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Ann Thorac Surg 1998;66:2029-2036
© 1998 The Society of Thoracic Surgeons
a Department of Surgery, Duke University Medical Center, Durham, North Carolina, USA
b Divisions of Cardiology, Duke University Medical Center, Durham, North Carolina, USA
c Department of Radiology, Duke University Medical Center, Durham, North Carolina, USA
Accepted for publication June 9, 1998.
Address reprint requests to Dr Landolfo, Duke University Medical Center, Box 3857, Durham, NC 27710
e-mail: Land001{at}mc.duke.edu
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Abstract |
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Methods. Six miniature pigs underwent subtotal left circumflex coronary artery occlusion to reduce resting blood flow to 10% of baseline. After 2 weeks in the low-flow state, dobutamine stress echocardiography and positron emission tomography were performed to document ischemic, viable myocardium. The animals then underwent TMR and were sacrificed 6 months later for histologic and immunohistochemical analysis.
Results. Histologic analysis of the lased left circumflex region demonstrated many hypocellular areas filled with connective tissue representing remnant TMR channels. Histochemical staining demonstrated a highly disorganized pattern of neovascularization consistent with angiogenesis located predominantly at the periphery of the channels. Immunohistochemical analysis confirmed the presence of endothelial cells within neovessels. Vascular density analysis revealed a mean of 29.2 ± 3.6 neovessels per high-power field in lased ischemic myocardium versus 4.0 ± 0.3 (p < 0.001) in nonlased ischemic myocardium.
Conclusions. This study provides evidence that neovascularization is present long term in regions of ischemic, viable myocardium after TMR. Angiogenesis may represent the mechanism of clinical improvement after TMR.
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Introduction |
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TopAbstractIntroductionMaterial and methodsResultsCommentAcknowledgmentsReferences |
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Despite the clinical evidence suggesting a benefit from TMR, the mechanism of action by which the technique improves myocardial perfusion is unknown. Original reports [1, 2] have suggested that TMR channels connected the ventricular cavity with "myocardial sinusoids," as originally described by Wearn and colleagues [7] in 1933, and in this manner produced direct myocardial perfusion. However, both the existence of these sinusoids [8] as well as the long-term patency of the channels [9] have recently been called into question, and multiple basic scientific studies have failed to demonstrate direct myocardial perfusion through TMR channels [10–12].
Angiogenesis, defined as the formation of new blood vessels from preexisting vessels by the process of cellular outgrowth, may represent an alternative mechanism for the clinical improvement seen after TMR. Several studies have shown evidence for neovascularization in the lased regions of normal canine [9, 13] and sheep myocardium [14]. However, none of the studies specifically identified the presence of endothelial cells within the areas of presumed neovascularization. In addition, no study to date has examined experimental TMR channels produced in chronically ischemic myocardium, and long-term follow-up studies of experimental TMR are lacking. In the clinical setting, TMR is applied to regions of ischemic yet viable myocardium [2–5], and, therefore, studies performed under these conditions are needed to truly elucidate the mechanism of action of TMR. We sought to fully characterize lased regions of ischemic, viable myocardium using histologic, histochemical, and immunohistochemical techniques to determine whether angiogenesis is present long-term after TMR.
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Material and methods |
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Model of chronic ischemia
Animals underwent induction of anesthesia with ketamine (22 mg/kg body weight intramuscularly) and thiopental (5 to 10 mg/kg intravenously). Orotracheal intubation was performed and anesthesia maintained with isoflurane (2% to 4%) while the animals were mechanically ventilated. Continuous electrocardiographic and pulse-oximetric monitoring was used throughout the procedure to ensure a stable cardiac rhythm and adequate oxygenation. Cefazolin (1 g intravenously) and lidocaine (1.5 mg/kg intravenously) were given preoperatively. Under sterile conditions, a left anterolateral thoracotomy was performed through the fourth intercostal space. The pericardium was incised longitudinally and the left atrial appendage retracted to allow exposure of the left circumflex coronary artery (LCX). The proximal LCX was dissected free to allow placement of a hydraulic occluder and a 2-mm ultrasonic flow probe (Transonic Systems, Inc, Ithaca, NY) around the vessel. The flow probe was placed distal to the occluder to record downstream flow through the LCX. The occluder and flow probe were then exteriorized through a separate stab incision. A 20F chest tube was placed and the wound closed in layers. The chest tube was removed at the conclusion of the procedure. Three days postoperatively the occluder was inflated to reduce resting blood flow in the LCX to approximately 10% of baseline as assessed using the implanted flow probe. The animals were then kept in this low-flow state for 2 weeks, with blood flow recordings performed 3 times per week to ensure continued occlusion.
