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Ann Thorac Surg 2001;72:817-822
© 2001 The Society of Thoracic Surgeons

Original article: cardiovascular

Transmyocardial laser revascularization dose response: enhanced perfusion in a porcine ischemia model as a function of channel density

Adam H. Hamawy, MDa, Leonard Y. Lee, MDa, Sanjay A. Samy, MDa, Dean R. Polce, BSa, Massimiliano Szulc, PhD, MDa, Madeline Vazquez, MDa, Todd K. Rosengart, MDb

a Weill Medical College of Cornell University, New York, New York, USA
b Evanston Northwestern Healthcare, Northwestern University Medical School, Evanston, Illinois, USA

Accepted for publication May 3, 2001.

Address reprint requests to Dr Rosengart, Division of Cardiothoracic Surgery, Evanston Hospital, Burch 100, 2650 Ridge Ave, Evanston, IL 60201
e-mail: trosengart{at}enh.org


   Abstract
Top
 Footnotes
 Abstract
Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
 References
 
Background. Transmyocardial laser revascularization (TMR) appears to provide symptomatic relief to patients with ischemic heart disease, but evidence that TMR enhances perfusion to ischemic myocardium remains limited. Furthermore, it is uncertain whether there exists a TMR dose–response relationship that is a function of channel number. We therefore compared restoration of blood flow as analyzed by rest and stress 99mTc-sestamibi scans and histologic grading of neovascularization after 50-channel, 25-channel, or 10-channel TMR using the excimer laser in an established model of porcine myocardial ischemia.

Methods. Yorkshire swine underwent a thoracotomy and placement of an ameroid constrictor around the proximal circumflex coronary artery. Three weeks later, the animals underwent resting and adenosine stress 99mTc-sestamibi scans for evaluation of ischemia immediately before repeat thoracotomy and TMR with either 50 channels (n = 4), 25 channels (n = 4), or 10 channels (n = 4) in the circumflex territory. The animals underwent repeat perfusion analyses 4 weeks later, after which the animals were sacrificed and the hearts were perfusion fixed for histologic evaluation of neovascularization.

Results. All animals survived to sacrifice. Semiquantitative analyses of the sestamibi perfusion scans 4 weeks after lasing demonstrated significant improvement (p < 0.04) in stress-induced ischemia in the 50-channel TMR animals, but not in the 25- or 10-channel TMR groups, as compared with scans obtained immediately before lasing. A computerized image analysis of perfusion scans similarly demonstrated an improvement in the area of ischemia of 42% ± 22% in the scans obtained 4 weeks after lasing compared with scans obtained immediately before lasing in the 50-channel group (p < 0.004), but only a 12% ± 9% improvement in the 25-channel group and an 8% ± 4% improvement in the 10-channel group (p > 0.05). Histologic assessment of neovascularization demonstrated significantly greater number of microvessels per low-power field in the 50- versus the 25- and 10-channel groups (p < 0.001).

Conclusions. In an animal model of myocardial ischemia, TMR appears to enhance myocardial perfusion. A dose–response relationship related to channel number may be of significance when evaluating the efficacy of various treatment strategies.


   Introduction
Top
 Footnotes
 Abstract
 Introduction
Material and methods
 Results
 Comment
 Acknowledgments
 References
 
Transmyocardial laser revascularization (TMR) is a promising new technique intended to improve blood flow to ischemic myocardium in patients with coronary artery disease. This new revascularization strategy may be ideally suited to individuals who are not candidates for more traditional revascularization therapies such as coronary artery bypass grafting or percutaneous transluminal coronary angioplasty owing to the severity or anatomic constraints of their coronary artery disease. Several clinical trials demonstrating improvements in angina class, nitroglycerin intake, and exercise performance testing have led to U.S. Food and Drug Administration approval of the clinical use of the CO2 and holmium:YAG lasers for TMR of myocardium that cannot be revascularized by conventional means [1–4].

