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Published online before print September 19, 2002, 10.1148/radiol.2252011325
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(Radiology 2002;225:487-493.)
© RSNA, 2002

Experimental Studies

Effect of Transmyocardial Laser Revascularization on Myocardial Perfusion and Left Ventricular Remodeling after Myocardial Infarction in Rats1

Matthias Nahrendorf, MD, Karl-Heinz Hiller, PhD, Dirk Theisen, Kai Hu, MD, Christiane Waller, MD, Ralf Kaiser, Axel Haase, PhD, Georg Ertl, MD, Ralf Brinkmann, PhD and Wolfgang R. Bauer, MD

1 From the Physikalisches Institut (EP5) (M.N., K.H.H., A.H.) and Medizinische Universitätsklinik (K.H., C.W., R.K., G.E., W.R.B.), Universität Würzburg, Josef Schneider-Strasse 2, 97080 Würzburg, Germany; and Medizinisches Laserzentrum Lübeck, Germany (D.T., R.B.). Received August 6, 2001; revision requested September 24; final revision received March 18, 2002; accepted April 1. Supported by Sonderforschungsbereich 355 Herzinsuffizienz and Graduiertenkolleg HA 1232/8-1. Address correspondence to W.R.B. (e-mail: w.bauer@medizin.uni-wuerzburg.de).


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
PURPOSE: To monitor perfusion changes in remote myocardium caused by transmyocardial laser revascularization (TMLR) and to investigate the influence of TMLR on left ventricular morphology and function.

MATERIALS AND METHODS: The coronary arteries were ligated in 32 Wistar rats. Eight weeks later, cine magnetic resonance (MR) imaging was performed in both the treatment (n = 12) and control group (n = 8). TMLR was then performed in the remote myocardium in the treated group. Twelve weeks after myocardial infarction, cine MR imaging, including dobutamine-induced (10 µg per kilogram of body weight per minute via the tail vein) stress, was repeated and followed with hemodynamic measurements in both groups and with perfusion MR imaging (in-plane resolution, 140 x 140 µm) of the isolated heart at rest and during nitroglycerin-induced stress in the TMLR group (n = 10).

RESULTS: Left ventricular dilatation and hypertrophy were enhanced in the TMLR group (change in end-diastolic volume at 8–12 weeks: control group, 24.6 µL ± 16.7 and TMLR group, 81.7 µL ± 15.7; change in left ventricular mass: control group, 54.5 mg ± 19.2 and TMLR group, 124.1 mg ± 30.7; P < .03 for both). Ejection fractions at rest were approximately equal (control group, 40% ± 2; TMLR group, 38% ± 2; P value not significant), but during dobutamine-induced stress, the ejection fraction was higher in the TMLR group (54.4% ± 4.9; control group, 47.4% ± 4.8; P < .05). TMLR-treated areas were better perfused than was untreated myocardium (difference in perfusion: TMLR-treated vs control region, 3.89 mL/min/g ± 0.83 at rest vs 2.29 mL/min/g ± 1.06 during nitroglycerin-induced stress; P < .05 for both). Hemodynamic measurements revealed no differences between groups.

CONCLUSION: High-spatial-resolution perfusion MR imaging depicted a significant perfusion improvement after TMLR. Post–myocardial infarction remodeling of the left ventricle was found to be enhanced.

© RSNA, 2002

Index terms: Animals • Experimental study • Heart, experimental studies, 511.129 • Heart, MR, 51.121412 • Heart, perfusion • Lasers • Myocardium, infarction, 511.771


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Clinical studies (1–5) have shown a beneficial effect of transmyocardial laser revascularization (TMLR) in patients with end-stage coronary disease. It is still unclear, however, whether TMLR improves perfusion (5–7), improved perfusion is caused by blood flow through open laser channels (5,8–10), there is relevant neoangiogenesis (7,9,11,12), or pain relief is caused by denervation (13,14) and placebo effects (2).

Hypertrophy of the remote region after myocardial infarction (MI) in rats causes changes in the microvasculatory system that consist of reduced capillary density (15) and diffuse hypoperfusion of the surviving myocardium (16). This finding has been demonstrated by Waller et al (17) in serial measurements after MI in rats. We anticipated that the effect of TMLR in regions with diffuse circulatory alteration would be more pronounced than that in tissue supplied by a stenotic coronary artery, if TMLR indeed modifies the microvasculatory bed with neoangiogenesis.

