Ann Thorac Surg 1998;66:2015-2021
© 1998 The Society of Thoracic Surgeons
Original Articles
Nitroglycerine reduces neutrophil activation and acute damage in latissimus dorsi muscle grafts
Augustine T.M. Tang, FRCS Eda,
Philip Geraghtyb,
Michael J. Dascombe, PhDc,
Jonathan C. Jarvis, PhDd,
Stanley Salmons, PhDd,
Timothy L. Hooper, MDa
a Department of Cardiothoracic Surgery, Wythenshawe Hospital, Manchester, United Kingdom
b Department of Immunology, School of Biological Sciences, University of Manchester, Manchester, United Kingdom
c Division of Neuroscience, School of Biological Sciences, University of Manchester, Manchester, United Kingdom
d Department of Human Anatomy and Cell Biology, University of Liverpool, Liverpool, United Kingdom
Accepted for publication June 7, 1998.
Address reprint requests to Dr Hooper, Department of Cardiothoracic Surgery, Wythenshawe Hospital, Southmoor Rd, Manchester M23 9LT UK
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Abstract
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Background. Damage to the latissimus dorsi muscle (LDM) may jeopardize a successful outcome to dynamic cardiomyoplasty. We and others have demonstrated muscle damage in LDM in various species including humans. Ischemia is now recognized to be an important contributory factor. We postulated that glyceryl trinitrate, a nitric oxide donor, might protect against ischemic endothelial dysfunction and so reduce resultant muscle damage.
Methods. In 20 adult rats the left LDM was mobilized on its thoracodorsal neurovascular pedicle and maintained as an orthotopic graft. Half of the animals received glycerol trinitrate intraoperatively and postoperatively for 24 hours. The other half served as untreated controls. Each group was further subdivided into two groups (n = 5 in each): animals in which the LDM was excised after 4 hours for myeloperoxidase studies, and animals in which the LDM was excised at 24 hours for analysis of muscle damage by histology and enzyme macrohistochemistry. Blood samples were taken at 24 hours for assay of plasma nitrite and nitrate as nitric oxide metabolites.
Results. Glycerol trinitrate-treated animals had higher plasma nitric oxide metabolite levels after 24 hours (after nitrate reductase treatment, total nitrite, 78.3 ± 11.8 nmol/mL, mean ± SEM) than controls (42.1 ± 3.7 nmol/mL, p = 0.008). The proportion of viable LDM in glycerol trinitrate-treated animals was greater than in untreated animals, mainly in the middle and distal regions of the graft (middle region, 96.3% ± 0.5% versus 75.7% ± 4.1%, p < 0.001; distal region, 94.4% ± 0.8% versus 40.9% ± 3.1%, p < 0.001). Macrohistochemical findings correlated well with the histologic findings. Myeloperoxidase activity (U/g) was markedly lower in glycerol trinitrate-treated LDMs, mainly in the distal part of the graft (glycerol trinitrate versus control, 20.5 ± 2.1 versus 40.9 ± 3.1 U/g, p < 0.001).
Conclusions. Glycerol trinitrate significantly reduced acute damage to the distal two-thirds of the mobilized LDM, possibly by modifying leukocyte activation and endothelial dysfunction associated with ischemic injury.
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Introduction
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The latissimus dorsi muscle (LDM) can be mobilized as a functional graft to provide cardiac assistance in end-stage heart failure. In dynamic cardiomyoplasty, a pedicled LDM graft is transposed into the chest and wrapped around the cardiac ventricles. Electrical stimulation synchronized to the electrocardiogram results in contraction of the muscle wrap during ventricular systole.
A successful outcome of dynamic cardioplasty depends to an extent on the functional integrity of the LDM wrap. It is therefore a matter of concern that replacement of muscle by fibrous fatty tissue, mainly in the distal part of the LDM graft, has been observed both in animals [1] and in man [2, 3]. The origins of this damage are probably multifactorial, but there are strong indications that ischemia is a key contributory factor. This may be aggravated by the cumulative effects of badly chosen regimens of chronic electrical stimulation [4], but damage can also occur at an early stage, even in the perioperative and immediate postoperative period, as evidenced by large peaks of serum creatine phosphokinase [3].
