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(Circulation. 1997;95:371-375.)
© 1997 American Heart Association, Inc.

Articles

Transmyocardial Laser Revascularization

Histological Features in Human Nonresponder Myocardium

Nikolaus Gassler, MD; Hanns-Olof Wintzer, MD; Hans-Martin Stubbe, MD; Andreas Wullbrand, MD; Udo Helmchen, MD

the Department of Pathology (N.G., H.-O.W., A.W., U.H.) and the Department for Thoracic and Cardiovascular Surgery (H.-M.S.), University Hospital Eppendorf, Hamburg, Germany.

Correspondence to Dr Nikolaus Gassler, Universitat Heidelberg, Institute for Anatomie und Zellbiologie, Im Neuenheimer Feld 307/3.OG, D-69120 Heidelberg, Germany.

	Abstract

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Background The creation of transmyocardial channels from the epicardium to the left ventricular cavity with the use of a CO₂ laser is a modern approach in the treatment of patients with chronic ischemic cardiac disease. The histological features of human myocardium at different times after transmyocardial laser therapy have not been previously described. We had the opportunity to examine hearts from patients who died without clinical evidence of a persistent therapeutic effect at 3, 16, and 150 days after transmyocardial laser revascularization (TMR), respectively.

Methods and Results We grossly localized the laser-created channels in unfixed and formalin-fixed tissue. Three ventricular levels were defined for cutting the hearts into four segments. Then, transmural blocks were excised and cut crosswise and lengthwise for histological investigation through the use of established staining methods. On day 3, laser-induced channels were filled with abundant granulocytes and thrombocytes, fibrinous network, and detritus and were surrounded by severe myocardial necrosis. Furthermore, the epicardial and endocardial portions were obstructed by fibrinous network and microclots. Granulocytes were mostly absent on day 16; in addition, the channels were filled with erythrocytes or fibrinous network. On day 150, we observed a string of cicatricial tissue admixed with a polymorphous blood-filled capillary network and small veins, which very rarely had a continuous wrinkled link to the left ventricular cavity.

Conclusions We found different stages of wound healing in human nonresponder myocardium after TMR, resulting in scarred tissue that displayed capillary network and dilated venules without evidence of patent and endothelialized laser-created channels. Experimental studies are necessary to analyze the morphological basis for TMR-mediated effects in human responder myocardium.

Key Words: heart diseases • lasers • revascularization

	Introduction

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An alternative method of myocardial revascularization in ischemic cardiac disease is the creation of transmyocardial channels through the use of a CO₂ laser. Patients who are not candidates for conventional methods of myocardial revascularization (eg, coronary artery bypass graft surgery or angioplasty) and do not respond to any kind of medical management could benefit from this new method. Examples include patients with severe diffuse coronary artery disease, poor ventricular function, or poor results from previous surgery.^{1 2 3} Mirhoseini and Cayton⁴ were the first to show that in dogs, CO₂ laser radiation can create transmyocardial channels from the epicardium to the left ventricular cavum. The laser-created channels (LCCs) could be demonstrated both grossly and microscopically 12 months after transmyocardial laser revascularization (TMR).⁵ Histologically, the LCCs were endothelialized and free of scar tissue. Patent scar-free LCCs 30 days after TMR were also described in sheep by Horvath et al.⁶ However, recent studies in animals failed to show a beneficial effect in dogs of patent LCCs on collateral myocardial blood flow^{7 8} or on infarct size after coronary artery occlusion.⁹ On the contrary, cardiac symptoms in humans, such as angina pectoris, are often immediately reduced after TMR.^{1 3 10} However, clinical experience indicates that successful therapy is achieved in 80% of TMR-treated patients, whereas 10% do not show any improvement and the remaining 10% die. This clinical evidence and findings from nuclear follow-up examinations in humans suggest that LCCs might improve the perfusion of ischemic myocardium, but there are very few morphological studies on the long-term patency of LCCs in human myocardium.¹¹ Possible reasons for beneficial short- and long-term TMR-mediated effects are complete channel patency with direct blood flow to the ischemic myocardium from the left ventricular cavity or other protective mechanisms (eg, the creation of a dense capillary network). We had the opportunity to examine a small number of hearts at different intervals after TMR.

