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Ann Thorac Surg 2002;74:1092-1096
© 2002 The Society of Thoracic Surgeons

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Original article: cardiovascular

Cardiomyoplasty reduces myocardial oxygen consumption: implications for direct mechanical compression

^a Cardiac Technology Centre, Department of Cardiology, Royal North Shore Hospital, Sydney, Australia
^b Department of Cardiovascular Surgery, Aichi Medical University, Aichi, Japan

Accepted for publication June 6, 2002.

* Address reprint requests to Dr 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 References

 
Background. This study investigates the possibility of reducing myocardial oxygen consumption by dynamic cardiomyoplasty in chronic heart failure. The sheep model used is relevant for cardiac assist using direct mechanical cardiac compression.

Methods. In 7 sheep, heart failure was induced by staged intracoronary microembolization followed by dynamic cardiomyoplasty. Six months later, the effect of latissimus dorsi muscle stimulation in the 2:1 mode (on, cardiomyoplasty; off, control) was studied. Left ventricular pressure-volume loops were obtained by conductance, micromanometer, and inferior vena cava occlusion catheter. Myocardial oxygen consumption was derived from left main coronary artery blood flow and oxygen content of arterial and coronary sinus blood.

Results. Cardiomyoplasty had no significant effect on left ventricular hemodynamic variables such as end-systolic pressure. However, cardiomyoplasty increased stroke volume and ejection fraction significantly by 11% ± 12% and 11% ± 10%, respectively. Although pressure-volume area and external work did not increase with cardiomyoplasty, myocardial oxygen consumption decreased by 21% ± 11%. Therefore, cardiomyoplasty increased myocardial efficiency (external work/myocardial oxygen consumption) by 16% ± 13%.

Conclusions. Despite limited hemodynamic improvement from dynamic cardiac compression by cardiomyoplasty in sheep with chronic heart failure, myocardial oxygen consumption was significantly reduced. These findings provide a rationale for reverse remodeling of the failing heart using direct mechanical compression.Keywords oxygen consumption, cardiomyoplasty, pressure volume area, Emax, heart failure

	Introduction

Top Abstract Introduction Material and methods Results Comment References

 
Cardiomyoplasty (CMP) aims to reinforce the failing heart by electrically stimulated compression with a skeletal muscle wrap [1, 2]. The latissimus dorsi muscle has adequate power to enhance systolic performance, but only limited improvement has been reported in hemodynamic variables [3–5], leaving in doubt its active squeezing effect. The principal mechanism of CMP action is thought to be an active girdling effect of the latissimus dorsi muscle, which limits dilatation of the failing heart [6].

Dynamic CMP also actively reduces heart size [6, 7], but the mechanism of this reverse remodeling is unclear. Because direct mechanical cardiac compression reduces myocardial oxygen consumption (MO₂) [8, 9], the latter has also been held responsible for improving patients’ symptoms with dynamic CMP [10, 11]. This oxygen sparing could be important in aiding reverse remodeling. However, there has been no direct evidence for MO₂ sparing in in vivo CMP. The present study evaluates this effect in sheep with chronic heart failure.

	Material and methods

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Seven Merino-Wether sheep (55.8 ± 4.7 kg, University of Sydney Farm, Sydney, NSW, Australia) involved in this study 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 Animal Research and published by the National Institutes of Health (National Institutes of Health Publication No. 86-23, revised 1985).

For each procedure, the animals were anesthetized with 20 mg/kg thiopental sodium as induction, intubated, and ventilated with 1.5 L/min oxygen, 2 L/min nitrogen dioxide, and isoflurane (1.5% to 1.8%) through a respirator (Bird model 8; Bird Australia, Pty, Ltd, Chatswood, NSW, Australia) as previously described [7, 11]. Maintenance fluid with Hartmann’s solution was provided through peripheral venous access. The electrocardiograph was monitored with electrodes clipped to the extremities. A 2-cm-diameter orogastric tube was used to decompress the ruminant stomach. All procedures were started 30 minutes after intubation, when the heart rate had stabilized.

