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Right arrow Coronary disease

Ann Thorac Surg 2002;74:956-970
© 2002 The Society of Thoracic Surgeons

Review

35 years of experimental research in transmyocardial revascularization: what have we learned?

Menno Huikeshoven, MS*a,b, Johan F. Beek, MD, PhDa, Jos A.P. van der Sloot, MDb, Raymond Tukkie, MD, PhDb, Jan van der Meulen, MDc, Martin J.C. van Gemert, PhDa

a Laser Center, University of Amsterdam, Amsterdam, The Netherlands
b Department of Cardiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
c Department of Cardiothoracic Surgery, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands

* Address reprint requests to Mr Huikeshoven, Laser Center, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands
e-mail: m.huikeshoven{at}amc.uva.nl


   Abstract
Top
 Abstract
Introduction
 Methods of channel creation
 Hypotheses of working mechanisms...
 Conclusion
 Acknowledgments
 References
 
In the past 35 years many experimental studies have been performed to investigate the revascularization potential of transmyocardial revascularization and the possible working mechanisms underlying the observed clinical improvement in angina pectoris after this treatment. In this review of the experimental literature, the various methods that have been used to create transmyocardial channels and the most supported hypotheses on the working mechanism (channel patency, angiogenesis and myocardial denervation) are discussed and evaluated.


   Introduction
Top
 Abstract
 Introduction
Methods of channel creation
 Hypotheses of working mechanisms...
 Conclusion
 Acknowledgments
 References
 
Transmyocardial revascularization (further referred to as TMR, which includes all methods of transmyocardial channel creation) has been a controversial therapy since it was first described by Sen and colleagues [1] more than 35 years ago. Their technique was based on the creation of small channels in ischemic myocardium by mechanical puncturing aimed to reduce anginal pain. TMR was later modified by Mirhoseini and Cayton [2] who used laser irradiation, which is still the most widely used method for channel creation. The controversy surrounding this so-called transmyocardial laser revascularization (further referred to as TMLR) stems from the fact that 18 years after its first clinical application [3], the mechanism of action by which the relief of angina is achieved is still unclear. The three major hypotheses include direct ventriculomyocardial blood flow through patent channels, angiogenesis leading to increased perfusion, and myocardial denervation leading to a decreased pain sensation.

The objective of this review is to give an overview of the animal experimental research (referred to as experimental research as opposed to clinical research) that has been published. The organization of this manuscript is as follows. First, a description of the various methods that have been used to create transmyocardial channels is given (together with a paragraph on laser-tissue interaction); and second, the most supported working-mechanism hypotheses are discussed and evaluated based on the experimental findings.

In this review, books, journal articles, reviews, and meeting abstracts reporting on experimental work are included. The literature acquisition was performed in the "1966 through May 2001" database of Medline (currently available through PubMed: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi) and the "all years" database from the Web Of Science (http://wos.library.tudelft.nl/CIW.cgi). The following keywords were used in the searches (both in American and Oxford English): transmyocardial laser revascularization, laser myocardial revascularization, transmyocardial revascularization, direct myocardial revascularization, percutaneous laser revascularization, percutaneous myocardial laser revascularization, percutaneous myocardial revascularization, TMLR, TMR, PMR, and DMR.


   Methods of channel creation
Top
 Abstract
 Introduction
 Methods of channel creation
Hypotheses of working mechanisms...
 Conclusion
 Acknowledgments
 References
 
As already mentioned, hollow needles were the first devices used. Many investigators have used this method for the creation of transmyocardial channels both in early research as well as more recently [1, 4–6]. In experimental research, several other methods of channel creation have been used such as a power drill [7], myocardial channeling devices [8, 9], ultrasound [10], cryoapplication [11], high or radiofrequency [12, 13], saline jets [14], and lasers (see below). In the past few years, endocardial nontransmural (as opposed to epicardial and transmural) channel creation has received growing interest (Fig 1). This technique, called percutaneous myocardial revascularization (PMR), is performed through cardiac catheterization and is therefore less invasive. Detailed descriptions of this clinically and experimentally used technique and its results have been provided elsewhere [15]. Furthermore, in addition to the currently widely used combination of laser treatment as an adjunct to coronary bypass surgery [16], recently combinations of laser energy and growth factor administration also have been applied to induce angiogenesis [17–21].