The purpose of our study, therefore, was to monitor perfusion changes in remote myocardium that are caused by TMLR and to investigate the influence of TMLR on left ventricular (LV) morphology and function.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Experimental Protocol
Thirty-two female Wistar rats (body weight, 260–280 g; Charles River, Sulzfeld, Germany) were subjected to left coronary arterial ligation, as described previously by Pfeffer et al (18), and were randomly assigned to one of two groups. LV geometry and performance were determined 8 and 12 weeks after MI by means of cine magnetic resonance (MR) imaging, described later. In the treatment group, 8-week MR imaging was performed 3 days prior to TMLR. At 12 weeks after MI, cine MR imaging was repeated at rest and under stress induced with intravenous administration of dobutamine (10 µg per kilogram of body weight multiplied by minutes of Dobutamin Liquid; Fresenius, Bad Homburg, Germany). Following the final cine MR imaging examination, hemodynamic measurements were performed. LV end-diastolic pressure was used for calculation of wall stress. Perfusion maps were acquired from the isolated beating hearts of the TMLR group at rest and during nitroglycerin-induced stress (Nitrolingual Infusion; Pohl, Hohenlockstedt, Germany). Finally, after the rats were sacrificed, histologic data were obtained (Fig 1). All procedures conformed with the European guidelines of the European Committee for Care and Use of Laboratory Animals (19).



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  		Figure 1. Diagram shows the experimental protocol. A total of 32 rats were studied. Six rats from each group died after MI induction. Two rats died during TMLR as a result of surgical complications. MRI = MR imaging.

 
TMLR Procedure
The procedure was performed by several of the authors together (M.N., K.H.H., D.T., R.B.). The rats were intubated and ventilated with isoflurane (Forene; Abbott, Wiesbaden, Germany) supplemented with oxygen. Lateral thoracotomy was performed. Four channels were ablated through the pericardium in a 4 x 4-mm square at the noninfarcted region (Fig 2). To determine the target region within the remote myocardium, pre-TMLR cine MR imaging was performed. Ablation was triggered by the QRS complex of electrocardiography (EKG), with a 5-msec delay to avoid the vulnerable phase of the cardiac cycle and minimize arrhythmia.



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  		Figure 2. Two TMLR-treated spots are seen shortly after TMLR, and the infarct scar is seen by means of lateral thoracotomy.

 
A high-energy holmium:yttrium-aluminum-garnet, or YAG, laser system designed by our department that emitted at a wavelength of 2.1 µm was used (20). For safe single-pulse TMLR, it is necessary to prevent laser energy from reaching the opposite wall of the LV. After penetration through the myocardium, the laser energy causes cavitation in the ventricle. To determine the optimal laser parameters for TMLR in rats, high-speed photography was used to observe the bubble size in a heart model (20,21). A laser pulse with energy of 4 J and a duration of 1 msec proved sufficient to penetrate the rat myocardium with a single pulse. The bubble size in the ventricle during the laser pulse was less than 5 mm in diameter.

The laser pulse was transmitted through a multimode quartz fiber with a 365-µm core diameter. The distal fiber tip was placed in soft contact with the myocardium. After ablation, pulsatile arterial bleeding was observed and stopped with slight pressure applied with a swab.

Cine MR Imaging
Because of the noninvasive character of cine MR imaging, it was possible to examine the rats prior to and 4 weeks after TMLR. Comparison with the control group enabled detection of therapy-induced changes. Cine MR imaging was performed with a 7.05-T unit (BIOSPEC 70/21; Bruker, Karlsruhe, Germany) and with the rats under inhaled anesthesia (isoflurane 1.5% volume supplemented with 0.5 L of oxygen per minute) applied with a nose cone, as described previously (22). An EKG-triggered fast low-angle shot, or FLASH, sequence (23) was used with the following parameters: 3.2/1.1 (repetition time msec/echo time msec); flip angle, 30°–40°; and 12 frames per cardiac cycle. For quantitative determination of morphology and function, 15–18 contiguous ventricular short-axis sections of 1-mm thickness were acquired to cover the entire LV. With a field of view of 30–40 mm and an image matrix of 128 x 128, in-plane resolution was 230–310 µm.

