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Ann Thorac Surg 1996;62:1051-1058
© 1996 The Society of Thoracic Surgeons
Divisions of Cardiac Surgery and Cardiology and Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland
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Abstract |
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 TopFootnotes Abstract IntroductionMaterial and MethodsResultsCommentAcknowledgmentsReferences |
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Methods. Triads of transmyocardial revascularization channels were placed in eight separate nonischemic sites on the hearts of 7 pigs weighing 68 to 78 kg, which were allowed to recover and were then sacrificed at 28 days. In addition, one triad pair was injected with vascular endothelial growth factor, and two triad pairs received an adenovirus vector with or without the gene encoding for human profilin, which increases endothelial cell motility and adhesion. The remaining triad pair stood untreated (laser only). The histologic changes were graded (0 through 3) by an independent pathologist without knowledge of the treatment modality. Profilin production and vascular endothelial growth factor activation using a tyrosine kinase assay were monitored.
Results. Transmyocardial revascularization alone resulted in a significant injury response (p < 0.01), including increased vascularity without patent channels. Vascular endothelial growth factor increased surrounding inflammation (p < 0.01) without improving vascularity or patency. Profilin content in tissues was increased but nonspecifically because inflammation resulting from adenovirus also induces higher profilin concentrations.
Conclusions. The clinical benefit of transmyocardial revascularization may result simply from a nonspecific histologic response to injury. Molecular interventions appear to stimulate more inflammation but no additional angiogenesis. Further improvement in the clinical benefit of transmyocardial revascularization awaits the successful stimulation of a true angiogenic response.
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Introduction |
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TopFootnotesAbstractIntroductionMaterial and MethodsResultsCommentAcknowledgmentsReferences |
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A substantial number of patients with symptomatic occlusive coronary artery disease are refractory to maximal medical therapy and are not candidates for conventional revascularization techniques (namely, percutaneous transluminal coronary angioplasty or coronary artery bypass grafting). Transmyocardial laser revascularization (TMR) is an alternative treatment currently being used on an investigational basis in this patient population. Preliminary clinical results suggest that TMR may effectively provide some symptomatic and functional myocardial improvement in select individuals [1–4].
Transmyocardial laser revascularization involves the use of a high-powered (850-W) carbon dioxide (CO2) laser to create transmyocardial (epicardial to endocardial) channels in regions of critically ischemic tissue. It has been speculated that these channels act as conduits to shunt oxygenated blood from the left ventricle into the extensive intramyocardial vascular plexus. However, there is growing debate over the long-term patency of TMR channels. A healing response to laser injury accompanied by neovascularization and increased collateral perfusion of thermally damaged tissue has been proposed as an alternative mechanism to explain the beneficial effects of direct CO2 laser revascularization.
Profilin, a regulator of cytoskeletal dynamics, plays an important role in endothelial cell motility [5, 6]. In this study, a replication-incompetent adenovirus carrying the human profilin-I complementary DNA was used to infect myocardial tissue after TMR to promote endothelialization of the laser channels. In addition, an attempt at direct stimulation of myocardial angiogenesis was undertaken to augment the vascular response secondary to TMR. Vascular endothelial growth factor (VEGF) was chosen as the mitogen because of its potency and endothelial cell specificity [7, 8].
This study was designed to evaluate the histologic changes associated with TMR in a 1-month nonischemic porcine model and to determine if adjunctive interventions at a molecular level might enhance myocardial vascularity.