The susceptibility of the LDM to ischemia after surgical mobilization is related to its blood supply. This comes from two sources: the thoracodorsal artery, which enters the proximal part of the muscle, and branches of the intercostal arteries, which perforate the chest wall and enter the distal part. The two vascular networks are interconnected through arterial anastomoses within the muscle [5, 6]. Anastomotic channels have been well documented by anatomic techniques, and recently we were able to confirm that they are functional under physiologic conditions of pressure and flow [7]. Thus, even after surgical mobilization and loss of the intercostal blood supply, the anastomotic channels could, in principle, enable the thoracodorsal artery to continue to perfuse the distal part of the LDM graft by means of an existing vascular network. However, the efficacy of these connecting vessels may be compromised at any early stage by a number of factors; these include electrocautery, handling and cooling of the LDM, and loss of normal resting tension during surgical mobilization. This would lead to a period of ischemia in the distal part of the muscle, with the possibility of subsequent ischemic and reperfusion injury.
There is considerable evidence for local endothelial regulation of vascular homeostasis by the production of nitric oxide to control tissue blood flow [8]. Ischemic injury to the endothelium interferes with this autoregulation and thus leads to inappropriate vasoconstriction, activation of leukocytes and platelets, and ultimately microvascular thrombosis and tissue damage [9]. We postulated that if ischemia were a significant factor in the early onset of muscle damage, then treatment with a nitric oxide donor might improve LDM viability. Studies focusing on ischemia-reperfusion injury in skeletal muscle have highlighted the important role of neutrophils in mediating acute damage. We have therefore measured myeloperoxidase (MPO) activity, which quantifies neutrophil accumulation, in the LDM shortly after surgical intervention.
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Materials and methods
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Experimental design
Animals were operated on and cared for in accordance with the Animal (Scientific Procedures) Act, 1986, which regulates animal experimentation in Great Britain and Northern Ireland. Twenty adult male Sprague-Dawley rats (Charles River, Kent, UK), weighing between 380 and 420 g, underwent surgical mobilization of the left LDM, with preservation of the thoracodorsal pedicle. Ten of the animals received glycerol trinitrate (GTN) therapy (group 1) and 10, which did not, served as controls (group 2). In each group, half of the animals were sacrificed after 4 hours and the right and left LDMs excised for MPO assays (groups 1a and 2a). The other 5 animals in each group were sacrificed after 24 hours, and LDMs were excised for assessment of muscle viability by enzyme macrohistochemistry and histology (groups 1b and 2b).
Glycerol trinitrate therapy
With the animal anesthetized and before any surgery was performed, a measured patch (18.3 mm2) of GTN (Deponit, Schwarz Pharma Ltd, Chesham, UK), designed to provide sustained transdermal release of the drug at a rate of 10 mg/24 hours from a matrix-gel, was secured to a shaved area of interscapular skin of animals in group 1. An intravenous dose (25 µg/kg) of GTN (DBL, Warwick, UK) was administered into a femoral vein to provide systemic loading of the drug before any surgical intervention. In pilot experiments we established the systemic doses of GTN needed to cause a reduction of about 30% in the mean arterial pressure.
Anesthesia and surgery
General anesthesia was induced and maintained with a 2:1 mixture of nitrous oxide and oxygen in combination with halothane (1% to 2%). Each rat breathed spontaneously throughout the procedure. A heating blanket, controlled by feedback from a rectal thermometer, regulated core body temperature within the normal range for rats (38° to 39.5°C). Analgesia was provided by intramuscular diclofenac sodium (Geigy Pharmaceuticals, Horsham, UK) given initially at a dose of 1 mg/kg and supplemented at 12-hour intervals when necessary. Blood gas analysis of samples (0.3 mL) taken from a femoral vein allowed intraoperative monitoring of respiratory function.
