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Ann Thorac Surg 1999;68:125-129
© 1999 The Society of Thoracic Surgeons

Original Articles

Are there vascular density gradients along myocardial laser channels?

Xavier M. Mueller, MDa, Hendrick T. Tevaearai, MDa, Claude-Yves Genton, MDb, Pascal Chaubert, MDb, Ludwig K. von Segesser, MDa

a Clinic for Cardiovascular Surgery, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland
b Department of Pathology, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland

Address reprint requests to Dr Mueller, Clinic for Cardiovascular Surgery, Centre Hospitalier Universitaire Vaudois, CH-1011 Lausanne, Switzerland
e-mail: xavier.mueller{at}chuv.hospvd.ch


   Abstract
Top
 Abstract
Introduction
 Material and methods
 Results
 Comment
 References
 
Background. Clinical studies suggest that transmyocardial laser revascularization may improve regional blood flow of the subendocardial layer. The vascular growth pattern of laser channels was analyzed.

Methods. Twenty pigs were randomized to undergo ligation of left marginal arteries (n = 5), to undergo transmyocardial laser revascularization of the left lateral wall (n = 5), to undergo both procedures (n = 5) or to a control group (n = 5). All the animals were sacrificed after 1 month. Computed morphometric analysis of vascular density of the involved area was expressed as number of vascular structures per square millimeter (±1 standard deviation).

Results. The vascular density of the scar tissue of the laser channel was significantly increased in comparison with myocardial infarction alone: 49.6 ± 12.8/mm2 versus 25.5 ± 8.6/mm2 (p < 0.0001). The vascular densities of subendocardial and subepicardial channel areas were similar: 52.9 ± 16.8/mm2 versus 46.3 ± 13.6/mm2 (p = 0.41). The area immediately adjacent to the channels showed a vascular density similar to that of normal tissue: 6.02 ± 1.7/mm2 versus 5.2 ± 1.9/mm2 (p = 0.08). In the infarction + transmyocardial laser revascularization group, the channels were indistinguishable from infarction scar.

Conclusions. Scars of transmyocardial laser revascularization channels exhibit an increased vascular density in comparison with scar tissue of myocardial infarction, which does not extend into their immediate vicinity. There was no vascular density gradient along the longitudinal axis of the channels.


   Introduction
Top
 Abstract
 Introduction
Material and methods
 Results
 Comment
 References
 
Transmyocardial revascularization (TMLR) is a procedure intended to treat patients with angina that is refractory to medical therapy and who are unsuitable for coronary artery bypass grafting or percutaneous transluminal angioplasty. Originally, the channels created with the laser through the myocardial wall of the ischemic left ventricle were supposed to provide direct access of endoventricular blood to the myocardium, thus bypassing the epicardial coronary vessels [1].

Results of clinical trials [2, 3] have shown uniformly an improvement of the angina of patients assigned to Canadian Cardiovascular Society class IV. Moreover, myocardial perfusion scan of treated regions of the heart at 3 months suggests an improvement of the ratio of subendocardial to subepicardial perfusion, a finding that persisted at 12 months [4]. However, the experimental studies that have specifically analyzed perfusion of the channels showed that they were unable to provide sufficient oxygenated blood to the myocardium in the acute and the subacute settings [5, 6]. Moreover, histologic studies of clinical specimens [7, 8] describe a progressive and complete replacement of the laser channels by scar tissue. Considering the increasing evidence against channel patency, angiogenesis stimulated by the laser has been suggested as a potential mechanism for clinical improvement.

This study was intended to analyze morphometrically the neovascularization of laser channels in both normal and ischemic settings with special emphasis on the vascular density variations along their tract. A pig model was chosen because of the strong similarity of its coronary anatomy with humans.


   Material and methods
Top
 Abstract
 Introduction
 Material and methods
Results
 Comment
 References
 
Laser variables
To create the laser channels, we used a holmium:yttrium-aluminum garnet (Ho-YAG) laser (CardioGenesis TMLR System, Santa Clara, CA), which emits a burst of three pulses of energy at the 2.1-µm wavelength, which is invisible radiation in the midinfrared portion of the spectrum. The pulsewidth is 350 µs in duration. The output of the Ho-YAG laser is focused into a 365-µm core diameter low-OH quartz fiber with a cylindrical tip (1.75 mm diameter). A 633-nm helium neon laser beam is used as an aiming beam. The pulse repetition rate is 16 Hz for a burst of three pulses, and the energy per pulse is 2.0 J.