	Methods

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Heart preparation at autopsy was performed according to the procedures of Roussy and Ameuille discussed by Arnold.¹² Laser-induced lesions in unfixed specimens were located before the right and left ventricles were incised to allow 5 days of fixation in 4% formalin. Then, the heart was cut into four segments (Fig 1), which were fixed in 4% formalin for an additional 10 days. Next, transmural blocks that included the laser-induced lesions were excised and cut crosswise and lengthwise for histological investigation. Staining with hematoxylin and eosin, trichrome (Masson-Goldner), and Prussian blue iron was performed on paraffin-embedded, 5-µm sections. In addition, representative tissue specimens were immunostained for CD31 (undiluted antibody; Biogenex), factor VIII (diluted 1:500; Dako), and Ki-67 (MiB-1 antibody, diluted 1:10; Dianova) with the use of the alkaline phosphatase–antialkaline phosphatase method (bridging antibody from Dako; alkaline phosphatase–antialkaline phosphatase complex from Progen).¹³ MiB-1–stained sections were microwaved before treatment as described by Shi et al.¹⁴

View larger version (32K): [in this window] [in a new window]   Figure 1. Preparation scheme for visualization of LCCs in heart.

Patients
Clinical and anamnestic data for the four patients treated with TMR are given in the Table.

View this table: [in this window] [in a new window]   Table 1. Clinical Data and Number of Laser Applications Compared With the Total of Histologically Identified Lesions From Four Transmyocardial Laser Revascularization–Treated Patients

	Results

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In general, the epicardial portions of LCCs were easy to localize grossly on day 3 after TMR because of prominent pointed fibrin exudation. Epicardial lesions were more difficult to identify on days 16 and 150 after TMR because they were smaller and scarred. Lesion size varied from 2 mm on day 3 to <1 mm on day 150. The endocardial portions of the lesions were small and occasionally showed a weak hemorrhagic margin (3-day-old samples). Gross identification of the lesions was difficult on days 16 and 150.

Not all clinically recorded lesions could be identified in every part of the myocardial wall (Table).

Histological Features of LCCs on Day 3 After TMR
LCCs were characterized by transmural circumscribed stringlike tissue defects that were filled with a fibrinous network containing granulocytes, thrombocytes, and erythrocytes (Fig 2). Epicardially, the defects were funnel shaped and sealed with laminated fibrinous precipitations. Adjacent fatty tissue was necrotic, densely infiltrated by granulocytes and some erythrocytes and included arterioles and venules with necrotic vessel walls and partial luminal obliteration by fibrin and granulocytes. In the myocardium, the defects were characterized by zonal alterations of muscle tissue (Fig 3). Directly contiguous to the defects was a thin layer of myocytic detritus, followed by a border zone of coagulation necrosis infiltrated by granulocytes. The adjacent myocardial zone showed prominent swollen cardiocytes with fibrillar cytoplasmic degenerations and an adjoining layer of typical contraction band necrosis. There was neither extensive infiltration of myocardium by erythrocytes nor positive Prussian blue iron staining of adjacent LCCs. The original vessels surrounding the channels were often hyperemic. A single small intramural hematoma was observed along the defect adjacent to a small intramyocardial artery that showed focal wall destruction. On the endocardial side, the LCCs were also sealed by fibrinous precipitations that were occasionally found in combination with a circumscribed parietal thrombosis of the ventricle cavity. Immunohistologically, neither endothelial nor proliferating cells could be demonstrated along the defect margins.

View larger version (1460K): [in this window] [in a new window]   Figure 2. Epicardial (A, D, and G), myocardial (B, E, and H), and endocardial (C, F, and I) aspects of LCCs at days 3 (A, B, and C), 16 (D, E, and F), and 150 (G, H, and I), respectively.

View larger version (995K): [in this window] [in a new window]   Figure 3. Cross sections of channels (A, C, and E) and myocardial zonal pattern (B, D, and F) at days 3 (A and B), 16 (C and D), and 150 (E and F), respectively.

