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Ann Thorac Surg 1999;68:2376-2382
© 1999 The Society of Thoracic Surgeons

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Current Reviews

Transmyocardial revascularization: the fate of myocardial channels

^a Heart Institute, Good Samaritan Hospital and Department of Medicine, Cardiology Section, University of Southern California, Los Angeles, California, USA

Address reprint requests to Dr Whittaker, Heart Institute, Good Samaritan Hospital, 1225 Wilshire Blvd, Los Angeles, CA 90017-2395
e-mail: pwhittaker{at}dnamail.com

	Abstract

Top Abstract Introduction Histologic assessment of... Short-term results Long-term results Open versus closed channels Animal versus human hearts Conclusion References

 
Attempted cardiac revascularization through laser-made channels has gained considerable recent notoriety. Although the treatment reduces angina, its ability to enhance perfusion is unclear, and the mechanism of action unknown. The fate of the channels appears an obvious place to look for insight. Therefore, this review focuses on temporal and spatial changes in channel morphology. An appreciation of the natural history of the channels not only has potential to elucidate mechanisms, but also to provide the basis for optimization of channel-making.

	Introduction

Top Abstract Introduction Histologic assessment of... Short-term results Long-term results Open versus closed channels Animal versus human hearts Conclusion References

 
It is the customary fate of new truths to begin as heresies and to end as superstitions. Thomas Huxley

It is premature to describe transmyocardial revascularization (TMR) as a "new truth"; however, the label of heresy is perhaps appropriate. Moreover, one definition of superstition is, a false conception of causation, which may be applicable. The procedure’s heretical nature, coupled with the lack of an accepted mechanism, and the evangelical fervor of some proponents makes TMR an interesting, but controversial, topic. If TMR is to progress from heresy to truth, evidence and facts will be required. Resolution of the controversies surrounding TMR is not yet possible, therefore the purpose of this review is to bring together the available evidence to focus on one crucial component of TMR: the fate of myocardial channels. Specifically, I will examine what happens to channels in the short term (that is, in the first hours and days after they are made) and over the course of weeks and months. I will also consider differences and similarities between closed and open channels and between animal and human studies. The title of this review, the fate of myocardial channels, carries some negative connotations because fate suggests an inevitable and adverse outcome. Therefore, an additional aim is to demonstrate that the outcome of channel-making is not preordained, but is determined by the method used. However, before comparisons can be made, a basis for assessment should be established. Thus, the first section will lay a foundation for subsequent comparisons.

	Histologic assessment of channels

Top Abstract Introduction Histologic assessment of... Short-term results Long-term results Open versus closed channels Animal versus human hearts Conclusion References

 
When evaluating the fate of myocardial channels, it is crucial to have a means of assessing injury and also of examining the morphology of the changes that occur. The possession of such methods allows the crucial steps in the TMR process to be discerned and enables quantitative comparison of different channel-making methods.

Two stages in the TMR process contribute to the channels’ ultimate fate: injury and healing. The injury phase is important for several reasons. The treated patients do not have an abundance of viable myocardium and therefore, it would appear desirable to create channels with a minimal amount of surrounding muscle necrosis. The amount and also the type of injury will influence the healing response. For example, myocardial lesion size strongly influences the speed with which it heals; smaller infarcts heal faster than large infarcts [1]. Injury assessment can be made using polarized light. The application of this microscopy method to myocardial tissue in general and TMR-treated hearts specifically is illustrated in several articles [2–4]. These methods exploit the fact that heat disrupts the molecular structure of the heart’s two major structural components, muscle and collagen, changing the specific optical property of birefringence. Different changes occur at different temperatures. For example, irreversible muscle injury in the form of contraction band necrosis occurs between about 45 and 49°C producing focal increases in birefringence, degradation of muscle cell structure occurs around 65°C reducing birefringence, and collagen denaturation occurs around 70°C also reducing birefringence [2, 4]. These structural changes allow the extent and nature of thermal injury to be identified. Although the implications of thermal injury in terms of muscle necrosis are clear, the significance of thermal injury to collagen is not; however, it has been suggested that healing progresses differently when collagen is denatured [4].