Positron emission tomography and dobutamine stress echocardiography
After 2 weeks in the low-flow state, the animals underwent PET and dobutamine stress echocardiography (DSE) to characterize the blood flow, metabolic, and functional status of the heart and document the presence of ischemic, viable myocardium in the LCX distribution. The PET scans were interpreted as showing ischemic, viable myocardium if a flow deficit was noted in the lateral and posteroinferior walls of the left ventricle supplied by the LCX accompanied by normal or increased glucose utilization in these same regions (both as compared with the nonischemic septum) [15]. Using DSE, viability in the lateral and posteroinferior walls of the left ventricle was defined as an improvement in systolic wall thickening with low-dose dobutamine in myocardial regions with severe hypocontractility at rest. Viable segments were considered ischemic if systolic wall motion deteriorated with stress (biphasic response) [6].
Dobutamine stress echocardiography was performed in 3-minute stages with incremental doses of dobutamine beginning with 5 µg · kg-1 · min-1 and increasing to 40 µg · kg-1 · min-1. Wall motion was graded on the basis of a standard 16-segment model as 1 = normal; 2 = hypokinetic (reduced systolic wall thickening); 3 = akinetic (absent systolic wall thickening); or 4 = dyskinetic (outward systolic wall motion). The regional wall motion score was calculated at rest, low dose, and peak stress. Animals were sedated with ketamine (22 mg/kg intramuscularly) before DSE. The echocardiograms were interpreted in a blinded manner by an experienced cardiologist (C.L.D.) with expertise in stress echocardiography.
After an overnight fast, dynamic PET emission imaging of the heart was performed at rest for 20 minutes after a 30-second intravenous infusion of nitrogen 13 (13N) ammonia (15 to 20 mCi). A 40-minute delay followed for decay of 13N activity. Then dynamic imaging of the heart for 60 minutes was performed after a 30-second infusion of fluorine 18 (18F) fluorodeoxyglucose (10 mCi). All emission images were corrected for photon attenuation using a transmission scan. Time–activity curves of tracer concentration in the left ventricular myocardium were obtained from short-axis views averaged over eight sectors in three short-axis slices (basal, mid, and apical). Previously validated compartmental modeling techniques were applied to the time–activity curves to obtain regional estimates of myocardial blood flow (milliliters per gram per minute) and glucose utilization (nanomoles per gram per minute) [16, 17]. A "lumped constant" of 1.0 was assumed for the calculation of glucose utilization from the fractional 18F-fluorodeoxyglucose uptake rate [18]. During the PET scans, the animals were maintained under general anesthesia and mechanically ventilated as described previously. The PET scans were interpreted both qualitatively by a physician (R.E.C.) experienced in reading cardiac PET scans and quantitatively using absolute values for blood flow (milliliters per gram per minute) and glucose utilization (nanomoles per gram per minute).
Transmyocardial laser revascularization
Once ischemic viable myocardium in the LCX distribution was documented by PET and DSE, the animals underwent repeat anterolateral thoracotomy through the fifth intercostal space. Anesthesia, preoperative medications, and intraoperative monitoring were as described previously. A holmium:yttrium-aluminum-garnet (YAG) (Cardiogenesis, Inc, Sunnyvale, CA) (n = 4) or 1,000-W carbon dioxide (CO2) (PLC Medical Systems, Inc, Franklin, MA) (n = 2) laser was used to create 20 transmyocardial channels at 1-cm intervals in the ischemic regions of the left ventricle as demonstrated on DSE and PET. Carbon dioxide laser channels were created using a single 40-J pulse; holmium:YAG channels were created using multiple 2-J pulses, with a total energy level of approximately 20 J per channel. Transmural penetration of laser channels was confirmed by visible spurting of blood from the channels during systole. Hemostasis was obtained by manual compression. The occluder and flow probe were left intact. The wound was closed as described previously. Continuous LCX occlusion was confirmed postoperatively by weekly flow monitoring with the flow probe.
Tissue procurement, sectioning, and histologic and immunohistochemical analysis
Animals were sacrificed 6 months after TMR and their hearts harvested for histologic, histochemical, and immunohistochemical analysis. At the time of sacrifice, the channels were identified as punctate regions of scar tissue easily visible at the endocardial surface. Of the 20 original channels per animal, approximately 6 were randomly chosen for histologic analysis. Five- by 5-mm sections of myocardium containing the entire channel length from epicardium to endocardium were made. In addition, an average of three 5- by 5-mm sections were randomly taken from regions of the ischemic LCX distribution not treated with TMR. The sections were then placed both longitudinally and cross-sectionally in OCT (Optimal Cutting Temperature, Sakura Finetek USA, Inc, Torrance, CA) and snap frozen in liquid nitrogen. Frozen sections (6 µm) were made in a cryostat on microscope slides (Superfrost Plus, Fisher Scientific, Pittsburgh, PA). Slides were allowed to come to room temperature. They were then fixed in ice-cold acetone for 10 minutes, followed by three 5-minute washes in phosphate-buffered saline solution. Routine histologic staining was performed with hematoxylin and eosin and Masson trichrome; hematoxylin and eosin displays general structural features, whereas the Masson stain is a connective tissue technique used to demonstrate supporting tissue elements (mainly collagen) that stain blue.