Animal preparation
The study was performed in 20 pigs weighing between 52 and 78 kg (mean, 66.9 ± 9.8 kg). The animals were premedicated with Ketaminol (10 mg/kg) (Ketamine, Veterinaria AG, Zürich, Switzerland) and atropine (2 mg) injected intramuscularly. Vascular access was established through a vein of the ear. After induction of anesthesia with sodium thiopental (5 mg/kg) through this venous line, the animals were intubated, and anesthesia was maintained by intravenous administration of sodium thiopental as needed. Animals were ventilated with room air. Respiratory rate and stroke volume were adjusted to maintain arterial blood gases within the normal physiologic range. Three electrocardiogram leads were installed. A left lateral cervicotomy was performed to provide vascular access. An arterial line was inserted into the carotid artery and a Swan-Ganz catheter was inserted through the jugular vein into the pulmonary artery to measure pressures of the right-side heart chambers. A left lateral thoracotomy was performed through the fifth intercostal space. The pericardium was opened and reflected to form a cradle for suspending the heart. Thirty minutes were allowed for stabilization after the completion of the surgical preparation.

Experimental protocol
The animals were randomized to a myocardial infarction (MI) group, a TMLR group, a TMLR and MI (TMLR-MI) group, or a control group. In the MI group, several marginal branches of the circumflex artery were ligated circumferentially at about the junction of their proximal and medial thirds to induce an acute MI on the lateral wall of the left ventricle. In the TMLR group, five channels were created at the mid-height of the left lateral wall, 1 cm apart. The epicardial opening of each channel was marked with a nonresorbable stitch to assist in locating them later. In the TMLR-MI group, the same procedure as in the TMLR group was realized first, followed 30 minutes later by ligation of the marginal branches irrigating the laser-treated area. The drilling of the channels was performed first to avoid the use of the laser on an acutely ischemic myocardium, which would have carried too high a risk of intractable ventricular arrhythmias. In the control group, the animals underwent a left lateral thoracotomy without any intervention on the heart. At the end of the operation, the thoracotomy was closed on a chest tube, which was removed after weaning from the ventilator.

All the animals were sacrificed after 28 days. After an intravenous bolus injection of saturated potassium chloride, the heart was rapidly excised for fixation in buffered formaldehyde 4% for histology.

Histology and morphometry
Area of interest was excised and sliced perpendicular to the channel axis at the subendocardial, subepicardial, and midlevels of the myocardial thickness. A tissue block from each of the three levels of the ventricular wall was chosen, dehydrated, and embedded in paraffin. Serial sections were stained with hematoxylin and eosin, and with Masson’s trichrome stain for microscopic analysis. The vascular endothelium was stained immunohistochemically with anti-factor VIII (Dako, Glostrup, Denmark) using the avidin-biotin-complex (ABC)-peroxidase method. The samples were digitized by an image-analysis system (Image Pro 3.0, Media Cybernetics, Silver Spring, MD). In the TMLR and TMLR-MI groups, the areas of interest included the channel itself, the area of 0.5 mm width surrounding the channel (area 1), and the area of 2 mm width surrounding area 1 (area 2). The analyzed areas were delineated with a cursor (Fig 1), and they were converted from pixels to square millimeters through a calibration procedure by use of a reference system. The boundary of the channel with the surrounding myocardium was irregular, and all the areas containing fibrous tissue were included in the channel area. The structures stained with antibodies to factor VIII were retained for analysis. The vascular density of the analyzed areas was expressed as the number of these structures per square millimeter. The vascular structures with at least one layer of smooth muscle cells were considered as arteriolar structures and were counted separately. The difference between vascular and arteriolar density counts was considered as capillary density.



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  		Fig 1. Trichrome Masson-stained channel scar and its surrounding areas 1 (0.5 mm width) and 2 (2 mm width).

 
Photographs of the areas of interest were taken with a low magnification power of 20x to cover the largest area and avoid the bias of regional differences. For computed analysis, these images were digitized and underwent a total magnification of 140x for the count of the vascular structures.

Statistics
The results of morphologic analysis were given as mean ± standard deviation. The vascular densities of the different areas were compared using a t test. Values were considered to differ significantly if p < 0.05.