In the healing phase, there are several important events. These include migration of fibroblasts and myofibroblasts into the wound, infiltration of cells associated with angiogenesis such as macrophages, endothelial cells, and mast cells, the presence and activation of growth factors, and collagen production. Fibroblasts and myofibroblasts have received almost no attention in TMR, even though these cells are crucial to collagen production and, as discussed later, can exert significant tractional and contractional forces capable of remodeling scars. Similarly mast cells, which are involved in angiogenesis [5], macrophages, which produce bioactive proteins [6], and endothelial cells, which line new blood vessels, have not been systematically examined in TMR. The cytokines involved in healing have also been neglected. One animal study of needle TMR used immunohistochemistry to detect the presence of transforming growth factor-ß and basic fibroblast growth factor [7]. Although the area of positive staining for antibodies to these growth factors increased with TMR, interpretation of the results is complicated because channels were made in tissue that was already dying after coronary artery ligation. Collagen examination has focused on measurement of the amount of scar tissue present at different times after TMR and will be discussed later.

Different healing responses to different lasers have been found in other fields. For example, dermal healing proceeded faster when lesions were created with an excimer laser than with a pulsed carbon dioxide laser, which in turn was faster than both continuous-wave carbon dioxide and holmium:yttrium-aluminum garnet (YAG) lasers [8]. These differences correlated with the amount of initial thermal injury: the smaller the injury, the faster the healing. Another dermal study found that carbon dioxide laser injury was associated with elevated levels of hyaluronidase, an enzyme important in tissue repair, versus that found after scalpel injury [9]. Therefore, it is likely that different TMR methods produce different tissue reactions. Quantitative histologic assessment will enable differences to be discerned and the optimal methods of channel-making determined.

	Short-term results

Top Abstract Introduction Histologic assessment of... Short-term results Long-term results Open versus closed channels Animal versus human hearts Conclusion References

 
There is no doubt that blood flows through channels immediately after they are made, as demonstrated by the pulsatile spurts of blood that frequently come from epicardial channel openings. However, a clot soon forms at the epicardial surface, but what then happens inside the channel has been the source of controversy. The early laser studies concluded, on the basis of improved survival after coronary artery occlusion in animals, that blood flowed from the ventricular cavity into the channels, and then through "sinusoids" into surrounding myocardium [10, 11]. However, these conclusions are not supported by studies that measured regional myocardial blood flow [12]. In addition, although sinusoidlike structures exist in reptilian hearts [13] and in some forms of human pathology [14], their existence in normal mammalian myocardium has never been substantiated [15]. Nevertheless, red blood cells can traverse the thermal injury surrounding channels and reach viable myocardium, but then become trapped in the interstitium [16]. Thus, there is no circulation. Furthermore, thermal coagulation of muscle and exposure of interstitial collagen by channel-making creates a thrombogenic surface. The time course of thrombus formation within channels can be constructed from reports of patients who died after TMR. However, only results of carbon dioxide laser treatment have been reported, and these comprise either single patients or small series. In a patient who died 2 hours after treatment with a carbon dioxide laser, each of the 15 channels made were still open and no fibrin thrombi were seen [17]. In the period from 1 to 10 days after treatment, the channels become occluded by a mixture of fibrin, polymorphonuclear leukocytes, macrophages, and foreign body giant cells [18–22]. The progression of these changes was reported to be slower if channels were made through scar or predominately fibrous myocardium [21, 22].

In contrast, data are available from animal studies using different lasers. However, most studies focused on either acute effects (within hours) or long-term changes (weeks). Channels made with carbon dioxide lasers in dog, pig, and sheep hearts examined hours after their creation contained red blood cells and fibrin [23–26]. Channels made in dog hearts with holmium:YAG lasers showed the same results [16, 23, 27]. Excimer laser channels in sheep hearts were completely occluded by clots at 72 hours [28]. Few animal studies have examined the 4- to 10-day period, but one reported a mixture of macrophages, polymorphonuclear leukocytes, fibroblasts, and endothelial cells occluding channels [24].

In conclusion, clots occupy the entire channel lumen within days after TMR in both animals and humans. Under these circumstances, there will be no blood flow through the channels, even if sinusoids did exist. In addition, the short-term thrombogenic response of diseased human and normal animal hearts appears similar.

	Long-term results

Top Abstract Introduction Histologic assessment of... Short-term results Long-term results Open versus closed channels Animal versus human hearts Conclusion References

 
After this early channel closure, there are two possible outcomes: either the channels remain closed or they reopen. However, each outcome contains several important issues.

Closed channels
There are three features of interest: channel appearance, scar shrinkage, and angiogenesis.