Histochemical staining was done with endogenous endothelial alkaline phosphatase, a sensitive but nonspecific endothelial cell marker. The staining was performed on unfixed frozen sections using a previously described technique [19]. Briefly, slides are incubated for 1 hour with nitroblue tetrazolium chloride and 5-bromo-4-chloro-3-indolylphosphate p-toluidine salt (Gibco BRL, Galthersburg, MD) and post-fixed in 4% paraformaldehyde. The tissue is then stained with eosin, and the endothelial cells appear blue against a red background.
Because vascular endothelial cells can be heterogeneous for the expression of endothelial cell markers [20], the results from the endogenous endothelial alkaline phosphatase staining were compared with results obtained from the immunohistochemical analysis. For immunohistochemical staining, blocking solution (10% horse serum in phosphate-buffered saline) was applied to the slides for a minimum of 20 minutes at room temperature. The endothelial cell–specific antibodies anti–von Willebrand factor (factor VIII-related antigen) (American Diagnostica, Inc, Greenwich, CT) and anti–human tie-2 (TEK) protein were used to identify endothelial cells. Factor VIII-related antigen is a reliable marker of endothelium present in both normal lining and cultured human endothelium [21]. Anti–human tie-2 is a murine monoclonal antibody raised against the soluble extracellular domain of the TEK protein, which is a receptor tyrosine kinase expressed exclusively in endothelial cells [22]. The antibodies were diluted (1:100) in blocking solution and applied to tissue sections for 1 hour. Incubation with the primary antibody was followed by sequential incubation with a biotinylated anti–mouse immunoglobulin G and ABC reagent according to manufacturer specifications (Vectastain ABC kit, Vector Laboratories, Burlingame, CA). Levamisole was added to block endogenous alkaline phosphatase activity, and immune complexes were localized using the chromogenic alkaline phosphatase substrate Vector Red (Vector Laboratories). The sections were counterstained with hematoxylin and dehydrated and mounted with Cytoseal (Fisher Scientific, Pittsburgh, PA). In this method the antigen appears red and the nuclei blue. To further characterize the structural features of microvascular endothelium in lased and nonlased chronically ischemic myocardium, additional staining was done with HHF-35 (Dako, Carpinteria, CA), a murine monoclonal antibody directed against human smooth muscle actin, and anti–collagen IV (type IV Clone CIV-22, Dako), a subtype-specific murine immunoglobulin G anti–human antibody directed against the collagen component of basement membrane. Under normal circumstances, HHF-35 stains primarily medium and large arteries. As with the anti-TEK and anti–von Willebrand factor stains, these techniques stain the antigen red and nuclei blue. For each sample, a serial section was incubated with a nonsense murine immunoglobulin G monoclonal antibody to serve as a negative control.
Vascular density analysis
To further describe differences in neovascularization between lased and nonlased ischemic myocardium, we made a comprehensive comparison of neovessel density in these regions. Using previously described techniques [19], vascular density was measured by endogenous endothelial alkaline phosphatase staining on unfixed frozen sections as described earlier. Vascular density was measured by counting. Six random high-power (200x) fields were examined per sample. Four randomly selected samples were examined from both the lased and nonlased ischemic LCX distribution. The lased samples included only regions within and immediately adjacent to the TMR channel remnants, whereas the control nonlased ischemic samples included regions within the LCX distribution but distant (>0.5 cm) from the channel remnants. Thus, a total of 144 different high-power fields (6 animals x 4 samples/animal x 6 fields/sample = 144 fields) from the lased LCX distribution were examined and compared with 144 nonlased ischemic fields (6 animals x 4 samples/animal x 6 fields/sample = 144 fields) for quantitative vascular density.
Statistical analysis
Results are presented as the mean ± standard error of the mean. The 95% confidence interval (95% CI) for the mean is presented in parentheses after the mean and standard error. Myocardial blood flow and glucose utilization by PET, as well as wall motion scores by DSE, were compared for the ischemic LCX distribution and nonischemic septum using a paired Student’s t test. Vascular density for the lased ischemic regions was compared with the corresponding nonlased ischemic regions using a paired Student’s t test. Statistical significance was considered at a p value less than 0.05.