With improving techniques and advances in laser technology, less invasive TMR procedures such as thoracoscopic techniques [5] and percutaneous techniques [6] have been developed to refine TMR as a clinical strategy. These less invasive procedures are potentially limited by the number of channels that can be performed, however, as suggested by the lack of benefit after percutaneous myocardial revascularization in a recently reported randomized, placebo-controlled trial [6]. In this regard, whether there exists a TMR dose–response relationship as a function of channel number has not yet been determined. Furthermore, the existing literature remains controversial as to whether even standard open TMR results in enhancement of perfusion to areas of ischemic myocardium.

Based on these considerations, we decided to use an established porcine myocardial ischemia model followed by either 10-, 25-, or 50-channel TMR using an excimer laser to demonstrate whether TMR causes an increase in perfusion of ischemic myocardium and whether this occurs as a function of channel number. These studies have demonstrated an increase in vessel number per low-power field and an improvement in perfusion proportional to channel number 4 weeks after TMR. These observations support the hypothesis that TMR enhances perfusion to ischemic myocardium and suggests that a TMR dose–response relationship is related to channel number.


   Material and methods
Top
 Footnotes
 Abstract
 Introduction
 Material and methods
Results
 Comment
 Acknowledgments
 References
 
Porcine model of myocardial ischemia and transmyocardial laser revascularization
A model of chronic myocardial ischemia was created in castrated, male Yorkshire swine (28 to 30 kg, Tom Morris Farms, Wetherstown, MD). All animal care procedures were in accordance with institutional animal care and use committee guidelines. The pigs were sedated with intramuscular xylazine (0.10 mg/kg) and tiletamine and zolazepam (3.3 mg/kg, Telazol, Elkins-Sinn, Inc, Cherry Hill, NJ); after endotracheal intubation, anesthesia was maintained with inhaled isoflurane (1% to 2% in 3 to 4 L O2). Under sterile conditions, a left lateral thoracotomy was performed, and a 2.5-mm internal diameter ameroid constrictor (Research Instruments & Mfg, Corvallis, OR) was placed around the proximal circumflex coronary artery as previously described [7]. The chest was closed, and the pigs were allowed to recover.

Three weeks after the ameroid placement, the pigs were prepared for operation in a manner identical to the initial operation except for the addition of 100 U/kg heparin (Elkins-Sinn, Inc) and 1 mg/kg of lidocaine (Abbott Laboratories, North Chicago, IL) given intravenously before commencement of lasing, as previously described [8]. A repeat thoracotomy was performed, and pigs were sequentially assigned to receive 10, 25, or 50 channels to obtain equal distribution among groups. An excimer laser (AccuLase, Inc, Van Nuys, CA) was used to create 1-mm channels in the region of the left ventricle centered on the region supplied by the circumflex marginal artery (9 mJ, 240 pulses/s, fiberoptic advancement rate of 1.55 cm/s) using a sterile 600-µm rotating fiberoptic [8]. The channel density was varied by placing them at regular intervals of no greater than 1 cm apart and covering approximately the same total surface area in each animal. Persistent bleeding was controlled either by direct manual compression or, on rare occasion, by placement of a 6-0 polypropylene epicardial suture. At the termination of the procedure, the chest was closed in layers, and the pigs were extubated and allowed to recover.

Perfusion analyses
Two-day combined rest-stress 99mTc-sestamibi studies were performed 3 weeks after ameroid placement (day 0) to assure ischemia in the circumflex distribution, and again at 28 days after TMR (day 28). One hour after intravenous administration of 99mTc-sestamibi (25 to 30 mCi), electrocardiogram-gated single-photon emission computerized tomography imaging was performed with and without pharmacologic stress with adenosine (140 µg · kg-1 · min-1 intravenously for > 6 minutes). Rest and stress images were evaluated in a blinded fashion by two nuclear cardiologists using a standard 20-segment analysis (18 short-axis and 2 long-axis segments) [9]. Rest and stress images of each segment were scored on a 5-point scale of 0 to 4, where 0 is normal perfusion, 1 is mild hypoperfusion, 2 is moderate hypoperfusion, 3 is severe hypoperfusion, and 4 is no perfusion. A stress-induced ischemia score was then calculated by subtracting the mean rest from the mean stress score for each animal. A semiquantitative improvement score was then calculated as the mean difference between the stress-induced ischemia scores from the day 28 scans and the stress-induced ischemia scores of the same animal on day 0.

