window] [in a new window]   Fig 3. Changes in external work efficiency (EW/PVA) from baseline to 30 weeks in the three groups. **p < 0.01 compared with baseline. #p < 0.05 compared with control. Abbreviations as in Figure 1.

	Comment

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

Few studies have reported the long-term effects of CMP on the failing heart. Among them, Kass and colleagues [13] reported on a 1-year clinical follow-up in 3 patients in whom LV chamber volume declined, leading to the speculation that CMP might have a predominantly passive girdling effect. Schreuder and colleagues [14] also reported marked decreases in left ventricular volume in 6 patients with dilated cardiomyopathy up to 1 year after CMP. However, it has been difficult to distinguish the relative contributions of passive and dynamic components of CMP’s effect because of a lack of passive CMP control groups. In another study that was also uncontrolled for passive CMP effects, Patel and associates [15] reported that long-term dynamic CMP improved myocardial energetics as well as decreased LV chamber volume. One study examined the comparative effects of adynamic (passive) and dynamic CMP using echocardiographic assessment [10]. Those investigators performed CMP before inducing heart failure by rapid pacing, to eliminate the effects of major surgical intervention. Their results showed less enlargement of LV end-diastolic volume and less decrease of LV ejection fraction in both dynamic and passive CMP compared with controls. These findings suggest that both dynamic and passive CMP have a preventive effect with respect to heart failure.

Our results show that dynamic CMP, when used for 6 months in chronic, moderately dilated heart failure, achieves reverse chamber remodeling and improved LV contractility (E_max) and external work efficiency (EW/PVA). The improvements in efficiency and contractility might relate to prevention of ventricular dilatation, which then limits increases in wall tension (the girdling effect) with a favorable effect on myocardial oxygen requirement. Myocardial wall stress might also be lowered because heart wall thickness is enhanced effectively as a result of the CMP wrap (ie, the sandwich effect) and also because of systolic compression of the LV wall [16, 17]. These considerations predict that dynamic as opposed to passive CMP has potential advantages in terms of energetics.

Furthermore, Kawaguchi and colleagues [18] have shown that direct cardiac compression has a sparing effect on myocardial oxygen consumption. By using an artificial external compression device to mimic CMP in an isolated, cross-circulated heart model that was fixed for end-diastolic and stroke volumes, they showed that direct compression increased E_max and external work without increasing measured myocardial oxygen consumption or coronary blood flow. Those findings indicate that increases in contractility and external work can be attributed to a contribution from direct compression assist, rather than requiring the imposition on the myocardium of an added oxygen requirement. We have also shown that d-CMP assist decreased the native heart’s total mechanical work (PVA) and improved its external work efficiency (EW/PVA) in a chronic ischemic heart failure model in sheep [19]. These findings are evidence that d-CMP has an effect over and above the girdling effect provided by p-CMP.

We showed that the myocardial oxygen-sparing effect of d-CMP is beneficial to the native heart, as illustrated by decreased LV volume and improved LV contractility and Eff_EW. The decrease in LV wall tension that results, in accordance with Laplace’s law, from a reduction in its volume leads to improvement in LV contractility (E_max), which then decreases potential energy. A consequence of this is improved external work efficiency (EW/PVA) with an associated sparing of the energy cost to the native heart. There is no direct evidence currently to support the hypothesis that these changes resulting from CMP improve function of hibernating myocardium in ischemic HF. However, there is increasing support for the notion that similar myocardial offloading with left ventricular assist devices leads to improvement in the contractile properties of the LV myocyte in vitro [20] as well as improvement of myocardial mitochondrial function in patients with HF [21].

Limitation
It is unknown whether the 6 months duration of this study was sufficient to evaluate the relative role of both dynamic and passive effects on reverse remodeling of the native heart. In a longer period, passive CMP might also induce reverse chamber remodeling to some extent. However, at 6 months the dominant effect was from dynamic CMP. In the passive CMP group a possible "girdling effect" may have been obscured by atrophy of the LDM due to lack of any pacing stimulus to the muscle. It could be argued that a better passive group would have been one in which the animals continued to receive 1 or 2 Hz single burst stimulation following the initial conditioning period. This might have ensured maintenance of muscle tone and prevented the atrophy that occurs in the absence of any electrical myostimulation. However, there are still controversies about how LDM condition can be maintained without actively assisting the heart. Additionally, in our histologic study of LDM obtained by thoracoscopic biopsy at 0, 6, 12, 18 and 24 weeks after CMP, in both dynamic and passive CMP groups [22], atrophy of the LDM was found to be less marked in those passively wrapped [23].

	Acknowledgments

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 
We acknowledge the technical assistance of Dr Xing Zheng, Mr Ray Kearns, Mr Gabrial Gomes, Mrs Janelle Young, Mr Peter Darge, Ms Marie Pryor, and Mr Chris Cruickshank. This work was performed under the Australian Government’s Cooperative Research Centre (CRC) Scheme in the CRC for Cardiac Technology.

	References

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 

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