A left flank incision was made from the posterior axilla to the 11th rib to expose the underlying LDM. Blood vessels supplying the LDM other than the thoracodorsal artery were divided. The muscle was mobilized from its truncal attachments, raised as a pedicled graft, and replaced at its resting length with a running 5-0 Prolene (Ethicon, Somerville, NJ) suture to preserve the physiologic tension. Wounds were closed after hemostasis and the animal was allowed to recover. After 4 hours in groups 1a and 2a, and after 24 hours in groups 1b and 2b, animals were killed by exsanguination under anesthesia. Blood was collected in a heparinized tube for assay of plasma nitrites and nitrates. The experimental LDMs were excised at the same time as the undisturbed contralateral muscles, which acted as matched controls.
Plasma nitrate determination
Plasma samples were separated immediately from whole blood by centrifugation at 1,500g for 5 minutes and then stored frozen at -70°C pending analysis. Nitric oxide metabolites in plasma were measured as nitrites using the Griess reaction, after first converting nitrates to nitrite with nitrate reductase. Plasma (60 µL) was placed in a 1.5-mL Eppendorf tube with 10 µL nitrate reductase (5 U/mL, Sigma, Poole, UK) and 30 µL reduced nicotinamide-adenine dinucleotide phosphate (1.25 mg/mL, Sigma) and incubated at room temperature (19° to 23°C) for 30 minutes. Griess reagent (5% phosphoric acid, 1% sulfanilic acid, 0.1% N-(1-napthyl)ethylene diamine in deionized water; 200 µL) was added and the solution incubated at room temperature for a further 10 minutes. Protein was precipitated by addition of 10% trichloroacetic acid (200 µL), with thorough mixing, and microcentrifuged (MSE MicroCentaur, Sanyo Gallenkamp, Leighster, UK) at 13,400 g for 15 minutes at 4°C. Supernatant was transferred onto a microplate, and the absorbance was read at 540 nm on a microplate reader (Dynatech Laboratories MRX). Nitrite concentrations were determined from a standard curve for sodium nitrites (0.1 to 50 µmol/L) in pooled rat plasma. Values are expressed as nitrite in nanomoles per milliliter of plasma and have been corrected for interference in the spectrophotometric assay (by the use of internal standard sodium nitrites in experimental samples) and incomplete conversion of nitrate to nitrite by nitrate reductase (by the use of external standard sodium nitrate).
Myeloperoxidase assay
Myeloperoxidase is a heme-containing enzyme found predominantly in neutrophils, and provides a suitable quantitative measure of neutrophil accumulation in skeletal muscle [10]. The assay has been established previously in our laboratory [11]. After excision, the LDM was divided into three equal parts, representing the proximal, middle, and distal regions (Fig 1). Muscle specimens were snap-frozen in liquid nitrogen and stored at -70°C pending the assay, which was performed by a single unbiased observer. Samples of muscle, each weighing approximately 50 mg, were homogenized in 1 mL of citrate phosphate buffer, pH 5 (BDH/Merck, Poole, UK). The homogenate was kept on ice and sonicated to disrupt the neutrophil granules and to solubilize the MPO. The resulting suspension was spun at 2,000g for 25 minutes at room temperature. One hundred-microliter samples of the supernatant were diluted across a 96-well Immulon II microtiter plate with sodium acetate, pH 5.5 (Sigma, Poole, Dorset, UK), as was 100 µL of purified human MPO (Sigma). To each well was added 100 µL of the assay solution, prepared by mixing together 1 mL of the peroxidase substrate 2,2'-azino-bis(ethylbenzylthiazoline-6-sulfonic acid) diammonium salt (Sigma), 50 mL of citrate phosphate buffer, and 5 µL of 30% hydrogen peroxide (BDH/Merck). The plate was allowed to develop at room temperature before the optical density at 405 nm was measured with a microplate reader (Molecular Devices, Sussex, UK); the most concentrated standard was arranged to give an absorbance of approximately 1. Each sample was assayed in duplicate wells. Background values, accounted for when necessary, were obtained by adding the assay solution alone to duplicate wells on each microtiter plate. Myeloperoxidase activities in the samples were calculated from their relative change in absorbance and calibrated against a standard curve based on human MPO (linear range, 0 to 2.99 U). Results were corrected for the weight of individual muscle samples and expressed as units of activity per gram (U/g).
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Fig 1. Division of the latissimus dorsi muscle along its length into three regions: proximal, middle, and distal.