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  		Fig 1. The number of publications on transmyocardial revascularization (TMR) and percutaneous myocardial revascularization (PMR) between 1981 and 2000 is shown. Included are all forms of publications, clinical and experimental, that were acquired from the literature search, which included journal articles, meeting abstracts, letters, replies to letters, conference discussions, reviews, and editorials. The data for 2001 were acquired by doubling the number of publications in the first 6 months of this year.

 
Lasers
Table 1 gives an overview of the lasers used in clinical and experimental TMLR. The carbon dioxide (CO2) laser was the first laser used for TMLR and is still the most widely used. Initially, an approximately 400 W CO2 laser was used, which required an arrested heart since long pulses were needed to penetrate completely through the myocardium. Subsequently, it became possible to perform the procedure on the beating heart with the development of a high power (800 to 1000 W) CO2 laser (PLC Medical Systems). This laser could create a transmyocardial channel in one single (50 ms) pulse, within the refractory period of the cardiac cycle. The second type of laser that was used in clinical TMLR is the mid infrared solid-state holmium:yttrium-aluminum-garnet (Ho:YAG) laser. The third and clinically least used type of laser for TMLR is the ultraviolet Xenon Chloride (XeCl) excimer laser. These latter two lasers deliver a train of short (ns-ms) pulses through a flexible fiber to the myocardium. Several other lasers have been used in experimental research such as the regular [23] and frequency-tripled [24] neodymium:YAG (Nd:YAG), the thulium-holmium-chromium:YAG laser (THC:YAG) [25, 26] and the Erbium:YAG laser (Er:YAG) [27].


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  		Table 1. Lasers Used in Clinical and Experimental Transmyocardial Laser Revascularization

 
Laser-tissue interaction
The various lasers described in Table 1 can induce a large variety in channel shape and diameter and in extent of thermal and mechanical damage adjacent to the channel, depending on laser and tissue properties.

Laser variables that influence treatment outcome include the delivery of the radiation to the myocardium (waist length and diameter of the beam, or in case of fiber delivery, index of refraction, diameter and shape of the fiber tip or intensity profile in air and myocardium), the laser wavelength, power (continuous wave) or peak power (pulsed), the duration of irradiation, and the interval between pulses. Relevant tissue variables include optical properties of the myocardium (scattering, absorption, and index of refraction); thermal properties such as initial tissue temperature, specific heat, heat capacity, thermal conductivity, blood perfusion and its dependence upon temperature in vessels and left ventricle (heat convection), heat exchange with the environment (eg, transport of steam and ablation gases to surrounding myocardium, left ventricle or operating room); mechanical properties (eg, elasticity and contractility); and finally biological properties, including myocardial susceptibility to heat and wound-healing characteristics. These factors determine the vaporization or ablation rate, the temperature evolution of a tissue volume, the resulting thermal damage, and the photoacoustic as well as gas-expansion-induced forces on the tissue and the resulting mechanical damage.

In other words, myocardial tissue is a complex medium and many of the optical-thermal events produced by laser irradiation are interdependent. However, for the sake of simplicity, let us assume that the optical, thermal, mechanical, and biological properties of treated myocardium are identical in all experiments (which they are not) and that channel shape and thermal and mechanical damage only depend on the laser and laser settings. Let us further assume that for one specific laser a fixed method of irradiation is used (eg, direct illumination for CO2 TMLR or delivery by bare fiber for XeCl excimer or Ho:YAG TMLR). The main variables that determine the outcome of the treatment would then be the laser wavelength, the incident irradiance and the exposure time. These variables are discussed below.