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Material and Methods |
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TopFootnotesAbstractIntroductionMaterial and MethodsResultsCommentAcknowledgmentsReferences |
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Operative exposure was achieved through a median sternotomy. The heart was suspended in a pericardial cradle. Lidocaine hydrochloride, 1.5 mg/kg, was administered intravenously. Transmyocardial laser revascularization was achieved with a high-powered (850-W), pulsed CO2 laser (The Heart Laser; PLC Medical Systems, Inc, Milford, MA). The handpiece was placed directly on the epicardial surface of the heart, and four rows of laser channel triad pairs were drilled in the anterolateral wall of the left ventricle (Fig 1
). The helium-neon light permitted aiming of the laser beam to reduce the risk of injury to the epicardial vessels. Transmural penetration was verified by intraoperative epicardial echocardiography (Hewlett-Packard). A laser pulse of 24 J (30 ms) consistently provided an easily visualized jet of bubbles in the left ventricular cavity. To minimize the risk of ventricular arrhythmias, laser pulse delivery was computer-synchronized with the peak of the R wave of the electrocardiogram. Epicardial surface bleeding from laser sites was controlled with several minutes of light direct pressure. No epicardial pursestring sutures were necessary to control bleeding.
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Four different interventions were administered to each heart (one row of laser triad pairs per intervention; total of eight triads per heart). The interventions were as follows: laser alone, laser plus VEGF, laser plus adenovirus without the complementary DNA for human profilin-I (control adenovirus), and laser plus adenovirus carrying the complementary DNA for human profilin-I (profilin adenovirus). Each row was randomly assigned an intervention. As a group, the animals served as their own controls.
A single layer of expanded polytetrafluoroethylene (Preclude pericardial membrane; W.L. Gore & Associates, Inc, Flagstaff, AZ) was secured to the pericardial edges to cover the anterior surface of the heart and facilitate the reexploration at 28 days. Two 36F chest tubes were inserted and placed to -20 cm of water suction. The sternum was closed with 3-0 stainless steel wires. Fascia, subcutaneous tissue, and skin were reapproximated in standard fashion with running monofilament suture. All animals remained anesthetized with halothane administered by way of the ventilator until the chest tubes were removed 90 minutes postoperatively. One gram of cefazolin was given before removal of the venous catheter at the end of the procedure. Animals were extubated when spontaneous ventilation returned. They were observed for 15 minutes in the transport cart to ensure satisfactory ventilatory status and then taken to the standard chronic animal care facility.
On day 28, animals were prepared for operation in a fashion similar to that already described for day 0 except under nonsterile conditions. After repeat median sternotomy and dissection of the heart, the fully anesthetized animals were sacrificed by intravenous injection of potassium chloride. The heart was excised and placed in cold saline solution.
All animals received humane care in accordance 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 National Academy of Sciences (NIH publication 85-23, revised 1985). After a 3-hour observation period with invasive monitoring, the animals were transferred to a standard chronic animal care facility and provided with standard porcine food and tap water ad libitum until the day of sacrifice.
Histology
After cardiectomy, myocardial regions subjected to laser treatment were identified and removed en bloc. Specimens were serially sectioned in a transverse fashion (perpendicular to the long axis of the triad from epicardial to endocardial surface) into smaller blocks. In select cases where endocardial dimpling with scarring was clearly evident, longitudinal sections of the triads were also obtained. One section from each site was harvested fresh for the biochemical and immunohistochemical analyses. The remaining sections were fixed in neutral buffered formalin, embedded in paraffin, sectioned in thicknesses of 5 µm, and stained with hematoxylin and eosin. Histologic changes (fibrosis, inflammation, and vascularity) were graded from 0 through 3 (least to greatest) by an independent pathologist who was not aware of the treatment modality. Laser channel patency was also assessed.
Two pairs of triads receiving different interventions near the apex of the heart were rejected because of their proximity on the endocardial surface to avoid data from potentially mixed therapies.
Protein Quantitation
Measurement of total protein concentration in pulverized fresh myocardial extracts was performed by Coomassie blue–stain gel technique. Tissues (
8 x 107 cells for Coomassie blue–stained gels and 107 cells for Western blots) were extracted with melting ice-cold lysis buffer (15 mmol/L Hepes [pH 7.0], 145 mmol/L NaCl, 0.1 mmol/L MgCl2, 10 mmol/L EGTA, 0.5% Triton X-100, 1 mmol/L 4-(2-aminoethyl)benzene-sulfonyl fluoride, and protease inhibitors [chymostatin, leupeptin, antipain, and pepstatin, each at 20 µg/mL]), transferred to 1-mL polycarbonate tubes (Beckman), and sonicated (Branson Sonifier 450, energy level 1 to 2) for 10 seconds. Protein concentration in each extract was determined by Bradford assay, and extracts were normalized for total protein content. All Coomassie and Western blot gels were performed on 4 randomly selected animals.