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Processing of the latissimus dorsi muscle
Intact specimens of LDM were incubated in a solution of nitroblue tetrazolium (Sigma Aldrich, Dorset, UK) containing 500 mg/L of nitroblue tetrazolium in deionized phosphate buffer, according to the method described by Nachlas and Schnitka [12]. In viable muscle cells, the colorless tetrazolium compound is reduced by electron carriers and oxidative enzymes to form an insoluble blue formazan deposit. Consequently, viable muscle stains dark blue, whereas nonviable areas remain unstained after incubation. After treatment each muscle was kept at its resting length in 10% buffered formalin (pH 7.4) and photographed within 24 hours. The formalin served as a fixative and had no significant effect on nitroblue tetrazolium staining. After photography a specimen of LDM was divided perpendicular to its long axis into three parts representing proximal, middle, and distal regions (Fig 1). The muscle samples were embedded in paraffin wax in a programmable automated processor (Shandon Hypercenter XP, Life Science International, Basingstoke, UK). Longitudinal sections (4 µm thickness), each representing an entire region, were obtained by cutting parallel to the surface of the muscle and stained with hematoxylin and eosin for microscopic examination.
Photography and image analysis
The stained surface of each intact LDM was photographed with color-sensitive film (Kodak Ektachrome 64 ASA) under a 5,500 K light source to produce 35 mm projection slides. An image generated from each projection slide by transillumination with a constant daylight source was captured on an image analyzer (Seescan, Cambridge, UK) by means of a video camera (CCD vision camera module, Sony, UK). Area measurements of each muscle specimen were made using customized software (Symphony, Seescan, Cambridge, UK). The captured image was analyzed to provide the total area and the stained area so that the percentages of viable and nonviable muscle could be calculated for each region of the LDM. Images were analyzed blind by a single observer.
Histologic assessment
All muscle sections were examined with a standardized setting (x4 objective and x10 eyepiece) on a dedicated microscope (Leitz Diaplan, Wetzlar, Germany) by a single unbiased observer. Assessments were made according to a damage scoring system (Table 1) that we have described previously [13]. The total damage score for each muscle section was calculated according to the following formula:
The grading of each parameter is defined in Table 1. By scanning a section encompassing an entire region from each of the three LDM regions, the observer could assess histologic changes within the whole LDM. This system of assessment was designed to account for both the extent and the severity of histologic changes in the LDM.
Statistical analysis
Data on muscle viability, histologic damage, and MPO activity were analyzed by three-factor repeated measures analysis of variance. Examination of the model residuals confirmed that the statistical model was a good fit for the data. Statistical significance was defined as p less than 0.05, and for each significant finding multiple comparisons were made by the Tukey post hoc test. Data on plasma nitrate concentration were compared between the groups by a two-tailed unpaired t test. The results are presented as means with standard errors of the mean (SEM). Computations were done using GLIM 3.77 statistical software (Royal Statistical Society, London, UK).
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Results
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Plasma nitrate concentration
Rats treated with GTN continuously for 24 hours (group 1b) had significantly higher plasma concentrations of nitric oxide metabolites, measured as total nitrite after nitrate reductase treatment of samples, than the untreated controls (group 2b) (total nitrite, 78.3 ± 11.8 versus 42.1 ± 3.7 nmol/mL, p = 0.008).
Myeloperoxidase activity—neutrophil accumulation
Myeloperoxidase activity was found to be uniform throughout the undisturbed contralateral LDM in the GTN-treated animals (group 1a), and was similar in level to that observed in the contralateral muscles of the untreated animals (group 2a, Fig 2). Four hours after it had been mobilized surgically, the LDM in the untreated animals (group 2a) showed a highly significant twofold to threefold increase in the MPO activity in the distal region (p < 0.001 compared with the undisturbed contralateral muscle, Figs 2, 3). In animals treated with GTN, the rise in MPO activity in the distal region was less than 50% of that observed in the untreated group (p < 0.001, Fig 3). The proximal two-thirds of the LDM showed no significant changes in MPO activity after surgical mobilization in either the treated or untreated groups (Figs 2, 3).
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Fig 2. Myeloperoxidase (MPO) activity (mean ± SEM, U/g) in the undisturbed contralateral latissimus dorsi muscle. The dark columns represent glycerol trinitrate-treated rats and the white columns represent untreated animals.