Wavelength
Optical properties of myocardium are wavelength dependent. The large variation in (estimated) absorption coefficients of myocardium at the various wavelengths (Table 1) gives an indication of the importance of this variable. In the ultraviolet (eg, XeCl excimer laser), absorption is relatively low in water but high in proteins, nucleic acids, and blood. As a result, the penetration depth of ultraviolet light is small, ie, inversely proportional to absorption. Lasers in the visible and the near-infrared (Nd:YAG laser) penetrate much deeper and are therefore not ideal for removal of myocardium by vaporization or ablation (predominant absorption in hemoglobin and oxyhemoglobin). Other infrared wavelengths (eg, Ho:YAG and CO2 laser) are absorbed predominantly in water. In this wavelength region water absorption is high compared to the ultraviolet and visible part of the electromagnetic spectrum and consequently, the penetration depth is small and local heat production can be very high.

Incident irradiance
The deposited energy in a myocardial volume (which is proportional to the heating rate) is proportional to the local absorption coefficient and the local intensity of light per second. A high local intensity at a wavelength that is sufficiently absorbed by the myocardium results in rapid heating. In the case of predominant absorption in water (eg, in CO2 TMLR), the water is vaporized, followed by photothermal disruption of the myocardium. The production of steam will lead to a pressure increase in the tissue and ejection of steam from the tissue, including tissue constituents, predominantly at the epicardial side of the heart. This plume has a temperature of 135°C or more and during the pulse or pulse train, this steam will heat up the inside of the channel that is created, resulting in a larger zone of thermal damage at the epicardial side of the channel than at the endocardial side [28]. The mechanisms for removal of myocardium by ultraviolet radiation are less clear. It has been demonstrated [29] that the hypothesis of bond-breaking mechanisms in tissue by XeCl excimer laser pulses [30, 31] is not very effective. More likely therefore is a photothermal mechanism, ie, a mechanism similar to the one described above (vaporization followed by photothermal disruption).

Exposure time
If TMLR is performed on a beating heart (which is mostly the case in stand-alone TMLR procedures), in order to minimize risk of arrhythmias the pulse duration must be shorter than the absolute refractory period of the cardiac cycle. Therefore, at perioperative heart rates, laser irradiation in patients is limited to 100 to 150 ms after the R wave (eg, 50 ms for the PLC Heart laser). In (experimental) CO2 TMLR using larger animal models, similar pulse durations are used. In smaller animal models with higher heart rates, often shorter pulse durations are used to perforate myocardium of limited thickness. During one single ms pulse, the myocardium is heated long enough to allow heat diffusion and thermal damage of tissue adjacent to the channel. The shape of a channel created with a single (CO2 laser) irradiation in most cases is relatively straight and resembles a rod or cone. The design of some lasers is such, that only pulsed laser irradiation can be generated. The rationale of using a sequence of multiple ns or µs pulses within the absolutely refractory period of the heart can be removal of (hot) tissue before heat is transferred to surrounding tissue (this is often not the case in TMLR). The shape of a channel created with multiple short pulses often is not straight and its contour can resemble a string of beads. Furthermore, each ns pulse can produce a photoacoustically induced shockwave that can create microtears in the myocardial tissue. Previous work [32, 33] showed that with pulse frequencies higher than 5 Hz, thermal accumulation is likely.

In this review, we have considered the above-described laser variables carefully. Although the range of incident irradiance and exposure time (which is proportional to the deposited energy) is broad, at the used wavelengths vaporization or ablation of myocardium was achieved in all experimental TMLR studies (which is only possible at sufficient deposited energy). Therefore we have focused the comparison between studies on laser wavelength.