Immunoprecipitation and Immunoblotting
Measurement of tyrosine kinase (TK) activity was performed by Western blot analysis of tyrosine phosphorylated substrates in pulverized myocardial extracts. The Triton X-100–lysed samples normalized for total protein (3 g/L) were incubated with a monoclonal antibody for phosphotyrosine residue covalently attached to agarose beads (Upstate Biology Inc). Samples were gently rotated for 90 minutes at 4°C. The beads were washed four times in melting ice-cold lysis buffer without Triton X-100 or protease inhibitors and then boiled in 60 µL of sodium dodecyl sulfate buffer for 5 minutes. The samples were analyzed by sodium dodecyl sulfate/polyacrylamide gel electrophoresis by use of 4% to 20% gradient gels. The proteins were transferred onto nitrocellulose membrane, and immunoblots were reacted with an anti-phosphotyrosine antibody (Upstate Biology Inc) at 0.2 mg/L in Tris-buffered saline solution (containing 20 mmol/L Tris base [pH 7.6] and 137 mmol/L NaCl) and then with a peroxidase-labeled goat anti-mouse antibody (1 mg/L) in Tris-buffered saline solution as previously described. Immunoblots were developed using the enhanced chemiluminescence system (Amersham Corp, Arlington Heights, IL). The intensity of individual bands on chemiluminograms was quantified by densitometry.
Profilin Quantitation
Quantitation of profilin content was performed by Western blot analysis of pulverized myocardial extracts. Extracts were centrifuged (100,000 g for 30 minutes at 4°C in 1-mL tubes) in a Beckman TLA-100.2 rotor, and profilin in the supernatants (which contain 
99% of cellular profilin) was concentrated on poly(L-proline) beads, boiled in SDS sample buffer, and analyzed by SDS/acrylamide gel electrophoresis (4% to 20% gradient gels) and Western blotting together with purified profilin standards. The Western blots were developed with a specific anti-profilin antibody, and chemiluminograms (Enhanced Chemiluminescence; Amersham) were obtained using horseradish peroxidase–labeled immunoglobulin Gs (HyClone, Logan, UT) at a dilution of 1:500. The profilin bands were measured by densitometry using profilin standards on the same chemiluminograms.
Statistical Analysis
Data are reported as the mean ± the standard deviation. Intergroup comparisons were made using Student's t test where appropriate. Statistical significance was accorded to p values of less than 0.05.
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Results |
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TopFootnotesAbstractIntroductionMaterial and MethodsResultsCommentAcknowledgmentsReferences |
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Histology
In all treatment groups, the TMR triads were easily identified at the time of tissue sectioning as regions of focal scarring along the course of each laser tract. Evaluation of the laser triads by light microscopy revealed a central fibrovascular scar with a narrow marginal zone of histologic changes consistent with mild thermal injury (Figs 2, 3). The diameter of the tracts ranged from 0.3 to 1.1 mm. The dense fibrous tracts were composed of spindle-shaped fibroblasts and collagen fibers admixed with variable numbers of small blood vessels, the vast majority of which were between 5 and 10 µm in diameter. These vascular structures were morphologically indistinguishable from normal small vessels seen in granulation tissue, and the area occupied by their lumens was only a small fraction of that occupied by the fibrous connective tissue. Degenerating cardiomyocytes, collections of amorphous coagulative material, hemosiderin-laden macrophages, and giant cells were also noted within or adjacent to many of the TMR tracts. These are the typical histologic features associated with laser thermal injury and the various stages of the subsequent myocardial remodeling and healing process.