Cardiac volumes were calculated, as described elsewhere (22). LV mass was calculated as LV myocardial volume multiplied by myocardial specific gravity (1.05 g/cm3). Stroke volume (SV) and ejection fraction (EF) were calculated by using end-diastolic volumes (EDVs) and end-systolic volumes (ESVs) as follows: (SV = EDV - ESV, and EF = SV/EDV). To calculate cardiac output, stroke volume was multiplied by heart rate. Infarct size was determined as the fraction of the myocardium with marked thinning of the wall and lost systolic function. It was calculated by dividing the sum of the endocardial and epicardial circumferences occupied by the infarct by the sum of the total epicardial and endocardial LV circumferences. This method has been validated previously against histologic determination of MI size (22). Myocardial thickness was measured in a control region (septum or posterior wall) and in the TMLR-treated segment, which was identified by using short-axis histologic slices.

Hemodynamic Measurements
In the rat model of infarction, LV end-diastolic pressure is important information relating to the remodeling process and can be used to calculate wall stress. Hemodynamic measurements were performed (K.H., M.N., C.W.) with the rats under isoflurane ventilation (0.8%–1.2% volume supplemented with oxygen). During intermittent positive pressure ventilation (respiration rate, 90 breaths per minute; tidal volume, 10 mL/kg), aortic and LV pressures were measured by using a catheter (Millar Instruments, Houston, Tex) advanced via the right carotid artery. LV end-diastolic pressure (LVEDP) was used for calculation of global diastolic LV wall stress (WS) as follows: WS = 1.33 x 10-2 x LVEDP x [216.9 + (EDV/EDMV)] (24), where EDMV is end-diastolic myocardial volume, and 1.33 x 10-2 is a factor for converting millimeters of mercury into newtons per square centimeter.

Perfusion Measurements
High spatial resolution is needed to assess perfusion after TMLR. Thus, high-spatial-resolution spin-label MR imaging with a pixel size of 140 µm2 was used to visualize perfusion changes within the channel remnants and their vicinity. This technique has previously been validated against microspheres and first-pass perfusion MR imaging measurements (25,26). Spin-label MR imaging was performed with an 11.75-T wide-bore imager (model AMX 500; Bruker). The principle of measurement is that spins of a selected imaging section are inverted, and T1 relaxation of these spins toward equilibrium is observed. Because of perfusion, noninverted (equilibrium) spins flow into the section. This results in a decrease in the apparent proton relaxation time in tissue. Perfusion imaging was performed in isolated hearts that were obtained from the TMLR group (n = 10) and perfused in a retrograde fashion. The rats were anesthetized with intraperitoneal administration of pentobarbital sodium (160 mg/kg Narcoren; Rhone Merieux, Laupheim, Germany). The hearts were rapidly excised, immersed in ice-cold buffer, and perfused within 2 minutes (Langendorff model [27]) with nonrecirculating 37°C Krebs-Henseleit buffer equilibrated with 95% oxygen and 5% carbon dioxide (pH, 7.4) at constant perfusion pressure (100 mm Hg). A drain piercing through the LV apex drained flow from the thebesian veins. A water-filled latex balloon was inserted in the LV and connected with a pressure transducer (model P23XL; Statham, Oxnard, Calif) to measure LV pressure, which was recorded to trigger the MR imaging pulse sequences. Global coronary flow was measured with an ultrasonic flow meter (model T106; Transonic Systems, Ithaca, NY).

Spins of a selected section in the short-axis view were inverted by using an adiabatic 180° pulse, with a section thickness of 3 mm. After section-selective inversion, a series of 16 diastole-triggered snapshot FLASH images (23) were acquired to observe T1 relaxation: 3.6/1.0; flip angle, 3°; in-plane resolution, 140 µm2; section thickness, 1.5 mm; and acquisition time, less than 1 minute. T1 maps were used to determine perfusion differences between a control region within the septum, the infarcted region, and the TMLR target region within the same heart. These regions were identified by comparing perfusion maps with the corresponding histologic slides. The high spatial resolution of the MR images allowed comparison of anatomic patterns and definition of regions of interest within relocated TMLR zones first identified on the histologic slides. Infarct scars served as anatomic landmarks.

In addition, perfusion changes within one region that were caused by nitroglycerin (0.5 mg/min) were calculated to assess flow reserve. This compound has been shown to be valuable for inducing stress in the described experimental setup (25).

Histologic Examination
The hearts were excised and fixed for 48 hours in distended form in 3.4% buffered formalin. TMLR-treated areas were visible on the epicardial surface of the ventricle. Myocardial rings were produced that included these areas. The rings were dehydrated in alcohol, washed in xylene, and embedded in paraffin. Transverse serial sections of 3-µm thickness were obtained with no intersection gap. The sections were mounted, and every tenth section was stained with hematoxylin-eosin and Elastica van Gieson.