Channel appearance
As with short-term appearance, there are more similarities than differences when channels made in animal and human hearts are examined. In human hearts examined more than 3 weeks after carbon dioxide laser TMR, channels were filled first with granulation tissue and subsequently fibrosis [19–21, 29]. The fibrotic regions contained a capillary network and also vessels that possessed a tunica media. The same changes were found in animal hearts after carbon dioxide and holmium:YAG laser TMR [23, 30]. In fact, this healing response is not restricted to lasers, but has been found after channels were made using a drill [31]. In this study, channels were made in sheep hearts using a carbon dioxide laser and a power drill. Four weeks later, all channels were closed. The diameter of scar tissue was the same for both devices, as was vessel density within the scar. The investigators concluded that the response to TMR injury was nonspecific. Thus, in addition to the similar physical appearance of scar tissue found in human and animal hearts, the time course of healing is also comparable.

Scar shrinkage
Scar tissue shrinks in many organs with time because of the mechanical action of fibroblasts and myofibroblasts [32]. Such shrinkage also occurs in the heart, often to an appreciable degree [1]. After the creation of laser channels, scar volume is substantially reduced. For example, Fisher and colleagues [23] found that the average area occupied by thermoaccoustic injury measured hours after creation of channels with a holmium:YAG laser decreased over 6 weeks to give a scar that occupied only 7% of the original injured area. Although a carbon dioxide laser caused significantly less initial injury, the shrinkage was similar in percentage terms (86% versus 93%). This pronounced contraction may cause channel closure. In addition, it is likely that scar contraction affects the surrounding tissue by distorting cellular organization. Disruption of muscle’s normal parallel alignment has been found adjacent to infarct scars [33]. This structural remodeling may be responsible for the dyskinesis often reported in the periinfarct region and may also provide a substrate for the genesis of arrhythmias. Similar adverse effects might occur after channels are made, because similar cellular disarray was found adjacent to TMR scars [34]. Individually, none of these scars will be as large as that produced by coronary occlusion; however, 20 to 40 channels are usually made and therefore, the total volume of necrosis could be large. Nevertheless, there have been no indications that scar contraction-induced dyskinesis or arrhythmias have been a problem in TMR. There are several possible explanations. The effect may be small and, in the context of the severe cardiovascular disease in these patients, any effect may be obscured by the existing disease. It is also possible that the contraction could be positive, reducing ventricular dimensions. Even if ventricular size is unchanged, the presence of a large number of what are essentially collagenous posts may limit cardiac expansion by increasing myocardial stiffness. Neither possibility has been examined, probably because emphasis has focused on detection of improved blood flow, an approach derived from the original "sinusoid" concept of TMR. Therefore any benefit, such as improved survival in animal studies and decreased angina in clinical studies, has usually been ascribed to improved perfusion.

New blood vessels
The feature of closed channels that has attracted most attention is the presence of blood vessels within TMR scars. The growth of these vessels has been interpreted as providing an explanation for positive clinical results. However, new vessel growth is a feature of many repair processes in the body including the heart [35], and therefore, should not be considered a surprise after TMR. Several researchers have also been excited by the apparent high vascular density within the scar. The appreciable scar contraction that occurs after TMR was discussed in the preceding section. Thus, if the original scar contained a certain number of vessels per square millimeter, scar contraction results in a significant increase in apparent density. Kohmoto and associates [30] found a significant increase in vascular density adjacent to closed channels with laser treatment, but no difference between carbon dioxide and holmium:YAG lasers. However, the potential influence of scar shrinkage on surrounding tissue was not considered.

After myocardial infarction, there is a change in the distribution of vessel diameters. In noninfarcted myocardium, Kramer and colleagues [36] reported that the majority of vessels had a diameter of less than 5 µm, that is, capillaries. In contrast, scar tissue contained a greater proportion of vessels with diameters larger than 5 µm. Although such analyses have not been performed for TMR, examination of published micrographs indicates a similar shift in vascular dimensions. Even if the apparent vascular density increase with TMR is real, the ability of such vessels to increase blood flow in compromised myocardium appears questionable. To increase blood flow to the treated region, the vessels must connect to regions where blood is not in short supply. If these vessels merely connect to other vessels within the treated area, then all that will be accomplished is redistribution of the limited blood flow that was available within the region before treatment. It is difficult to imagine how such redistribution will help.