Histological Features of LCCs on Day 16 After TMR
The lumina of the LCCs included both segments filled almost exclusively with fibrinous networks and segments with abundant erythrocytes that were occasionally admixed with thrombocytes, macrophages, inflammatory cells, and laminated fibrinous precipitations (Fig 2). Very rarely, small endothelium-like cells with a weak positive stain for CD31 and FVIII were observed in the marginal areas. In myocardium around the LCCs, Prussian blue iron and Ki-67 staining results were completely negative. Epicardially, the LCCs were obstructed by small membranes of fibrinous and collagenous fibers, rarely found in combination with granulocytes, thrombocytes, macrophages, lymphocytes, and erythrocytes. The only changes in the zonal pattern of the myocardium that could be observed were the disappearance of the thin layer of myocytic detritus adjacent to LCCs and a reduced differentiation of the remaining zones (Fig 3). Identical necrotic zones were occasionally found around small subendocardial vessels, which were traversed by LCCs. Lumina of the LCCs in the endocardium were almost densely filled with fibrinous and collagenous fibers, occasionally admixed with erythrocytes, thrombocytes, and inflammatory cells.

Histological Features of LCCs on Day 150 After TMR
Dense fibrinous tissue with a blood-filled capillary network and small veins was found in the original LCCs (Fig 2). In the epicardium, the laser-induced necrotic area was replaced by scar tissue with a few inflammatory cells, adipocytes, and, very rarely, foreign body granulomas. Neither a zonal pattern nor original hyperemic capillary vessels could be observed in myocardium around the scarred LCCs (Fig 3). Occasionally, a link between the capillary network in the LCCs and the original small myocardial vessels was found. The majority of endocardial lesions were filled completely with dense fibrinous tissue without any histological evidence of open anastomosis between the left ventricular cavity and the lumina of capillary vessels, whereas a few lesions had a continuous wrinkled link, which showed positive immunohistological staining for CD31 and factor VIII but negative Ki-67 and Prussian blue iron staining.

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
There is clinical evidence that indicates that LCCs can result in short- and long-term improvement of perfusion in ischemic myocardium.^{1 3 10} To analyze the morphological basis for beneficial effects in humans, we examined four hearts from patients who died as a result of the complications of chronic ischemic cardiac disease at 3, 16, and 150 days after TMR treatment, respectively. For interpretation of the data, two facts must be considered. First, no clinical benefit was observed immediately after TMR in patients with 3- and 16-day post-TMR survival. On the contrary, the patient with the 150-day survival period showed a short-term effect from TMR, but long-term benefit was dubious. Second, the actual sequence of events in LCC remodeling can only be hypothesized. The patients differ in age, sex, and their anamnestic data (Table), and the cardiac morphology of only three different intervals after TMR was investigated. Our histological data suggest, however, that the steps that occurred after left ventricular TMR were similar to those in wound repair after ischemic myocardial necrosis, ventriculotomy,¹⁵ or radiofrequency catheter ablation,¹⁶ all of which result in a fibrinous scar. The morphological aspects on day 3 or 16 (eg, myocardial necrosis and inflammation) could account for the missing clinical benefit immediately after TMR. At day 150, LCCs are healed as a fibrinous scar combined with both an extensive capillary network, which probably promotes myocardial microperfusion, and some adipocytes. This capillary network may result in better intramural microcirculation, which would explain a beneficial long-term effect of TMR, but clinically, the long-term benefit from TMR was dubious in the 150-day patient. On the other hand, the second cause for a positive long-term effect of TMR, a genuine link between endothelialized structures in laser-created scars and left ventricular cavity, is very rarely found at day 150. Taken together, our histological study clearly shows that LCCs are not patent and endothelialized after TMR in human nonresponder myocardium.