   Hypotheses of working mechanisms underlying the clinical improvement
Top
 Abstract
 Introduction
 Methods of channel creation
 Hypotheses of working mechanisms...
Conclusion
 Acknowledgments
 References
 
The patent channels hypothesis
The initial hypothesis from which the treatment has originated was based on the description of myocardial sinusoids by Wearn and colleagues [34] in 1933. In reptilian (and some amphibian) hearts perfusion through these sinusoids provides the majority of blood delivery to the myocardium. The (small) rest perfusion is delivered through an underdeveloped coronary artery system [1]. The aim of TMR was to establish connections from the left ventricle to these sinusoids in the human heart by creating transmyocardial channels. The concept was that these myocardial channels would occlude at the epicardial side, endothelialize and connect to the sinusoids and possibly to the native coronary artery system. The myocardium would then be supplied with oxygenated blood through direct perfusion from the left ventricular cavity. The research on this hypothesis has mainly been focused on the (short- and long-term) patency of the channels and the flow of blood through these channels.

Patency has been a subject of controversy ever since the first report on open transmyocardial channels. In these studies needles were used in canine hearts and at follow-up times of up to 11 months patent channels containing erythrocytes were found [1, 4, 35, 36]. Although these first "myocardial acupuncture" results fueled the hypothesis of direct perfusion, other studies that also used needles reported occluded channels in the postoperative period [5, 37, 38]. This indirectly led to the use of laser irradiation as an alternative method of channel creation, based on the observation that carbonization associated with laser energy inhibits lymphocyte, macrophage, and fibroblast migration. That would cause channels to heal slower and with less scar formation, facilitating endothelialization, and subsequently improve patency. Using both infrared and ultraviolet lasers, several experimental studies have reported some form of patent channels (ranging from a few microns to 1 mm in diameter) at short- and long-term follow-up. A wide variation of animal species was used in these studies including dogs [2, 25, 39, 40], sheep [41–43], swine [44], and rats [24]. Only one of these studies used a chronic ischemia model [43], which shows pathologic similarities (hibernation) to the human heart. In all other studies acute ischemia models (coronary artery ligation in otherwise healthy hearts) were used. Because the response to injury may differ significantly between acute and chronic ischemic myocardium [45], the acute ischemia results may have less value when extrapolated to the clinical application.

Furthermore, in the studies that reported open channels, the efficacy of TMR was usually evaluated by its limiting effect on infarct size before or after induction of acute ischemia. Most studies showed less infarction in TMR-treated animals and concluded that this could be contributed to patent channels. When using infarct size as a measure, an important characteristic of the animal model used should be a minimal (native) collateral circulation that could contribute to perfusion of the acutely ischemic myocardium. However, the majority of the studies that reported smaller infarction after TMR were performed in canine and ovine hearts, species that have been reported to have strongly varying and sometimes extensive collateral circulation [45]. Thus it can be doubted whether protection against infarction in these models is due to functional open channels.

In contrast to the reports on patent channels, many other studies have reported occluded channels in the postoperative period. These occluded channels were found after both infrared and ultraviolet TMLR in canine [38, 46–51], porcine [17, 27, 52–55], ovine [7, 56, 57], and rat [6, 58] studies. Therefore patency cannot be as important as initially thought, which is supported by clinical observations showing that occluded channels were found at various follow-up times after CO2 [59–61] or excimer [62] TMLR in the majority of clinical postmortem reports. Further details on the histology of channel patency and the long- and short-term fate of transmyocardial channels have extensively been described elsewhere [63].

Even if transmyocardial channels would remain patent and endothelialize, effective myocardial perfusion and flow of blood through such channels is doubtful. Although there can hardly be any doubt that blood flow through the channels is present immediately following creation (indicated by the pulsatile spurts of blood coming from the epicardial openings), conflicting results were found in studies investigating the physiologic possibility and presence of this flow at longer follow-up. For instance, using canine hearts, Okada and coworkers [39] claimed flow through channels when they found intraventricularly injected methylene blue in patent laser channels at 3-year follow-up. Contesting this theory, Pifarré [5] stated that flow from the cavity into the channels was a physiologic impossibility because the pressure in the cavity is usually less than the intramyocardial pressure surrounding the channels. However, we acknowledge that intramyocardial pressure may be decreased and left ventricular pressure increased owing to ischemia [41]. Support for the statement of Pifarré comes from several experimental studies that investigated the acute effect of TMR on myocardial perfusion, because none of these studies has demonstrated any acute improvement (Table 3), which is expected immediately if patency is the mechanism of action.