A quantitative computer analysis was performed using AutoQUANT software (ADAC Laboratories, Milpitas, CA). This software consists of an automatic program, capable of batch processing, which, among various calculations on cardiac single-photon emission computerized tomography perfusion images, performs automatic scoring of these images based on a standard 20-segment analysis (see previous) on a 5-point scoring system (4 is normal perfusion, 0 is no perfusion) [9]. Scoring was based on a normal database that was established for the 99mTc-sestamibi 2-day protocol using 40 untreated control pigs, according to manufacturer’s specifications [10, 11]. The algorithm is independent of myocardial shape, size, and orientation, and establishes a standard three-dimensional point-to-point correspondence among all sampled myocardial segments. Percent improvement in summed stress scores was calculated as the day 28 mean score minus the day 0 score divided by the day 0 score multiplied by 100.

Histology
The animals were prepared and sedated as described above before sacrifice. Sacrifice was performed through a median sternotomy to allow full exposure and access to the heart. The hearts were arrested with 40 mEq of potassium chloride infused into the aortic root after clamping distally. The heart was perfusion-fixed at a pressure of 100 mm Hg with McDowel-Trump fixative (4% formaldehyde, 1% glutaraldehyde, pH 7.2). The heart was then explanted and placed in McDowel-Trump fixative for histologic preparation.

The region of TMR treatment was easily identified by visual inspection of the ventricle. Transverse sections of the regions of interest were made at multiple levels as previously described [8]. Four specimens, each representing a quadrant of the ischemic circumflex region that was treated with the laser, were processed through paraffin cut at 5 µm and stained with hematoxylin and eosin. For each specimen two observers blinded to treatment category, including an expert pathologist, evaluated a longitudinal and transverse section of tissue for neovascularization. Five high-power (x200) and five low-power (x40) fields were examined per section. Small capillaries and arterioles were recorded as number of vessels per high-power and low-power fields.

Statistics
Values were expressed as mean ± standard deviation. The difference was considered statistically significant at p less than 0.05. A paired Student’s t test was used to compare the semiquantitative single-photon emission computerized tomography analysis of the day 0 versus the day 28 stress-induced ischemia scores of the same animal. Analysis of computer-generated quantitative perfusion improvement and vessel number was performed using one-way repeated measures analysis of variance. Bonferroni’s and Dunnett’s multiple comparison tests were used to detect differences among groups.


   Results
Top
 Footnotes
 Abstract
 Introduction
 Material and methods
 Results
Comment
 Acknowledgments
 References
 
Operative outcome
The operative procedure was tolerated well in all animals. There were transient nonsustained ventricular arrhythmias that occurred during the passage of the laser that were self-limited and had no hemodynamic sequelae. All animals survived to sacrifice without postoperative complications.

Stress analyses
Semiquantitative analysis of the 99mTc-sestamibi perfusion scans demonstrated significant improvement (p < 0.04) in stress-induced ischemia 4 weeks after 50-channel TMR (day 28) as compared with scans obtained immediately before lasing (day 0), whereas 25- and 10-channel TMR did not demonstrate a significant improvement in stress-induced ischemia (Fig 1).



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  		Fig 1. Semiquantitative improvement in stress-induced ischemia after 10-, 25-, or 50-channel transmyocardial laser revascularization. Perfusion was assessed using a 20-segment analysis (18 short-axis and 2 long-axis segments) and scored by two nuclear cardiologists in a blinded fashion. Depicted is the mean difference (± standard deviation) in stress-induced ischemia in the same animal, as calculated according to "Material and Methods," for the animals at day 28 versus immediately before lasing.