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Fig 3. Myeloperoxidase (MPO) activity (mean ± SEM, U/g) in the mobilized latissimus dorsi muscle. The dark columns represent glycerol trinitrate-treated rats and the white columns represent untreated animals.
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Enzyme macrohistochemistry—muscle viability
The undisturbed contralateral LDMs showed no evidence of damage in either GTN-treated animals (group 1b) or untreated controls (group 2b, Fig 4). Twenty-four hours after surgical mobilization, the LDM in the untreated animals showed some evidence of damage. The proximal region was not significantly affected, but there was a loss of 24% of viable muscle tissue in the middle region (p < 0.01 compared with the proximal region), and 34% of muscle in the distal region (p < 0.001 compared with the proximal region). Treatment with GTN after surgical mobilization appeared to have preserved muscle viability completely (Figs 4, 5). This protective effect was observed to be uniform throughout the muscle. As a result animals that had received GTN (group 1b) had significantly greater viability in the distal region (p < 0.001) and the middle region (p < 0.001) of the LDM after surgical mobilization than the untreated animals (group 2b) (Fig 5).
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Fig 4. Muscle viability (mean ± SEM, %), measured by enzyme macrohistochemistry, in the undisturbed contralateral latissimus dorsi muscle. The dark columns represent glycerol trinitrate-treated rats and the white columns represent untreated animals.
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Fig 5. Muscle viability (mean ± SEM, %), measured by enzyme macrohistochemistry, in the mobilized latissimus dorsi muscle. The dark columns represent glycerol trinitrate-treated rats and the white columns represent untreated animals.
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Histologic assessment—muscle damage
Twenty-four hours after surgical mobilization, the LDM in the untreated animals (group 2b) showed significantly more damage in the distal region than in the proximal region (p < 0.001) or in the middle region (p < 0.001, Fig 6). Animals treated with GTN (group 1b) did not exhibit regional variations in muscle damage and were significantly (p < 0.001) less damaged in the distal region than the untreated animals (Fig 6).
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Fig 6. Muscle damage (mean ± SEM), measured histologically by a damage score, in the mobilized latissimus dorsi muscle. The dark columns represent glycerol trinitrate-treated rats and the white columns represent untreated animals.
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Comment
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Our use of a rodent model has two main justifications. First, we have previously demonstrated significant damage to the distal LDM 24 hours after surgical mobilization [13], confirming that the rat muscle is susceptible to this type of ischemic injury. Second, arterial anastomoses similar to those seen in larger species have been demonstrated linking the vascular networks within the rodent muscle [6]. Moreover, the rat is an inexpensive alternative to a large animal model such as the sheep, and the small size of the rodent LDM allowed the enzymatic quantification of muscle viability to be performed with greater simplicity and accuracy.
The results show that GTN therapy initiated before, and maintained after, surgical mobilization produces a substantial reduction in muscle damage in the LDM in rats after 24 hours, as indicated by significant improvements in both functional (enzyme macrohistochemistry) and structural (histologic) integrity. The enhanced muscle viability, with demonstrably less interstitial edema, inflammatory infiltrate, and muscle fiber degeneration, was associated with a significant elevation in the plasma nitrite and nitrate concentration and a substantial reduction in the accumulation of neutrophils in the muscle.
Since 1985, dynamic cardiomyoplasty with a functional graft of LDM has been used to provide cardiac assistance in more than 700 patients with end-stage heart failure. Significant damage to the distal portion of the LDM has been recorded in animals [1] and man [2, 3, 14]. Muscle damage is known to occur after weeks and months of providing functional cardiac assistance [14, 15]. However, there is also evidence that significant damage to the LDM can develop at a much earlier stage, shortly after surgical mobilization [3]. Loss of viable muscle has been shown to impair graft function [15] and clinical outcome both in the acute [3] and in the chronic setting [2].