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  		Table 3. Reported Perfusion in Animal Studies

 
Another argument contesting the effectiveness of transmyocardial channels in directly and effectively oxygenating the myocardium is that the total internal surface area of the channels is less than 0.01% of the internal surface area of the capillaries within the left ventricular myocardium [64]. Therefore any blood flow through the channels would contribute minimally to the actual oxygen exchange (unless patent intersections with nearly all traversed capillaries would be present).

Over the years the conflicting experimental findings regarding the patency of laser channels and their (in)ability to increase the blood flow to ischemic myocardium gradually led to the rejection of this hypothesis.

The angiogenesis hypothesis
Angiogenesis as an explanation for the efficacy of TMR has two sides: an (anatomical) increase in vascular density and an increase in perfusion.

Vascular density
Table 2 summarizes results of experimental studies in canine, porcine, ovine, rat, and mouse models, with or without acute or chronic ischemia, on the occurrence of angiogenesis in and around TMR channels. Although many different methods have been used (needles, different lasers, radio frequency [RF] energy, growth factors and even a power drill), an almost universal finding has been the filling of the original channel with scar tissue. In this scar tissue high concentrations of vascular structures ranging from capillaries to small arterioles have been found and it has been hypothesized that these new vessels may increase the perfusion in and to the ischemic myocardium. The increase in vascular density in the treated area is believed to be induced by a local inflammatory response, which induces a locally enhanced production of vascular growth factors by the inflammatory cells. Comparison of the published studies (Table 2) is complicated by differences in methodology and presentation of the results. Although all but one studies described to have found angiogenesis, in a substantial number (12 out of 28) the actual number of vessels was not reported. This was either because quantification was not performed [47, 48, 51, 68, 71], relative vascular density measurements were reported [17, 42, 72], or only significant increases without providing the numbers of vessels were reported [19, 27, 67, 76]. Although in the remaining studies quantification was performed, controls were used, and vessel numbers were provided, comparison remains difficult since they used different methods (which counted different structures) and a huge variation in numbers of vessel was presented. Generally, either several types of vessels or only vessels with at least one smooth muscle cell (SMC) layer were counted. Results were presented as the number of vessels per high power field (HPF) or the number of vessels per square unit (mm2 or cm2). For comparison between studies, the vessel per square unit method is most useful since the size of a HPF not only depends on the magnification (here varying from x10 to x400) but also on the microscope used. In the six studies in which at least one SMC layer was counted, five used the number per cm2 which were all in the same order of magnitude (110 to 197 vessels/cm2) [13, 21, 49, 50, 74]. Contrasting, in the group that counted several types of vessels (using either endothelial, growth factor or basement membrane staining methods), seven used a HPF [8, 54, 65, 66, 69, 70, 75] and only three presented a number per square unit (mm2). Two of these three used a von Willebrand factor (vWF/F VIII) staining and reported the overall density of vessels (claiming that capillaries, small arteries and veins were included) [73, 77] while the third used a basement membrane staining and only reported the density of capillaries [6]. Interestingly, this last study is the only one (of 28) that did not report an increase in (capillary) density after TMR. Since this is also the only study that presented a baseline (capillary) density consistent with accepted values ( > 2000/mm2), probably none of the other studies included capillaries in their assessment of vascular density.