 
Quantitative computer-based analysis of 99mTc-sestamibi perfusion scans obtained 4 weeks after TMR (day 28) demonstrated a 42% ± 22% improvement in stress-induced ischemia (p < 0.004) in those animals receiving 50-channel TMR as compared with scans obtained immediately before lasing (Fig 2). In contrast, animals receiving 25- and 10-channel TMR demonstrated only a 13% ± 9% and an 8% ± 4% improvement in ischemia, respectively (p > 0.05). Although the 50-channel TMR appeared to induce greater improvement in perfusion than did the 25-channel TMR (p = 0.05), the difference between the 25 and 10 channels was not significant (p = 0.45).



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  		Fig 2. Quantitative percent improvement (± standard deviation) in stress-induced ischemic area at day 28 after lasing compared with corresponding value immediately before lasing after 10-, 25-, or 50-channel transmyocardial laser revascularization. Improvement was ascertained by computer analysis, as described in "Material and Methods."

 
Histologic analyses of neovascularization
Longitudinal and transverse sections of myocardium obtained 28 days after treatment with the excimer laser demonstrated characteristic laser channels including a central tissue ablated core with organizing fibrin thrombus and a surrounding circumferential response zone (Fig 3). In the viable myocardium surrounding the laser channels there was a variable degree of blood tracking between myofibers and around blood vessels. Cells lining the channels, suggesting early endothelialization, could be seen, as well as a high degree of neovascularization in the loose connective tissue surrounding these channels (Fig 3). Vessels appeared clustered and were not all related to main branches or arterioles.



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  		Fig 3. (A) Photomicrograph of the region of myocardium subjected to transmyocardial laser revascularization showing a stellate area of fibrosis with a proliferation of small blood vessels at its periphery (50-channel transmyocardial laser revascularization; hematoxylin and eosin, x40). (B) Photomicrograph of the area of vascularization at the periphery of the transmyocardial laser revascularization region of injury. The vessels are lined by plump oval endothelial cells. Additionally, myofibroblasts with reactive nuclei and spindled cytoplasm are seen. (50-channel transmyocardial laser revascularization; hematoxylin and eosin, x600).

 
The degree of vascularization in the perichannel zone as viewed under high-power (x200) appeared consistent among the 10-, 25-, and 50-channel groups (10 ± 3, 8 ± 2, and 10 ± 4 vessels, respectively, p > 0.10). However, the overall number of vessels per x40 low-power field were greater in the pigs receiving 50 channels (25 ± 6 vessels) compared with those receiving 10 and 25 channels (13 ± 4 and 9 ± 5 vessels, respectively, p < 0.001; Fig 4).



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  		Fig 4. Histologic analysis of left ventricular wall in the circumflex coronary artery distribution after 10-, 25-, or 50-channel transmyocardial laser revascularization (day 28). Vessel counts were quantified by microscopy with hematoxylin and eosin staining at x40 magnification by two observers blinded to treatment group and are presented as mean ± standard deviation of vessel count per field.

 

   Comment
Top
 Footnotes
 Abstract
 Introduction
 Material and methods
 Results
 Comment
Acknowledgments
 References
 
Transmyocardial laser revascularization was initially developed in an effort to mimic reptilian myocardial anatomy in which a complex series of endocardial sinusoids contributes significantly to myocardial blood flow [12]. Sen and associates [13] in 1965 first used myocardial acupuncture in an effort to mimic this reptilian anatomy and to bathe cells in an ischemic region of myocardium with oxygenated blood derived directly from the left ventricle. The work of early investigators culminated in the first clinical application of TMR by Mirhoseini and colleagues [14] in 1982 using an 80-W CO2 laser to make transventricular channels on the beating heart. With other clinical trials of TMR demonstrating evidence of improved clinical outcomes, the U.S. Food and Drug Administration recently approved the CO2 and holmium:YAG lasers for the purpose of performing TMR for patients not suitable for revascularization by conventional means.