Statistical Data Analysis
All data were calculated as means ± standard errors of the mean. Statistical analysis was performed with commercially available software (SPSS version 10.0 for Windows; SPSS, Chicago, Ill). Two-factor repetitive-measurements analysis of variance, or ANOVA, was used to analyze data acquired from both groups before and after treatment. The first factor was the study group (TMLR vs control), and the second factor was time (before vs after treatment). For LV dilatation (end-diastolic and end-systolic volume), the two-way interaction of the test was significant (P = .025), meaning that there was a different time effect in each group. The main effects of the test could therefore not be used, and a paired Student t test was performed for the TMLR group for changes caused by treatment (12 vs 8 weeks), as well as an unpaired t test for comparison of the treatment group and the control group. For hypertrophy (of LV mass), interaction of two-factor repetitive-measurements ANOVA was not significant (P = .09); therefore, main effects were studied. There was a significant difference 8–12 weeks after MI (P < .001) but no difference between groups. However, when change in LV mass was compared between groups by using the unpaired Student t test, a P value of .03 was found to indicate a significant difference. When multiple tests were performed, a Bonferroni-Holmes procedure was used to correct P values.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
 REFERENCES
 
Twenty rats survived the MI procedure. The initial infarct size, determined with cine MR imaging, was similar in both groups (Table 1). There was no statistically significant difference in body weight or heart rate between groups or time points. Baseline values of LV morphology and performance obtained with the first cine MR imaging examination did not differ (Table 1). Twelve rats were assigned to the TMLR group; two died immediately after TMLR because of surgical difficulties. The acute macroscopic result of TMLR is shown in Figure 2.


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  		TABLE 1. LV Performance after MI

 
Resting perfusion was higher in areas treated with TMLR than in control regions (visible on perfusion map [Fig 3]). This result is expressed in Figure 4 as the difference from the control region (3.89 mL/min x g ± 0.83). During nitroglycerin-induced stress, perfusion in TMLR-treated areas was higher than that in control areas, as well (difference in perfusion between TMLR-treated and control areas, 2.29 mL/min x g ± 1.06; P < .05). However, the relative perfusion reserve in response to nitroglycerin-induced stress was higher in control areas (Fig 4). The region of interest within the TMLR-treated area consisted of 266 pixels ± 38, and the control region within the septum consisted of 251 pixels ± 31.



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  		Figure 3. Systolic short-axis cine MR frame perfusion image of the isolated heart (left and center) and corresponding histologic findings (right) obtained in the same heart 4 weeks after TMLR. (Hematoxylin-eosin stain; original magnification, x5.) Arrows point to TMLR-treated regions, and the box represents the region of interest within the TMLR-treated area. All images were obtained in the same heart at the same level of the LV. MR images and histologic findings are shown to demonstrate how landmarks such as the infarct scar and the strong similarity in the pattern of TMLR-induced changes helped to determine the regions of interest for measurement of perfusion and wall thickening.

 


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  		Figure 4. Graphs show the results of perfusion measurements as differences from the control region within the septum of the same heart at rest (left, the change in perfusion is the difference from the control region in milliliters per minute multiplied by grams). TMLR-treated regions exhibited higher perfusion than did control regions. In the graph on the right, the perfusion increase within the same region from baseline toward nitroglycerin-induced stress is shown (right, change in perfusion is the difference between perfusion during stress vs perfusion in the same region at rest). The relative perfusion reserve was higher in the control region, but during nitroglycerin-induced stress, absolute perfusion of TMLR-treated areas was still higher by 2.29 mL/min x g ± 1.06. x = P < .05 versus the control region, {dagger} = P < .05 versus the same region at rest.

 
Figure 5 shows that the increase in end-diastolic volume 8–12 weeks after MI was significant in only the TMLR group. The LVs dilated by 81.7 µL ± 15.7 (13.5% of end-diastolic volume) in the TMLR group and by 24.6 µL ± 16.7 in the control group (P < .05 for the difference in end-diastolic volume change between groups). LV mass increased in both groups because of post-MI remodeling but was more pronounced in the TMLR group (change in LV mass, 124.1 mg ± 30.7 vs 54.5 mg ± 19.2; P < .03). The wall thickness of the TMLR-treated region was higher than that of the control region in the same LV (1.92 mm ± 0.07 vs 1.59 mm ± 0.03; P < .01). Systolic wall thickening as an indicator of segmental function was significantly higher in TMLR-treated segments than in the control region at rest (57% ± 7 vs 37% ± 6; P = .03) but not during stress measurements. Global LV and segmental performance at rest showed no differences between groups (Table 1), but during stress MR imaging, the ejection fraction was higher in the TMLR group (Table 2). Hemodynamic and wall stress measurements did not differ between groups (Table 3).