Open channels
Early experimental laser TMR studies purported to show channels that were open months after they were made [10, 11]. These observations were in contrast to most needle TMR studies, in which channels closed within a few weeks [37]. The suggested explanation was that the laser, in these cases a carbon dioxide laser, caused less damage to surrounding tissue than the needle-based methods. It was on the basis of such reports in animal hearts that human trials began.

However, subsequent evaluation of carbon dioxide lasers in animals indicates that channels become permanently occluded by fibrosis after about 2 weeks. The reasons for such discrepancies are unknown; however, there are several explanations. The laser "dose" used to make channels in the early studies was not the same in the later studies. In fact, there are many important dosage variables: pulse energy, width, and density, spot size, continuous versus pulsed irradiation, and wavelength. The literature contains examples of laser effects that could not be duplicated when one or more of these variables was altered. The other confounding issue is channel identification. Pericardial adhesions often make it impossible to identify epicardial entry points. In addition, the trabeculated endocardial surface can hide the exit point, and within the myocardium, scar shrinkage hinders channel identification.

In the absence of gross identification, histologic examination is used; however, even this has the potential to mislead. For example, the first choice is whether to section parallel or perpendicular to the channel. Perpendicular cuts have the advantage of increasing the likelihood of "capturing" channels in a single section. On the other hand, studies have found large cisternlike structures in scar tissue associated with the original channel, although the channel was closed [23]. The appearance of such structures in a perpendicular section plane gives the false impression of open channels. Thus, serial sectioning to the endocardium is necessary before conclusions regarding patency are made. The parallel cut has the advantage that the channel connection (either open or closed) to the ventricular cavity can be identified. On the other hand, serial sectioning of many ventricular slices is necessary to examine the entire treated region. This method is labor intensive for rat hearts and becomes more so when larger animals are used.

It is also possible to interpret naturally occurring features as open channels. For example, gaps between muscle fascicles look like open, collagen-lined channels (Fig 1A). In untreated human hearts, naturally occurring "channels" have been found [38] that bear a striking resemblance to purported open laser channels [39, 40]. For these reasons, serial sectioning to identify the entire transmural length and three-dimensional reconstruction of supposed channels is imperative before conclusions are made [41].

View larger version (60K): [in this window] [in a new window]   Fig 1. Rat heart 2 months after transmyocardial revascularization with a frequency-tripled neodymium:yttrium-aluminum garnet laser. Tissue stained with picrosirius red: collagen, red; muscle, yellow. (A) Open channel created with a 600-µm optic fiber (maximum width, 45 µm). In this section, open channel segments appear in the midmyocardium; however, serial sectioning confirmed patency from the ventricular cavity to the subepicardium and discriminated between laser channels and natural structures. The apparent channels marked by arrows are natural indentations of the endocardium (bar, 200 µm). (B) Open channel in the midmyocardium from a different heart. The channel was created using a 400-µm diameter optic fiber (maximum width, 80 µm). Collagen fiber alignment parallel to the channel’s long axis can be seen most easily along the "lower" side of the channel. Serial sectioning confirmed an open connection to the ventricular cavity (bar, 50 µm).

View larger version (148K): [in this window] [in a new window]   Fig 2. Rat heart stained with hematoxylin and eosin and examined 86 days after transmyocardial revascularization with an excimer laser. Numerous vascular connections to an open channel (maximum width, 80 µm) can be seen. Serial sectioning confirmed patency across more than 75% of the wall thickness with an open connection to the ventricular cavity (bar, 20 µm).

	Open versus closed channels

Top Abstract Introduction Histologic assessment of... Short-term results Long-term results Open versus closed channels Animal versus human hearts Conclusion References

 
Why do some channels close while others reopen? As mentioned, the tissue from animal experiments has been examined either hours or weeks after channels were made. Tissue examination at intermediate time points has not been done. Therefore, how the fibrin network is removed and the channel reopened is unknown. It is possible that collagen organization within the scar determines whether or not channels close. In an examination of scar structure several months after TMR with an ultraviolet frequency-tripled neodymium:YAG laser, substantial differences were found between open and closed channels [42]. Collagen fibers adjacent to open channels were aligned parallel to the channel’s long axis (Fig 1B). In contrast, collagen fibers in closed channels were aligned perpendicular to the channel’s long axis. Whether such organization represents cause or effect is unknown.