Despite the approval of TMR for clinical use, continued controversy exists as to whether TMR is capable of enhancing perfusion to ischemic myocardium. Results of sestamibi scans in the present study provide clear evidence that there is enhancement of perfusion using the excimer laser to perform TMR, at least in this experimental setting. This evidence of enhanced perfusion in the present study does not, however, completely discount additional mechanisms underlying clinical outcomes, such as cardiac denervation, which has been proposed as an alternative mechanism underlying the clinical effects of TMR [15, 16]. Similarly, evidence of improved angina class in our previously reported clinical experience with the excimer laser [17] cannot necessarily be ascribed to these experimental findings. Furthermore, although our current positive findings with the excimer laser are consistent with our previous clinical and experimental animal studies [8, 17], it is unclear why Hughes and coworkers [18] were unable in a previous study to demonstrate enhanced angiogenesis using the excimer laser. Finally, it must also be stated that the current data using an excimer laser cannot necessarily be extrapolated to the high-energy CO2 and holmium:YAG lasers.

There is some evidence in the literature to suggest that TMR injury induces the upregulation of growth factors that are capable of mediating angiogenesis to enhance perfusion in ischemic myocardial segments treated with TMR [8, 14, 19–21]. This angiogenic response is a likely result of the small amounts of localized injury resulting from the TMR itself [19, 22–26]. The histologic evidence of neovascularization noted in this study, similar to previous observations [24–26], favors this theory, although a causal mechanism is not established.

Although the present study does not prove or disprove the relevance of laser energy in this process, our previous animal studies using the same excimer device demonstrated that mechanical advancement of the laser fiber without using laser energy is less effective in inducing this neovascularization response [8]. This is in apparent contrast to the results of Chu and associates [27], who showed that with increasing puncture density with a needle, discrepancies between needle and CO2 TMR in regard to neovascularization could be overcome, at least in regard to histologic evidence of vascularization. The present study, however, correlates channel density with enhancement of perfusion, which was not examined in the study of Chu and colleagues [27].

One aspect of the TMR literature currently lacking, therefore, is the potential importance of channel number as a determinant of enhanced perfusion induced by TMR. In our study, the comparatively greater perfusion of the (ameroid) circumflex territory versus the unligated remainder of the myocardium of the same animal with 50-channel TMR as compared with the 25- and 10-channel groups suggests that such a dose–response relationship does exist. Histologic evaluation of the hearts receiving such different doses of TMR would similarly suggest a dose-dependent angiogenic mechanism underlies the efficacy of TMR related to the density of channels made in a given area of the ventricular wall. Consistent with this hypothesis, for each of the channel density groups at high power, we report visualization of a consistent number of microvessels in the area of each individual laser tract. This is not surprising, as each channel was created with the same laser settings, and the perichannel zone visualized under high power is therefore likely to be similar. The greater number of vessel counts seen per field under low power, in contrast, correlates with the number of lased channels as a function of channel density and the likelihood of encountering the effects of more channels under low power.

Undoubtedly, the clinical setting for TMR is much more variable than the described experimental model in terms of angiogenic response to TMR as well as the size of ischemic area to be treated. In addition, there must be an upper limit to the number of channels that could be inflicted on the ischemic myocardium, which could be related to the preoperative ventricular function of the patient. These variables were not ascertainable from our investigation. Thus, although animal experiments may be encouraging, they are not always directly translatable into clinical outcomes. Nevertheless, the present study suggests that TMR enhances perfusion, possibly as a result of an induced angiogenic response, and that this outcome is related to the total channel number. These results may have implications when evaluating the efficacy of standard versus less invasive procedures, such as percutaneous myocardial revascularization, in terms of ability to deliver an adequate number of channels.


   Acknowledgments
Top
 Footnotes
 Abstract
 Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
References
 
We thank Julia Moores, RT, and Irene Blanco, BA, for their assistance and efforts.


   Footnotes
Top
 Footnotes
Abstract
 Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
 References
 
Dr Rosengart discloses that he has a financial relationship with Edwards Lifesciences LLC.


   References
Top
 Footnotes
 Abstract
 Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
 References
 

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