Heart failure induction
Staged coronary microembolization was used to induce heart failure, defined as left ventricular (LV) ejection fraction less than 35% [7 11]. Cardiac catheterization through the exposed left carotid artery was followed by an injection of heparin (5,000 U bolus). A 6F pigtail catheter (Cordis Surgical Australia, Auburn, NSW, Australia) passed into the LV allowed contrast ventriculography (iopamidol, 755 mg/mL) and assessment of LV ejection fraction (Siremobile; Siemens Ltd, Artarmon, NSW, Australia). For selective coronary embolization, a 5F Judkins right coronary catheter (JR-4, Cordis Surgical Australia) engaged the left anterior descending or circumflex coronary artery. A slow injection (range, 0.1 to 0.8 mL) of polystyrene microspheres (90 µm diameter; 2.5% solid by volume; Polyscience, Warrington, PA) followed. To prevent ventricular arrhythmias, 25 mg of lidocaine was given as a slow intravenous bolus before each injection of microspheres. Immediately after microsphere delivery the Judkins catheter was replaced with a catheter-tipped micromanometer (5F; Millar Instruments, Inc, Houston, TX) to monitor aortic pressure. Metaraminol bitartrate (0.2 ± 0.5 mg, intravenous bolus) was administered as needed to prevent critical hypotension. Embolization alternated between left anterior descending and circumflex coronary arteries, depending on the extent of previously inflicted damage as judged from the ventriculogram. It was repeated every 2 weeks until ejection fraction reached 35% or less. On average, 4 ± 2 embolizations induced this degree of heart failure. When ejection fraction stabilized for 4 weeks at less than 35% (27% ± 7%), the animals underwent CMP.

Cardiomyoplasty
We performed left posterior cardiocostal CMP [7, 11] after the left latissimus dorsi muscle had been completely mobilized through a left flank incision, 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 50 to 100 mm apart, and threshold and total recruitment stimulation amplitudes were assured. The latissimus dorsi muscle was passed into the left chest cavity through a 5-cm window in the third rib, and the humeral insertion was anchored to the periosteum of the fourth rib. Through a fifth left anterior thoracotomy 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 muscle was wrapped around both ventricles in a clockwise fashion, with the costal surface of the latissimus dorsi muscle 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, and 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 stimulation protocol
For the first 2 weeks after CMP, the latissimus dorsi muscle remained unstimulated to allow for a vascular recovery period. During the subsequent 2 weeks, the implanted myostimulator was programed to deliver an electrical burst of 2.5-V amplitude, 100-µs pulse width, one pulse per burst, with a 1:2 synchronization ratio. After the fourth week, voltage was increased to 5 V. The number of pulses (35 Hz pulse frequency) per burst was then progressively increased every 2 weeks to a maximum of 6 pulses per burst during a 6-week period and maintained for 18 weeks. At commencement of the hemodynamic study, performed after 6 months of dynamic CMP, the cardiomyostimulator was turned off. After the sheep had stabilized from a hemodynamic standpoint for 30 to 60 minutes, an unstimulated baseline period was observed. Then the effect of CMP pacing was studied (stimulator on, CMP). The unstimulated baseline period served as control (stimulator off, control).

Hemodynamic assessment
The catheter-tipped micromanometer and a 12-electrode conductance catheter (5F; CardioDynamics, Rijinsberg, The Netherlands) were placed longitudinally in the LV cavity (Fig 1) through the left carotid artery. The conductance catheter was connected to a Sigma 5 signal-conditioner processor (CardioDynamics). We corrected our volume measurement using a standard procedure (hypertonic saline solution injection and blood resistivity measurement) while the myostimulator was off. However, we did not correct the gain factor, . The jugular vein was cannulated with an inferior vena cava occlusion balloon (Fogarty 22F; Baxter International Inc, Irvine, CA). Left ventricular pressure, volume, and electrocardiogram were displayed and digitized at 200 Hz on a personal computer during steady-state and during transient inferior vena cava occlusion. Ventilation was held at end expiration during the measurements. Data were stored on hard disk and analyzed off-line with custom-designed software.