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). There were no differences between treatment groups in regard to fibrosis.
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). Determination of tract diameter was difficult in some cases of adenovirus-infected tracts because of the architectural distortion caused by the lymphocytic infiltrates.
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). They had the histologic appearance of normal myocardial sinusoids or venules. Within distinct fibrous scars on the endocardial surface of the left ventricle, small pinpoint depressions were noted on gross examination; however, longitudinal sections through these randomly selected triad depressions also did not reveal any channellike connection with the left ventricular cavity.
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Total Myocardial Protein
There was no change in total protein concentration of the laser triads in the treatment groups at 28 days postoperatively.
Myocardial Tyrosine Kinase Assay
No significant increase in TK activity was noted in the treatment groups at 28 days postoperatively (Fig 6a).
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). In some animals, profilin concentration was increased in tissues infected with profilin adenovirus; in others, profilin was increased in tissues infected with the control adenovirus. Consequently, profilin concentration was not reliably increased in extracts from tissue infected with profilin adenovirus. |
Comment |
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TopFootnotesAbstractIntroductionMaterial and MethodsResultsCommentAcknowledgmentsReferences |
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The concept of TMR was developed from these early ideas and was pioneered by Mirhoseini and Cayton [13] in 1981. A CO2 laser with its high tissue absorption and minimal scatter was chosen to create the transmural channels to minimize thermal injury to surrounding myocardium. At that time, low-energy (80-W) CO2 lasers mandated that the heart be cardioplegically arrested to safely create the TMR channels. Recent advances in laser technology now permit a single laser pulse to traverse the left ventricular wall in less than 50 ms. Because these high-energy (850-W) CO2 lasers are capable of drilling a channel between myocardial contractions, the procedure can be performed on a beating heart, and cardiopulmonary bypass is no longer necessary. In addition, synchronization of this very brief pulse to the R wave of the electrocardiogram has greatly reduced the risk of arrhythmias. Transmyocardial laser revascularization is currently an investigational therapy reserved for select patients with symptomatic occlusive coronary artery disease refractory to maximal medical therapy and interventional techniques.
Much of the evidence concerning the beneficial effects of TMR lies in clinical studies examining improvement in angina class, myocardial perfusion, and cardiac function [1–4]. It is clear that TMR provides some clinical improvement in many patients, but the mechanism by which myocardial laser injury is therapeutic remains controversial. In fact, the debate over long-term patency of channels as the primary mechanism for TMR has intensified with accumulating experimental and clinical experience.
Most investigators agree that transmyocardial laser channels remain patent for at least a short period after TMR. This may be explained by a transient delay in the normal reparative process of the myocardium associated with cellular vaporization and carbonization by the laser, which inhibit lymphocyte, macrophage, and fibroblast migration. Studies [14] of the healing response of skin and buccal mucosa after laser surgical intervention have demonstrated delays in epithelial cell migration over the zone of thermal injury. There is some evidence that a similar mechanism may also occur in the myocardium after TMR. A study by Hardy and associates [15] compared the histologic appearance of transmyocardial laser channels and needle acupunctures over 1 month. The acupuncture tracts became occluded within 2 days, whereas similarly sized laser tracts maintained partial patency for up to 14 days.
Few studies have explored the natural history of laser-drilled myocardial channels. Much of the early work in the field of TMR was done by Mirhoseini, and he has championed the hypothesis of long-term transmyocardial channel patency. In several studies, he and colleagues [13, 16] presented histologic evidence of endothelialized laser channels up to 2 years after operation. Other early experimental investigators including Okada and co-workers [17] and Skobelkin [18] also reported microscopic detection of endothelialized channels several years postoperatively. Recently, Horvath and associates [19] demonstrated channel patency and improved myocardial contractility after acute infarction in a 30-day ovine TMR model. Complementing these experimental findings are scattered case reports [1, 2] of laser channel patency at postmortem examination of patients at various intervals after TMR.