Damage in the mobilized LDM appears to result from interaction of several factors, including ischemia, reduced muscle tension, electrical stimulation, and surgical trauma [1]. Even in the absence of other contributing factors the effects of muscle ischemia have been demonstrated [1, 16]. Although this is usually ascribed to the unavoidable sacrifice of the collateral blood supply to the LDM, there are reasons to suggest that this alone should not result in ischemia of the distal muscle [7]. A series of anastomotic channels within the muscle connects the vascular network of the thoracodorsal artery proximally with that of the perforating arteries distally and should therefore enable the thoracodorsal artery to sustain perfusion to the distal muscle despite the loss of the collateral blood supply. These anastomoses have been demonstrated in several species, including the rat [6], with the use of angiography or resin injection techniques, and recent experiments in the sheep have confirmed that they are functional under normal physiologic conditions of pressure and flow [7]. The fact that the distal region of the LDM usually does become ischemic suggests that the efficacy of these arterial anastomoses may be compromised during surgical mobilization. Factors such as handling and cooling of the LDM, excessive electrocautery, and reduced muscle tension may combine to impair vascular patency.
Any injury sustained during this ischemic episode could be exacerbated by reperfusion if the anastomotic channels subsequently recover their patency. Ischemia-reperfusion injury to skeletal muscle is of recognized clinical significance, affecting the outcome of revascularization of ischemic limbs, reimplantation of severed extremities, and setting a time limit for tourniquet application. These problems have been addressed experimentally and the findings suggest that duration of ischemia, temperature, collateral blood flow, muscle location, and fiber type may each play a role in determining the amount of muscle damage [17]. These factors were controlled as far as possible in the present study by using an orthotopic graft of LDM, raised by a standardized technique, and examined after the same elapse of time. It is difficult to ascertain whether GTN exerts its cytoprotective effects mainly during ischemia, reperfusion, or a combination of the two. Experimental studies of the kind mentioned previously in skeletal muscle [18], cardiac muscle [19], and kidney [20] have not established which phase is more important for therapeutic purposes.
Muscle damage from different causes may involve such common final pathways as depletion of energy supply to the cell, loss of intracellular calcium homeostasis, and overactivity of superoxide anions [21]. These processes interact closely, making it difficult to attribute muscle damage in any particular situation to one specific mechanism [21]. There has nevertheless been particular interest in the role of superoxide anions and neutrophil infiltration in ischemia-reperfusion injury to skeletal muscle. During ischemia, the endothelial enzyme nitric oxide synthase is capable of generating superoxide anions [18]. Ischemic damage to the endothelial cells also triggers the expression of leukocyte adhesion molecules, activating circulating neutrophils that infiltrate the reperfused muscle, generating more superoxide anions and so causing acute myonecrosis. In ischemic cardiac muscle, reperfusion is followed by rapid accumulation of neutrophils, with infiltration beginning in 3 minutes and peaking in 2 to 3 hours [22]. Nitric oxide donors administered during myocardial reperfusion are known to suppress neutrophil infiltration, with markedly inhibitory effects on muscle damage [19]. In skeletal muscle subjected to ischemia-reperfusion, preventing neutrophil adherence and infiltration also reduced the resultant injury [23]. The above observations provide an explanatory framework for our findings in the surgically mobilized LDM, in which treatment with GTN significantly reduced neutrophil accumulation and limited acute myonecrosis.
In experiments of broadly similar design, we previously found that vasodilators with no known direct action on the nitric oxide pathway (papaverine, hydralazine, and verapamil) failed to protect against damage to the rodent LDM [24]. This suggests relief of acute vasospasm alone may not have a major influence on early graft survival. The cytoprotective effect of GTN observed in the present study may therefore be exerted not so much through its vasodilatory action as through an influence on other events precipitated by reperfusion [25]. The observations on reduced neutrophil accumulation and plasma nitrite and nitrate levels in GTN-treated animals would be consistent with this hypothesis.
Whatever its precise mechanism of action, this study indicates that GTN therapy could offer a simple way of protecting LDM grafts from early loss of viability related to ischemia.
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Acknowledgments
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Augustine T. M. Tang, FRCS Ed., conducted this work during the tenure of a British Heart Foundation Research Fellowship. We thank Ruslizar Basir and Trudy E. Shaw for their technical assistance, and Dr. E. Brian Farragher, head of medical statistics support unit, University of Manchester, for his help with the statistical analysis.
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Abstract
Introduction