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  		Figure 5. Graphs show LV morphologic changes from 8 to 12 weeks in the control group and the TMLR group. An increase in LV mass and end-diastolic volume (EDV) was enhanced with TMLR treatment.

 

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  		TABLE 2. Stress MR Imaging Findings 12 Weeks after MI

 

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  		TABLE 3. Wall Stress and Hemodynamic Measurements 12 Weeks after MI

 
Histologic analysis revealed that TMLR-treated regions consisted of a highly vascularized granulation tissue. Starting from the epicardial zone that was in contact with the laser fiber, a region with granulation tissue and rarification of myocytes followed the original orientation of the myofibrils rather than connecting epicardium and endocardium by way of the shortest possible route. Vessels within that region included large venules, arterioles, and capillaries (Fig 6). Granulocytes were also visible, which indicates that there was still activity 4 weeks after treatment.



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  		Figure 6a. (a) Photomicrograph shows histologic findings in the TMLR-treated region, with unaffected remote myocardium at the lower corners. Arrow shows original direction of TMLR. Four weeks after the procedure, necrosis was replaced by a richly vascularized granulation tissue. (Hematoxylin-eosin stain; original magnification, x20.) (b) Photomicrograph shows histologic findings in the TMLR-treated region only; there is no myocardium within this expanded view. Note the numerous small vessels within the granulation tissue that has replaced the TMLR-induced necrosis. (Hematoxylin-eosin stain; original magnification, x32.)

 


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  		Figure 6b. (a) Photomicrograph shows histologic findings in the TMLR-treated region, with unaffected remote myocardium at the lower corners. Arrow shows original direction of TMLR. Four weeks after the procedure, necrosis was replaced by a richly vascularized granulation tissue. (Hematoxylin-eosin stain; original magnification, x20.) (b) Photomicrograph shows histologic findings in the TMLR-treated region only; there is no myocardium within this expanded view. Note the numerous small vessels within the granulation tissue that has replaced the TMLR-induced necrosis. (Hematoxylin-eosin stain; original magnification, x32.)

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
REFERENCES
 
The current study helps to answer some of the debated issues in the discussion of TMLR. A sensitive high-spatial-resolution spin-labeling MR imaging technique for perfusion measurement enabled detection of small perfusion improvements in TMLR-treated areas. These improvements were related to vessels linked to the coronary vascular bed. Serial cine MR imaging measurements showed improved regional function (systolic wall thickening) of remote myocardium treated with TMLR, but LV dilatation and hypertrophy were increased in comparison with those in control areas.

Perfusion Improvement
One limitation of this study was the problem of identifying TMLR target regions with MR imaging measurements. We found no easy solution (such as long-term labeling of the target region) to make identification more observer independent. However, there are topographic landmarks both in histologic findings and on short-axis MR images (the MI scar, the right ventricle, and the septum) that aid in determining corresponding regions. In addition, there was a strong similarity between the pattern and shape of regions with improved perfusion and those of histologic structures resulting from TMLR.

Improved perfusion in the TMLR-treated segments agrees with findings of previous experimental (5,7) and clinical (4,5) studies. While some patient studies in which positron emission tomography (PET) and radionuclide scanning were used showed no changes (1,2), TMLR appears to reduce anginal pain (1–3,7). However, it is possible that the improvement in perfusion is too small to be detected with PET and radionuclide scanning but is sufficient to decrease anginal pain. With a spatial resolution of 140 µm2, spin-label MR imaging resulted in significantly higher resolution (28,29) and made possible the visualization of perfusion changes within the channel remnants and their vicinities.

Some authors (4,5,10) have postulated that laser channels remain open and may enhance perfusion of the ischemic myocardium from directly inside the LV cavity. The retrograde perfusion setup of the Langendorff model used in the current study helped rule out the theory that perfusion improvements were due to blood flow through open laser channels from inside the LV, since the aortic valve was closed. Improved perfusion must therefore be related to new vessel formation, which is linked to the coronary system.