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  		Table 2. Reported Angiogenesis in Animal Studies

 
Besides the methodology of the studies several other points are worth considering. First, it is interesting to know whether the reaction is laser specific or whether other devices can induce the same effects. Results of studies that investigated the angiogenic effect of lasers compared to nonlaser devices are conflicting. Only one study found a difference in angiogenic effect between laser and nonlaser devices [42] whereas several others did not [7, 54, 74]. The experimental studies that have compared different lasers reported similar effects of CO2, Er:YAG, and Ho:YAG lasers on angiogenesis [27, 47, 49]. One study has compared all three clinically used laser types and found neovascularization in CO2 and Ho:YAG treated hearts but not following excimer TMLR and sham treatments [76]. So far, virtually all devices that have been investigated for TMR have been able to induce angiogenesis in some form. Because it is impossible to draw a conclusion on which method is most effective, we and others [7] believe that angiogenesis may be just a nonspecific healing response to myocardial injury.

Second, it is crucial that the newly created vessels connect the hypoperfused regions to areas of the ventricle that are adequately perfused. An important point here is the extent to which the neovascularization/angiogenesis expands into the myocardium surrounding the channels. Again, conflicting results have been reported. Several studies have reported neovascularization limited to the channel remnants [51, 73]. Others reported extension of neovascularization up to 5 mm adjacent to the channel remnants [72]. In these two situations the extent of "angiogenic revascularization" differs dramatically. If for instance one channel of 1 mm diameter is created per cm2 (the clinical standard) in 1 cm thick ischemic myocardium and neovascularization is confined to the channel remnant, approximately only 0.8% of the ischemic area is "revascularized." If, however, the neovascularization extends 5 mm from the channel center into the surrounding myocardium the effectively "revascularized" area increases 100-fold to approximately 80% of the ischemic area. As this would highly increase the probability of connection to normally perfused regions, it seems obvious that the credibility of the angiogenesis hypothesis requires extension of neovascularization outside the channel remnant.

A third point is the time span in which the increased vascular density develops, which is species dependent (generally the smaller the animal, the quicker the neovascularization develops), and even more important, how long it lasts. Increased vascular density has been described at time intervals ranging from 1 week [54, 65, 67] to 6 months [75, 76]. The studies that evaluated different time points within one protocol have all shown an initial increase in vascular density followed by a relative decrease (although in all studies still higher than in controls) after several weeks [47, 65–67]. This can be explained by the role of growth factors (GF) and wound remodeling after TMR. In the initial phase after injury an inflammatory reaction of the myocardium leads to an increase in GF production by inflammatory cells. This is confirmed by several studies that found increased growth factors such as VEGF, bFGF, FGF-2, and TGF-ß up to 6 weeks after TMR [54, 66, 67, 69]. We hypothesize that, normally, after some time the inflammation will decrease, less inflammatory cells will be present and the GF production will return to baseline. In the following process of wound remodeling, scar tissue may cause a portion of the new vessels to occlude, thus decreasing the vascular density. Although this may seem like "losing of benefit," if the initial increase is high enough the net result can still be positive. This is confirmed by the already mentioned findings of increased vascular density (versus control) up to 6 months. Thus, from these studies we hypothesize that after the initial inflammation-induced increase and the subsequent (wound) remodeling-induced decrease a new (lasting) steady-state in (increased) vascular density is reached. The degree of vascular density in this steady-state may be one of the determinants for the lasting efficacy of the treatment.

Recently, several investigators have taken another new step in optimizing the angiogenic response of TMR by administering vascular growth factors as an adjunct to channel creation. This enhances the angiogenic response [19, 21], although not for all types of growth factors [17].

To conclude, although a formation of new vessels (larger than capillaries) is demonstrated after TMR by most studies and these results support the angiogenesis hypothesis as far as vascular density is concerned, the comparability between studies is low and most results (from 20 out of 28 studies) can only be used for comparison within the same study. Furthermore, from the results that are currently available the optimal "angiogenesis-inducing" device cannot be identified. Because it is not known what kind of damage (thermal/mechanical or other) gives the optimal angiogenic "trigger," knowledge of the differences in laser-tissue interactions may yet be of limited use to identify the optimal device.