Conversely, other studies demonstrate occlusion of TMR channels. Hardy and coauthors [15] reported early postoperative patency with obliteration of the lumen by 2 weeks. Owen and associates [20] demonstrated occlusion of transmyocardial channels in a chronic rat model. Questions about histologic interpretation of the vascular structures found within the region of laser injury have recently prompted several investigators including us to take a closer look at the proposed mechanisms of TMR.
In our study using a nonischemic porcine model, we were unable to demonstrate channel patency at 28 days after TMR. Most (90%) histologic sections of the laser triads were performed in a transverse fashion to increase our sensitivity for the detection of channel patency. More than 100 cross sections of laser triads were carefully inspected for the presence of a patent vascular lumen within the fibrous tracts that might represent an endothelialized TMR channel. Virtually all vascular structures noted within the tracts were small blood vessels (5 to 10 µm in diameter) morphologically indistinguishable from those seen in normal granulation or scar tissue. In addition, no ventricular channellike structures were noted on the specimens sectioned in a longitudinal fashion along the endocardial surface. Clearly, additional studies are needed to determine the origin and functional importance of the small vascular structures associated with the laser tracts.
Larger vascular lumens lined with a single layer of endothelium were noted only intermittently among the fibroblasts and densely packed collagen fibers of the laser tract in all treatment groups (see Fig 5). In light of their histologic features and their infrequent appearance on the numerous transverse sections obtained, we believe that these structures represent intramyocardial sinusoids or venules. We contend that the reparative capacity of the viable myocardial tissue surrounding the laser channel ultimately does not permit long-term patency of TMR channels. The infiltration of inflammatory cells and fibroblasts, albeit somewhat delayed, eventually results in channel thrombosis and fibrosis.
Despite the fact that no patent channels were noted in our study, laser-treated regions of the myocardium did demonstrate increased vascularity as part of the healing response to laser injury. It is currently unclear whether the neovascularity associated with this granulation response provides a therapeutic or protective effect in the setting of chronic myocardial ischemia. However, this important finding does raise the question of what the ideal extent of laser injury might be for TMR. If the benefits of TMR lie in the angiogenesis stimulated by laser damage, further investigations will be necessary to define the optimal thermal injury for myocardial angiogenesis.
To better elucidate the mechanisms involved in TMR, adjunctive interventions were attempted to enhance myocardial vascularity at a molecular level. The delivery of genes to target tissue followed by the expression of a therapeutic protein by the host cell is becoming a valuable application of molecular biology in the clinical arena. We used this technique of gene therapy with an adenovirus that carries the gene for profilin. Profilin is a 15-kDa actin-binding protein important in the regulation of cellular cytoskeletal dynamics [5]. It plays a critical role in promoting endothelial cell migration and adhesion [6]. We hypothesized that if TMR channel patency was important in the mechanism of revascularization of critically ischemic myocardium, then perhaps the acceleration of endothelial cell migration into the region of laser channels at the time of their creation might increase the channel patency rate. However, our histologic findings suggest that the TMR channels may, in fact, become occluded as part of the healing response to injury and that long-term patency may not be as important as previously thought. Therefore, it is not surprising that the triads treated with the adenovirus encoded with the profilin gene did not yield increased channel patency or vascularity on histologic examination. Unknown at the time of the initiation of the study was the intense inflammatory response exhibited in the myocardium in response to the introduction of both profilin adenovirus and control adenovirus. The degree of lymphocytic infiltration into the myocardium varied from animal to animal and ranged from scattered collections of inflammatory cells to frank lymphoid nodules. Aggregation of lymphocytes often resulted in distortion of the laser tract but not in increased myocardial vascularity. Inflammatory cells produce fivefold to tenfold more profilin than do endothelial cells or cardiomyocytes. Therefore, the intense inflammatory response was likely at least in part responsible for our inability to demonstrate increased production of profilin in the regions infected with the profilin adenovirus compared with those infected with the control adenovirus.