   Results
Top
 Abstract
 Introduction
 Material and methods
 Results
Comment
 References
 
In the TMLR group, the laser channels were completely replaced by scar tissue, leaving no central patent lumen. On the trichrome-stained sections, the scar was composed of numerous and thickened collagen fibers as well as of a substantial amount of small vessels. This was confirmed by the factor VIII immunostaining. For comparison, the vascular density of granulation tissue of the MI group was half the density of the TMLR group: 25.5 ± 8.6/mm2 versus 49.6 ± 12.8/mm2, respectively (p < 0.0001). As expected, both densities were significantly higher than the density of 5.2 ± 1.9/mm2 of normal myocardial tissue (p < 0.0001 for both differences). When the capillary and arteriolar structures were counted separately, the same level of significance was found for all comparisons. Figure 2 shows a sample of neovascularization in a channel scar.



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  		Fig 2. Factor VIII immunostaining of a sample of channel scar. The numerous neovessels are well delineated within the scar tissue. Scale = 0.1 mm.

 
Comparison of vascular density between subendocardial, midlevel, and subepicardial channel areas did not reveal any significant differences: 52.9 ± 16.8, 50.7 ± 9.5, and 46.3 ± 13.6/mm2, respectively. Area 1, which lies immediately adjacent to the channel scar, and area 2, which is 0.5 mm distant from the channel border, showed vascular densities of 6.02 ± 1.7/mm2 and 5.6 ± 1.7/mm2, respectively, which are not significantly different from normal tissue (p = 0.08 and 0.37, respectively). There was no vascular density gradient between subendocardial and subepicardial levels in area 1, 15.1 ± 1.7 versus 14 ± 3.4/mm2, respectively, nor in area 2, 5.6 ± 0.9 versus 5.1 ± 1.7/mm2, respectively. When the capillaries and arteriolar structures were analyzed separately, the above differences were not statistically significant either. The detailed results are given in Figures 3 and 4.



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  		Fig 3. Capillary density counts with 1 standard deviation. (Normal = normal myocardium; MI = myocardial infarction; Channel = channel area; area 1 = area of 0.5 mm width surrounding the channel; area 2 = area of 2 mm width surrounding area 1.)

 


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  		Fig 4. Arteriolar density counts with 1 standard deviation. (Normal = normal myocardium; MI = myocardial infarction; Channel = channel area; area 1 = area of 0.5 mm width surrounding the channel; area 2 = area of 2 mm width surrounding area 1.)

 
In the infarction + TMLR group, the channels were completely obliterated by the scar tissue caused by myocardial infarction, rendering their delineation impossible. Therefore their vascular density was considered analogous to that of the myocardial infarction itself.


   Comment
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
References
 
This study analyzes the neovascularization of laser channels 28 days after their creation in a pig model. The laser channels exhibit an increased vascular density in comparison with usual myocardial scar tissue without evidence of vascular growth in their immediate vicinity. Moreover, there was no vascular density gradient along the longitudinal axis of the channels. When compared with scar tissue of MI, vascular density of laser channels is increased.

The initial theory of TMLR with endocavitary blood passing through the channels has been seriously questioned. First, to support this theory, the human heart has been compared with the reptilian heart, which is perfused by sinusoids. These sinusoids would have brought the blood from the laser channels to the myocardial cells. However, their existence in the human heart has never been proved anatomically [9]. Second, the short- and long-term patency of the channels could not be established by experimental [10, 11] or autopsy [7, 8] reports. Initially the channels are occluded by a fresh clot, then they are progressively and completely invaded by granulation tissue followed by a scar. Third, there is the physiologic barrier of diffusion. Oxygen diffusion distance requires an average of three capillaries surrounding each muscular cell [12]. The required number of channels necessary to ensure adequate oxygenation solely through diffusion is impossible to realize. Therefore the short- and long-term benefits of TMLR are unlikely to be related to flow through the channels. Neovascularization related to the inflammatory response elicited by the laser lesion has been suspected as a potential mechanism of the long-term benefit of TMLR. This mechanism has been suggested usually by lack of physiologic or morphologic substrate [6, 13] for blood flow through the channels. However, two experimental [13, 14] and one clinical [15] reports provide indirect evidence for this mechanism, with regional motion improvement at 3 months using ultrasonic crystals, echocardiography, and dobutamine stress test, respectively.