Perfusion
An increased local perfusion due to increased vascular density is essential to the angiogenesis hypothesis and two mechanisms have been suggested. First, myocardial perfusion could increase through new vessels connected with the normally functioning native vessels surrounding the ischemic myocardium; and second, local perfusion could increase through redistribution of perfusion within the ischemic myocardium [78]. Physiologically, redistribution is more likely since myocardial ischemia is often not completely transmural but predominantly endocardial. As mentioned earlier, the channel patency hypothesis does not comply with the results of acute perfusion studies (Table 3). However, the absence of acutely increased perfusion in these studies does comply with the angiogenesis hypothesis. Furthermore, results from studies with a longer follow-up (ranging from 4 to 26 weeks) also comply with the angiogenesis hypothesis because these studies have all shown a significant improvement in perfusion. This improvement has not only been reported in studies that used microspheres (which are limited to experimental research) but also in studies that used clinically accepted perfusion assessment techniques such as positron emission tomography (PET) and Tc-sestamibi scintigraphy. Interestingly, the acute studies have mostly used canine models whereas the long-term studies have mostly used porcine models. This increases the validity of the perfusion studies since the acute studies lacked improvement in perfusion in a model which has been reported to have strongly varying and sometimes extensive collateral perfusion (canine), whereas in the long-term studies improvement was shown in a model that is known to have little collateral perfusion (porcine). Furthermore, the studies with a long-term follow-up all used chronic ischemia models, which augments comparability with cardiac pathology in TMR patients.

Long-term studies, separately using the CO2, Ho:YAG, and excimer laser have all reported significant improvement in perfusion. Furthermore, studies that compared either the CO2 with the Ho:YAG laser [87] or the CO2 with the excimer laser [88] reported similar effects of these lasers on myocardial perfusion (in a porcine model of chronic ischemia). For the excimer laser, conflicting results are however presented by the only study that compared the effect of all three lasers (CO2, Ho:YAG, and excimer), also in a porcine model of chronic ischemia. This study reported similar improvement after CO2 and Ho:YAG TMLR but no change after excimer TMLR [76]. More laser-comparing studies must be performed before a clear statement can be made on which laser is most effective in increasing the myocardial perfusion after experimental TMLR.

In conclusion, none of the experimental studies that assessed perfusion acutely after TMR showed any increase in perfusion or flow. However, in contrast, all experimental studies that assessed perfusion at 4 weeks after treatment or later (using CO2, Ho:YAG, and excimer lasers) demonstrated an improved perfusion (Table 3). This difference can logically be attributed to the time required for new vessels to grow. Although in humans no evident improved myocardial perfusion has been confirmed, the experimental findings correlate with the clinical finding that TMR is more effective as a treatment for chronic ischemia than for acute ischemia. However, the enormous discrepancy in perfusion results between animal (increase in all long-term studies) and human research (increase in only one out of five long-term randomized clinical trials) is a point of concern. Whether it is because of a lack of correlation between human pathology and animal models or because human perfusion assessment techniques may not be suitable for TMR research [89] remains unknown.

The denervation hypothesis
The third mechanistic explanation originates from the observation that many patients have some relief of angina within days after treatment. As angiogenesis cannot explain this acute improvement (it is unlikely that the growth of new blood vessels occurs that fast), another explanation was found in myocardial denervation. This concept is based on direct intervention in the (neural) pain sensation rather than reducing anginal pain through increased perfusion of the ischemic myocardium. The hypothesis is based on a combination of observations. The perception of anginal pain is believed to be transported to the brain through cardiac nociceptors and afferent sympathetic fibers [90]. Histologic studies have shown that bundles of these fibers are located superficially in the epicardium [91], giving off deeper branches toward the endocardium, and thus are easily accessible by epicardially oriented laser treatment. Furthermore, in diabetic patients silent myocardial ischemia, ie, ischemia without anginal pain, is frequently observed [92]. Here, the diabetic neuropathy that these patients often have may cause a destruction of the above-mentioned sympathetic fibers in the myocardium. Other (clinical) indications that denervation may relieve anginal pain are the reported beneficial effects on angina of neuromodulating therapies such as spinal cord stimulation [93] and thoracic epidural anesthesia [94], and the observation that patients who have undergone a heart transplant do not experience anginal pain even though they can develop extensive coronary artery disease.