An attempt at direct stimulation of myocardial angiogenesis was also undertaken to augment the vascular response secondary to TMR. Vascular endothelial growth factor was chosen as the mitogen for this study because of its potency and endothelial cell specificity. Tyrosine kinase is a key component of the intracellular signaling system responsible for the mitogenic effects of growth factors. An increase in TK activity results with exposure to VEGF, and it can be quantitated by measurement of phosphorylated substrates on Western blot analysis developed with an anti-phosphotyrosine monoclonal antibody. We administered a single intraoperative dose of VEGF at the time of TMR but did not detect a rise in TK activity 1 month postoperatively. An increase in tyrosine phosphorylated proteins would likely have been detected had a group of animals been sacrificed in the early postoperative period. Although VEGF is a very potent and specific mitogen for endothelial cells, its effects on the TK signaling cascade are transient if it is not administered continuously. Thus, the lack of increased TK activity 28 days after our single intraoperative bolus of VEGF was not unexpected. Nevertheless, it had been hoped that this dosing regimen would result in a significant increase in myocardial vascularity in VEGF–treated laser triads compared with untreated triads. No significant difference was noted.
Several factors may have contributed to this finding. First, our initial investigations with molecular enhancement of TMR with VEGF were performed on a nonischemic model. Recent studies [7, 8] have demonstrated that VEGF yields the most dramatic angiogenic response in ischemic tissue. We are currently investigating techniques that can be used to establish a chronic ischemic model and in turn provide a more clinically applicable setting in which to study the effects of VEGF and TMR. In addition, a longer duration of VEGF may be necessary to stimulate marked angiogenesis in the myocardium. Efforts are currently underway in the laboratory to increase the duration of in vivo activation of TK through viral vectors. It is uncertain if the intense inflammatory response observed with the adenovirus used in this study will occur with this new gene-delivery system. Further, functional studies will be necessary to determine if this infiltration of lymphocytes results in any untoward myocardial sequelae.
The choice of the nonischemic porcine model for our initial investigations of TMR was twofold. First, we were uncertain whether the stress of the surgical procedure in combination with the proposed molecular interventions would have major untoward effects on our porcine model. All animals in the study survived the surgical procedure, and the subsequent 28-day observation period was uneventful. There was no clinical evidence of gross myocardial dysfunction at the time of sacrifice. Thus, although our study did not demonstrate any histologic evidence of augmented vascularity or channel patency in regions treated with VEGF or the adenovirus encoded for the profilin gene, it did show that these agents could be safely administered in the porcine TMR model without gross adverse effects. Another factor in the decision to use a nonischemic model rests in the fact that an acceptable chronic ischemic model that consistently simulates the coronary artery occlusive disease in humans remains an elusive (but vitally necessary) component of TMR research. A multicenter effort is currently underway to develop a chronic ischemic model with which we plan to repeat this study.
In conclusion, TMR stimulates a nonspecific healing response to injury associated with increased myocardial vascularity. This tissue response to laser energy may at least in part explain the mechanism by which TMR provides its clinical benefits. In our nonischemic porcine model, there was no evidence of patent endothelialized myocardial channels 1 month after TMR. Molecular interventions stimulated more myocardial inflammation but not additional angiogenesis. Further improvement in the efficacy of this investigational therapy awaits a more complete understanding of its complex mechanism and the stimulation of a true angiogenic response in ischemic myocardium.
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Acknowledgments |
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TopFootnotesAbstractIntroductionMaterial and MethodsResultsCommentAcknowledgmentsReferences |
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Preclude pericardial membrane is a trademark of W.L. Gore & Associates, Flagstaff, AZ.
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Footnotes |
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TopFootnotesAbstractIntroductionMaterial and MethodsResultsCommentAcknowledgmentsReferences |
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Address reprint requests to Dr Fonger, The Johns Hopkins Hospital, 600 N Wolfe St, Blalock 618, Baltimore, MD 21287.
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TopFootnotesAbstractIntroductionMaterial and MethodsResultsCommentAcknowledgmentsReferences |
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