Channel patency after TMR is a subject of considerable controversy among cardiologists, cardiac surgeons, and pathologists involved with TMR-treated patients with cardiac disease. In the literature, the histological data on the patency of LCCs differ considerably. Hardy et al¹⁷ demonstrated partial patency of laser-created lesions for a 2-week period, after which they became fully occluded. In contrast, the patency of laser-induced endothelialized channels in dogs was observed 12 months after TMR.^{2 5} Cooley et al¹¹ reported anatomic evidence of channel patency in a patient who died after a post-TMR survival period of 94 days. The rheological consequences of patent LCCs in mongrel dogs were investigated by Hardy et al.⁸ It is possible, however, that patent endothelialized laser channels may produce a diastolic shunting effect under normal left ventricular pressure. Consequently, Hardy et al⁸ were unable to document improved perfusion via LCCs in normal myocardium exposed to acute coronary ligation. In contrast, Horvath et al⁶ established improved contractility, as well as diminished necrosis in the area at risk, after myocardial infarct in sheep. Recently, direct blood flow to the myocardium from the left ventricular cavity was demonstrated in rats.¹⁸ The crucial question of whether a true link exists among transmyocardial CO₂ laser use, coagulation, and angiogenesis or endothelialization of laser-induced myocardial necrosis is unresolved.^{19 20} All published studies on the laser-induced creation of endothelialized channels have been performed on animal models with acute ischemic cardiac disease, without possible changes in the wound healing in chronic ischemic myocardium taken into account. To estimate these effects, further investigations of long-term channel patency after TMR must be performed with animals that have chronic ischemic cardiac disease, such as pigs.

In the present study, an area of myocardial necrosis with a zonelike pattern around the LCCs was found that was likely to be temperature and pressure induced. There are two main effects of the interaction of laser radiation with tissue: (1) the energy can be absorbed and then reemitted as fluorescence at a longer wavelength, and (2) the energy can be absorbed and converted into heat with a resulting rise in tissue temperature.² Bromm and Treede²¹ described a skin temperature profile caused by a single CO₂ laser stimulus of 0.24 W/mm² with a 50-millisecond duration. Baseline skin temperature can be increased by twofold with the use of a laser depending on the depth. Comparative data about heart tissue do not exist. However, it is known that in animals, irreversible myocardial injury occurs within a temperature range of 52°C to 55°C.¹⁶ Furthermore, a reduction in myocardial microvascular perfusion observed during radiofrequency ablation appears to be thermally mediated and most probably occurs at temperatures of >45°C. In the present study, the Heart Laser system (1000 W/mm²; PLC Medical Systems Inc) was used, and our results indicate that the thermal effects on myocytes and connective tissue might be mediated over a longer distance than previously assumed.¹⁶ Furthermore, the lack of infiltrating erythrocytes and the negative Prussian blue iron staining around LCCs could be the result of thermally mediated laser-induced coagulation of LCC margins and sealing of small myocardial vessels within this diameter. Because light does not readily penetrate blood, the laser contact must be contiguous to the target tissue to prevent dissipation of the energy into the blood; therefore, the maximal tissue heating occurs at the point of laser contact, resulting in tissue vaporization. The laser energy dissipation into blood occasionally occurs in human myocardium and could induce the necrosis that was found around vessels. In conclusion, the laser-induced thermally mediated effects on myocytes are of great diversity and at present only incompletely understood.

Because the effects of laser energy application in creating endothelialized channels are possibly dependent on the different types of cardiac tissue remodeling, further investigations of the extracellular matrix in chronic ischemic cardiac disease would be useful. Furthermore, additional experimental studies are necessary to establish both the rheological consequences of patent LCCs and the laser-induced thermally mediated effects on myocytes. Also, it will be desirable to analyze the morphological basis for TMR-mediated effects in human responder myocardium.

We examined hearts from four patients who died from complications of chronic ischemic cardiac disease at 3, 16, and 150 days without clinical evidence for a persistent therapeutic effect after TMR treatment, respectively. Our histological data suggest, however, that the steps that occur after TMR are similar to those in wound repair after ischemic myocardial necrosis, ventriculotomy, or radiofrequency catheter ablation, all of which result in a fibrinous scar, and that the channels that were created were neither patent nor endothelialized. For future TMR applications, it is desirable to establish strict criteria for the selection of suitable patients for whom positive short- and long-term effects can be expected.

Received June 10, 1996; revision received August 14, 1996; accepted August 31, 1996.

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