Improvement of myocardial perfusion could not be substantiated by clinical studies either. Investigators at the Texas Heart Institute were unable to demonstrate differences between baseline and 12-month studies in ejection fraction as might be expected if perfusion were improved [4]. Transmural perfusion analysis by positron emission tomography did not show a clear improvement of treated areas. On the basis of the theory of blood flow from the ventricular cavity through patent channels, these authors argued that subendocardial flow would be expected to improve more than subepicardial flow. They performed a subregion analysis of the positron emission tomographic data and calculated the ratio of subendocardial to subepicardial flow, which was increased in the treated territories. These results are at variance with chronic experimental studies in swine in which blood flow improved equally in both subregions with a ratio of 1.1 at 3 months [16]. In view of these uncertainties about the validity of nuclear medicine in determining subregional flow analysis, we performed a morphometric analysis of vascularization density along the channels. Our results do not substantiate the hypothesis of a flow ratio, inasmuch as the vascular density is similar along the channel tracts.

Several considerations of our methods should be pointed out. First, we used a pig model in contrast to most previous studies on TMLR using a dog model. Dogs have a variable native collateral circulation. Therefore it is difficult to know whether any beneficial, preventive effect against ischemia was caused by neovascularization or whether treated hearts had intrinsic collateral blood flow. In contrast, pig hearts have very little native collateral circulations, similar to human hearts.

Second, we performed a morphometric analysis of vascularization in contrast to most experiments focusing on channel physiology using either indirect methods of measurement, such as myocardial infarct size limitation [17], or direct methods, mainly the microsphere technique [5, 6, 18, 19]. Microsphere technique has its limitations, too. It is not sensitive enough to detect small amounts of blood through the channels, as it could be overwhelmed by collateral flow from the native coronary circulation, especially in the dog model. Moreover, the microsphere estimate of flow through the channels depends on the assumption that the blood flows through the myocardium. However, if flow is of a to-and-fro nature, then the spheres would continuously be washing in and out the myocardium, and their absolute number would not relate to the magnitude of myocardial perfusion.

Third, we used a computed analysis with an image software to improve the precision of vessel counts and area surface measurements. In other studies dealing with vascular density analysis after TMLR, counting was performed using a high magnification of the area analyzed [20], the surfaces of the channel area and its surrounding, applying an oval-shaped estimation, were measured [21], or the vascular density was visually estimated [22].

Fourth, we compared laser channels associated with MI because both involve substantial destruction of myocardial cells, which stimulates the development of granulation tissue and then scar tissue. Several studies have compared laser channels with needle channels [22, 23]. However, needles involve a different type of injury with limited cellular destruction and subsequent healing with minimal scar tissue. It is thus expected that vascular density of the laser-induced lesion is increased in comarison with that after needle lesion, which was the case in the study of Mack and associates [22]. Therefore, it seems inappropriate to conclude from this type of comparison that laser energy is critical in stimulating angiogenesis, because reactive vascular density is rather related to the extent of cellular destruction. However, such inference can be made from our analysis comparing two types of lesions involving extensive cellular destruction and a significant reparative process.

Last, the number of capillaries reported here is much less than their actual number. Previous ultrastructural analyses have estimated that at least three capillaries surround each myocardial cell [12]. Our small figures are because of the low magnification we used for microscopic analysis. This magnification allowed the analysis of large areas for counting, thus excluding the possibility of missing capillary growth confined to localized regions. For the purpose of this study it is the proportion of capillaries in the different analyzed areas that is important and not their absolute number.

This experiment has two main limitations. First, it compares the effect of TMLR performed on healthy versus acutely ischemic myocardium, whereas clinically, TMLR has proved to improve angina in chronic ischemic disease. So far, experimental studies have been performed mainly on acutely ischemic heart [6, 13, 18–20] because of the lack of a reliable method mimicking chronic ischemia. Whether these findings pertain to the chronic setting remains to be demonstrated. Second, the Ho-YAG TMLR has been used, which has physical properties different from those of the CO2 laser used in other experimental works [10, 13, 18, 19]. However, Fischer and colleagues [11] recently compared both lasers in a dog model, and the results suggest that their effects are similar and differ essentially in the amount of acute thermoaccoustic injury. Channels of both groups were initially occluded by thrombus and then replaced by neovascularized collagen. Moreover, there is substantial evidence that CO2 laser-made channels cannot provide blood flow to ischemic myocardium, either in dog hearts, when collateral flow was measured [18, 24] or in pig hearts, which have little collateral circulation [25].

In summary, channel patency is highly unlikely in the short or the long term. Neovascularization can be considered as a result of the healing process of the laser channels. It is increased in comparison with scar tissue after MI. Whether this neovascularization limited to the channels is sufficient to explain the symptomatic effect of TMLR remains to be determined.


   References
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
 References
 

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Accepted for publication February 3, 1999.


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