View larger version (36K): [in this window] [in a new window]   Fig 1. Experimental preparation for measurement of left ventricular (LV) pressure-volume and myocardial oxygen consumption. (AO = aorta; IVC = inferior vena cava; LA = left atrium; PA = pulmonary artery; RA = right atrium; SVC = superior vena cava.)

At the end of the experiment, the animals were euthanized with high-dose thiopentone.

Data analysis
All hemodynamic variables during steady-state 2:1 burst pacing were calculated as the average of 8 to 10 beats. Global LV contractility was assessed by the end-systolic pressure-volume relationship. To define this relationship a straight line was fitted, by least-squares linear regression with an iterative technique, to end-systolic pressure and volume data points during abrupt preload reduction resulting from a transient inferior vena cava occlusion. Pressure-volume area (PVA) and external work (EW) were calculated. The MO₂ of the heart was calculated as follows:

where mCBF is mean coronary blood flow, Hb is hemoglobin content, SaO₂ is arterial O₂ saturation, SvO₂ is coronary sinus O₂ saturation, and HR is heart rate.

Statistical analysis
Mean values of measurements between groups were compared by two-tailed paired Student’s t test. Data are presented as mean ± standard deviation.

	Results

Top Abstract Introduction Material and methods Results Comment References

 
Table 1 shows the hemodynamic measurements based on the pressure-volume relationship study during control periods and when the heart was assisted by CMP (2:1 duty cycle). Cardiomyoplasty did not affect heart rate. When LV hemodynamic variables such as end-systolic pressure were compared under the two conditions, no significant differences were observed, although stroke volume and ejection fraction increased significantly by 11% ± 12% and 11% ± 10%, respectively. Pressure-volume area (1,851 ± 717 mm Hg/mL to 1,787 ± 737 mm Hg/mL) and EW (909 ± 383 mm Hg/mL to 849 ± 369 mm Hg/mL) did not increase significantly with the direct cardiac compression (DCC) provided by CMP (Fig 2). This PVA includes mechanical energy transferred from the latissimus dorsi muscle as well as native heart PVA. As a consequence, when the overall mechanical efficiency was evaluated, there was no difference between control and CMP. On the other hand, MO₂ decreased by 21% ± 11% (from 0.0370 ± 0.0128 mL O₂/beat to 0.0287 ± 0.0082 mL O₂/beat; p = 0.035) with CMP. Therefore the oxygen demand for the same cardiac workload fell with CMP. As a result, CMP increased myocardial efficiency (EW/MO₂) and PVA/MO₂ by 16% ± 13% (p = 0.038) and 18% ± 12% (p = 0.014), respectively (Fig 3). Direct cardiac compression with dynamic CMP did not affect coronary blood flow (from 127 ± 42 mL/min to 123 ± 40 mL/min), whereas coronary sinus oxygen saturation increased from 58.6% ± 7.4% to 64.9% ± 5.9% with DCC. Arterial oxygen saturation was stable at 92.8% ± 5.6% (Table 2).

View larger version (17K): [in this window] [in a new window]   Fig 2. Effects of direct cardiac compression by cardiomyoplasty on overall left ventricular mechanics. Overall left ventricular mechanics were not altered by cardiomyoplasty. Open bars = baseline; hatched bars = cardiomyoplasty. (EW = external work; PVA = pressure-volume area; NS = not significant.)

View larger version (14K): [in this window] [in a new window]   Fig 3. Effect of direct cardiac compression on myocardial oxygen consumption (MO2) and coronary blood flow (CBF). Open bars = baseline; hatched bars = cardiomyoplasty. (EW = external work; PVA = pressure-volume area; LV = left ventricle; NS = not significant; * = p < 0.05.)