The difference between open and closed cannot simply be attributed to the use of different devices. For example, in our studies, both open and closed channels were found using the same device at the same dose under the same conditions [42, 45]. In these instances, the difference was attributed to the optic fiber advancement rate. The advancement was manual and with the laser firing at 20 Hz, any hesitation increased the amount of energy deposited in the tissue and hence increased thermal injury. Similarly, mechanical TMR has produced both open and closed channels [28, 34]. There are clearly many variables in TMR that have yet to be controlled or perhaps even appreciated.

The mechanisms responsible for the clinical benefits found with TMR are unknown. Therefore, it is not possible to say whether open or closed channels are better. However, some conclusions can be made. If open channels are not required for clinical efficacy, then there are no data to suggest that lasers provide an advantage over other methods. The qualitative appearance of the closed channels obtained with a drill was the same as that obtained with a laser. Nevertheless, it should be emphasized that qualitative similarities may contain real differences when quantitative analysis is applied.

	Animal versus human hearts

Top Abstract Introduction Histologic assessment of... Short-term results Long-term results Open versus closed channels Animal versus human hearts Conclusion References

 
The frequent failure to obtain positive results in animals using the same device at the same dose used in clinical studies with positive results has been attributed to differences between normal animal and diseased human hearts. This argument has relevance not only because myocardial structure differs, but also because the injury response will differ. In terms of structure, the collagen content of diseased human hearts is greater than that of normal animal hearts. This difference could be significant because collagen is harder to ablate than muscle and contains less water. The latter fact is important because the infrared lasers most commonly used for TMR rely primarily on water absorption to achieve ablation [46]. Thus, the ablation rate and efficiency for these lasers will be reduced in collagenous hearts. Another structural difference is that human hearts often have a substantial layer of epicardial fat. This can cause problems for infrared lasers, especially carbon dioxide lasers that cannot couple to optic fibers. In one clinical study, to compensate for the presence of fat, pulse energy was increased from 40J to 60J [47], which allows penetration of the fat layer, but increases thermal damage.

The second difference is injury response. Diseased human myocardium contains increased levels of cytokines, for example, basic fibroblast growth factor [48]. Thus, the tissue may be "primed" to respond to TMR injury. On the other hand, blood flow in this region is compromised and therefore, healing may be slower than in normal hearts.

Although the arguments concerning differences between normal animal and diseased human hearts are logical, histologic examination suggests that these differences may be minimal. As described above, the appearance of tissue after carbon dioxide laser TMR in animal and human hearts is similar. The channels are closed, the scar looks the same, as does the angiogenic/vasculogenic response. In an attempt to duplicate the human disease state, several groups have examined TMR after placement of ameroid constrictors on coronary arteries. Although data from these animal studies have so far only been presented in abstracts, the channel appearance appears to be the same as that in normal hearts [49]. If these findings are substantiated, it would lend further support to the concept that channel-making in animal hearts does not differ from that in humans. However, some have argued that examination of human autopsy samples is misleading because these patients died, and hence represent treatment failures. This question should be resolved when tissue from patients that benefited from TMR, but died of noncardiovascular causes, is examined.

	Conclusion

Top Abstract Introduction Histologic assessment of... Short-term results Long-term results Open versus closed channels Animal versus human hearts Conclusion References

 
Huxley also wrote, "the great tragedy of Science—the slaying of a beautiful hypothesis by an ugly fact." The facts have been "ugly" enough to slay the original hypothesis of immediate blood flow through open channels. Nevertheless, pronounced reductions in angina are found soon after channels are made. That these channels become occluded in the short term by clots no matter what method is used, and that they then either reopen or become permanently occluded by fibrosis indicates the need for new hypotheses. This suggestion comes from the realization that the fate of all channels is not the same. Whether the channel is eventually open or closed, or whether there is a large or small amount of scar contraction, appears to be determined by the amount (and perhaps the type) of injury to the surrounding tissue. The divergence of tissue response to TMR suggests that once we discover the mechanisms, the type of channel can be tailored to fit the specific requirements. However, the multidisciplinary nature of TMR suggests that mechanisms will most likely be determined only through the combined efforts of scientists from many different disciplines. Thus, whether this particular heretic will be figuratively (and perhaps literally) burned, or whether it will cut through to the truth is still to be determined.

	Acknowledgments

 
I thank Seda Dzhandzhapanyan for assistance with histology. Peter Whittaker is an Established Investigator of the American Heart Association.

	References

Top Abstract Introduction Histologic assessment of... Short-term results Long-term results Open versus closed channels Animal versus human hearts Conclusion References

 

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