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Immunohistochemical staining
The presence of endothelial cells within the neovessels seen in TMR channels was confirmed with the endothelial cell–specific antibodies anti–von Willebrand factor (factor VIII–related antigen) and anti–human tie-2 (TEK) (Fig 3). The vessels were further characterized by staining with HHF-35, an anti–smooth muscle actin antibody, and anti–collagen IV, an antibody to the collagen component of normal basement membrane. Compared with normal penetrating intramyocardial blood vessels, the neovessels demonstrated relatively increased staining with HHF-35 and decreased staining with anti–collagen IV (Fig 4). Similar to the histologic and histochemical findings, neovascularization analogous to that occurring in the TMR channels was not observed by immunohistochemical staining in the nonlased ischemic regions.
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Comment |
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Hardy and colleagues [24] were among the first investigators to note new blood vessels in the region of TMR channels. They used a low-power CO2 laser to produce channels in normal canine myocardium and found histologic evidence for new blood vessel formation as early as 5 days postoperatively. These capillaries were seen as part of a general reparative process that resulted in the formation of granulation tissue and, ultimately, scar in the channel regions. Landreneau and associates [11] found that TMR did not acutely improve perfusion or oxidative metabolism of canine myocardium after LAD ligation and hypothesized that the benefits of TMR may result from augmentation of angiogenesis. Whittaker and coworkers [12] likewise found that TMR channels failed to acutely increase myocardial blood flow after coronary artery ligation. However, when channels were made 2 months in advance of occlusion, evidence for myocardial protection in areas adjacent to TMR channels was seen [25]. Although the latter study found no increase in capillary density the findings of delayed improvement are consistent with possible angiogenesis in response to the channel-making process.
A recent study [9] using both holmium:YAG and CO2 lasers to produce channels in normal canine myocardium found histologic evidence for neovascularization within a rim of fibrous scar surrounding the channels at 2 to 3 weeks postoperatively, with the degree of vascularity diminished by 6 weeks after TMR. Similar results were found using an excimer laser in normal sheep myocardium [14]. These studies were performed over relatively short intervals, with the animals surviving for 4 to 6 weeks before sacrifice. Histologic analysis of areas of presumed angiogenesis was performed using nonspecific stains, including hematoxylin and eosin and Masson trichrome or immunostaining for proliferating smooth muscle cells [9, 13, 14].
The present study is unique in several respects. First and foremost, TMR was performed in chronically ischemic myocardium, thus reproducing the conditions under which the technique is applied clinically. Therefore, unlike previous studies to date, we believe that these findings may have direct clinical implications. Second, the animals in this study were sacrificed 6 months after TMR. This long time course was chosen because multiple clinical studies [2–5] have demonstrated a 3- to 6-month delay in clinical improvement in human subjects after TMR. Consequently, any structural changes contributing to this clinical improvement may not yet have occurred in the shorter time course used in previous studies. Third, the present study uses immunohistochemical techniques, including two different endothelial cell–specific antibodies (anti–von Willebrand factor and anti-TEK), to demonstrate the presence of endothelial cells in neovessels seen in ischemic myocardium after TMR. These techniques leave little doubt that neovascularization is occurring in the region of the TMR channels 6 months postoperatively. This neovascularization was seen in the regions of both the holmium:YAG and CO2 laser channels. There were no readily apparent differences in the quantity of neovascularization seen with each laser, although the purpose of the present study was not a direct comparison between holmium:YAG and CO2 lasers.
An additional finding of interest in this study was the differences in structural characteristics of the neovessels seen in the TMR channels and normal penetrating myocardial vessels. First, compared with normal penetrating vessels, the neovessels were present in a highly disorganized manner. Second, the neovessels demonstrated increased staining with the anti–smooth muscle actin antibody HHF-35 and decreased staining with an antibody to collagen IV, the primary collagen component of normal basement membrane. We hypothesize that these structural differences may relate to as yet unknown functional differences in the two types of vessels. Theoretically, these functional differences may play a role in the mechanism of clinical improvement after TMR. Further study in this area is warranted.
In conclusion, this study demonstrates definite angiogenesis in the regions of TMR channels in chronically ischemic myocardium 6 months postoperatively. This neovascularization response was seen after TMR with both holmium:YAG and CO2 lasers. In addition, the neovessels appear to differ structurally from normal intramyocardial vessels, suggesting a possible functional difference. We propose that angiogenesis most likely represents the mechanism of clinical improvement after TMR in chronically ischemic myocardium.
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