The fairly high level of perfusion differences between regions was in part caused by the high overall coronary flow typically found in the isolated buffer-perfused heart (23.7 mL/min ± 0.7 at rest in the current study).

During nitroglycerin-induced stress, perfusion in TMLR-treated segments was higher than that in the control areas, but the perfusion increase was better in the control areas. This finding may be due to the irregular structure of the vessels that are created by the laser treatment. Some of them may be described as cavities partly resembling large venules and are lined with an endothelial layer but possess no smooth-muscle cells. Therefore, dilation during stress might be limited in comparison with that in normal vessels. Similar histologic findings after TMLR in other species have been described by other authors (7,9,11).

An important question to be addressed regards the type of ischemia that is being treated. TMLR is used mostly in patients with widespread coronary arterial disease that includes stenotic main branches of the coronary system (5). In the present study, a model was used that exhibited a state of diffuse hypoperfusion of the remote myocardium, which resulted from induction of post-MI remodeling (16,17). Our results support TMLR as a promising therapeutic option for patients with diffuse hypoperfusion, as seen in small-vessel disease or transplant vasculopathy.

Enhanced LV Remodeling
Dilatation and hypertrophy after MI have been identified as deleterious and as predictors of poor outcome (30). The rat model of MI offers important parallels to the process of cardiac remodeling and the development of heart failure in humans (31). In the current study, both hypertrophy and dilatation increased in the TMLR group. These increases might have resulted from additional necrosis that was induced by laser injury. Histologic findings of granulation tissue within the vicinity of TMLR zones and an increase in end-diastolic wall thickness at cine MR imaging support this conclusion. Direct translation of the enhanced remodeling caused by TMLR in this model into a clinical situation is not easy, especially when laser parameters are taken into account. For example, the diameters of the laser fiber used (365 µm) and of the resulting channel were twice the size, relative to the wall thickness, of the usual 1-mm fiber used in humans (2). The small number of ablations (four) might compensate for this effect. Nevertheless, to our knowledge, there are no published data addressing the effect of TMLR on post-MI remodeling in humans; therefore, TMLR should be performed with caution in this situation.

However, the TMLR-treated segments demonstrated improved segmental function. In contrast with enhanced ventricular dilation, the ejection fraction was higher in the TMLR group than in the control group during stress MR imaging. This increase might be explained by the results of stress perfusion MR imaging. Despite the reduced reserve, perfusion was still higher in TMLR-treated segments during nitroglycerin-induced stress. Higher perfusion might allow for a greater degree of wall thickening of the treated segment, with consequent improved global performance.

In conclusion, TMLR has beneficial effects on myocardial perfusion and segmental function in a model of diffuse hypoperfusion and results in enhanced LV remodeling after MI. MR imaging has proved to be a valuable research tool for noninvasive serial assessment of cardiac remodeling, and high-spatial-resolution spin-label perfusion measurement has enabled better insight into perfusion changes caused by TMLR.

Practical application: Extrapolation of our results into the patient’s situation is not straightforward; however, some conclusions can be drawn. Because the histologic findings of our study are parallel to those of other authors using clinical laser systems, we think that extrapolation of our results into the clinical setting is possible. One explanation for the discrepancy of improved angina in patients but failure of major studies to show improved perfusion after TMLR may be due to insufficient spatial resolution of the applied imaging techniques. In addition, patients with impaired microcirculation may be successfully treated with TMLR. In relation to LV size in the rat, the diameter of the laser fiber was large; however, the finding of enhanced LV remodeling should lead to additional caution with regard to the application of TMLR for post-MI remodeling.


   FOOTNOTES
 
Abbreviations: EKG = electrocardiography, LV = left ventricle, MI = myocardial infarction, TMLR = transmyocardial laser revascularization

Author contributions: Guarantors of integrity of entire study, M.N., K.H.H., W.R.B.; study concepts and design, all authors; literature research, M.N., W.R.B., D.T., K.H., G.E., K.H.H.; experimental studies, M.N., D.T., K.H., C.W., R.K., K.H.H.; data acquisition, M.N., D.T., K.H., C.W., R.K., K.H.H.; data analysis/interpretation, all authors; statistical analysis, M.N., K.H.H., G.E., W.R.B.; manuscript preparation and definition of intellectual content, all authors; manuscript editing, M.N., W.R.B., D.T., K.H., C.W., A.H., G.E., K.H.H.; manuscript revision/review and final version approval, all authors.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 

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