	Comment

Top Abstract Introduction Material and methods Results Comment References

The MO₂ sparing effect of DCC was initially reported in excised dog heart, in which the heart was compressed with a DCC cup and an actuator [8]. This revealed that DCC increased PVA and EW without any rise in MO₂. When the loading condition was adjusted to maintain EW constant, MO₂ was significantly reduced. Therefore, in the excised heart, MO₂ conservation was observed during DCC implemented by an air compression chamber. This suggested that DCC with CMP may also preserve MO₂ because its mechanical effect is assumed to mimic CMP. On the other hand, this extrapolation is subject to the criticism that the difference in squeezing action between the two modes of compression may affect the result. Therefore, it has remained unclear whether DCC achieved with CMP has the same in vivo MO₂ preserving effect as mechanical compression.

Data on the way MO₂ changes during CMP DCC assist in the in vivo heart are limited. Monnet and Orton [15] reported that mechanical efficiency is improved, but found only a reduction of MO₂, while failing to demonstrate any myocardial oxygen-sparing effect. Because they could find no difference in MO₂ between stimulation on and off of the CMP wrap, the mechanism of MO₂ reduction was unclear. On the other hand, by comparing stimulation on and off we found the reduction of MO₂ to be induced by the active squeezing action of CMP. This inconsistency in results may be related to differences in animal species or the strength of the latissimus dorsi muscle preparation.

Reverse remodeling has been postulated as an effect of CMP in a clinical study [6]. However, the mechanism that induces reverse remodeling has been unclear because the hemodynamic changes resulting from CMP were very limited. A mechanical constraint on the heart has been assumed to be the main mechanism of this remodeling, but other factors must also be operating inasmuch as active CMP is more effective in this regard than is a simple constraint [7]. From our results we speculate that not only the mechanical constraint but also improvement of LV metabolism has an important role in the LV reverse remodeling achieved with CMP.

With the squeezing action of CMP, there is the possibility that increase in intramyocardial pressure will limit coronary blood flow, which may even lead to LV ischemia. There had been no previous report on in vivo coronary blood flow addressing this effect, so it is significant that we found no difference in this measurement between controls and CMP sheep. This confirms that the squeezing action of CMP does not compromise coronary blood flow or induce ischemia. In contrast, we found the coronary arterial and venous oxygen concentration difference to be reduced. Our data therefore support an improved oxygen supply-demand balance in sheep with heart failure that underwent CMP DCC. Because the direct girdling effect is the only reported mechanism for the induction of reverse remodeling, our findings of a myocardial oxygen-sparing effect could provide an additional route. These mechanisms could be operative in CMP patients and presumably also with mechanical DCC devices.

In this study we used 2:1 stimulation to analyze the effect of DCC on MO₂ and coronary blood flow because this pacing duty cycle is commonly used with CMP to assist the failing heart. There are many studies comparing the effect of CMP between periods of pacing on and off in the 2:1 stimulation mode, even though this may not be the best way to assess the overall hemodynamic effect. The squeezing effect of CMP on LV performance is complex and may affect not only systolic function but also subsequent diastolic filling because of the possibility that active squeezing assist unloads the LV or because slow relaxation of the transformed muscle after the assisted beat may interrupt LV filling during the subsequent cardiac cycle. We believe we have largely surmounted this obstacle by averaging the measurements in 2:1 mode and comparing them to the control situation without stimulation. Therefore, our data are likely to represent the overall effect of dynamic CMP in the clinical setting.

A limitation of this study is the number of animals involved, but this is believed to be more than offset by the use of an untreated chronic stable heart failure model that has diffuse LV dysfunction based on pure ischemic origin. Despite this potential limitation, the reduction of MO₂, and hence the improvement of LV energetics, directly related to the squeezing action of CMP was clearly demonstrable.

In conclusion, dynamic CMP did not change overall cardiac work but reduced MO₂. This provides direct evidence for transmission of the power of the latissimus dorsi muscle to the LV, leading to improved mechanical efficiency of the native heart—the so-called oxygen-sparing effect of dynamic CMP in heart failure hearts. These findings also have implications for operation of mechanical DCC devices.

	References

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