Currently, four experimental studies reported on myocardial denervation as a possible effect of TMR. In a canine model, Kwong and coworkers [95] performed either Ho:YAG TMLR or chemical destruction of cardiac nerves by epicardial application of phenol (positive control), or a sham operation (negative control). After 2 weeks, cardiac afferent nerve function was assessed by the effect of epicardial application of high concentrations of bradykinin (2 g/L) on the central nervous system-mediated mean arterial pressure (MAP). Furthermore, innervation was assessed by analyzing the content of the sympathetic nerve-specific enzyme tyrosine hydroxylase. Both in laser- and in phenol-treated animals no change in MAP was seen after bradykinin stimulation and complete loss of tyrosine hydroxylase was demonstrated in the affected areas. In contrast, in the untreated (sham) animals a decrease in MAP and no loss of tyrosine hydroxylase was found, and the investigators concluded that TMR using a Ho:YAG laser destroys cardiac nerve fibers.

With the same assessment techniques as Kwong and associates, Yamamoto and colleagues [13] used RF energy to create transmyocardial channels in canine hearts. Four weeks after RF-TMR they found (compared with controls) a decreased effect of epicardial application of bradykinin on MAP and a decrease in tyrosine hydroxylase content in treated regions. They concluded that RF-TMR denervates canine myocardium and has effects comparable to laser TMR.

A puzzling result in both these studies is the decrease in MAP after epicardial administration of bradykinin in healthy untreated canine, which the authors attributed to a local bradykinin-induced stimulation of afferent fibers. However, in contrast, others have described an increase in MAP after epicardial application of bradykinin, and a decrease in MAP was described only after systemic administration [96]. This is in conflict with the results of Kwong and Yamamoto. We hypothesize that the pre-TMR decrease in MAP described by them is due to diffusion of the high dose of epicardial bradykinin into the systemic circulation. That could mask any locally induced pressure-increasing effect. The reported absence of the systemic MAP decrease after TMR might then be due to an inability of bradykinin to diffuse through TMR-treated myocardium into the circulation. Nevertheless the reported absence of a then expected bradykinin-induced increase in MAP (which would be due to the local effect) after TMR indicates denervation, which is also supported by the reported decrease of tyrosine hydroxylase content.

In contrast to these two studies, other reports do not support direct efferent and afferent denervation as a mechanistic explanation. Hirsch and coworkers [97] reported on a canine study using a Ho:YAG laser with three different methods to assess the acute effect of TMLR on myocardial innervation: direct measurement (neural recording) of afferent neuron activation by epicardial application of bradykinin (in a much lower dose than used by Kwong and Yamamoto), electrical or chemical activation of sympathetic or parasympathetic efferent neurons, and direct intravenous ß-adrenergic receptor stimulation. No acute effect of TMLR was found on either afferent or efferent neuronal function. This study lacked a positive control, however, and it can therefore not be ruled out that global effects of the anesthesia masked local effects caused by the laser treatment. This is supported by the fact that although an increase in afferent neural activity was recorded after epicardial bradykinin application, at no point (preoperatively or postoperatively, control or TMLR) did the epicardial bradykinin have any effect on arterial pressures. Whether this was caused by the anesthesia or the low bradykinin dose is unknown. In a later study by the same group (Arora and colleagues [98]), chronic effects of TMLR were investigated using the same laser and assessment methods. Here, a positive control group was included (destruction of nerves by epicardial application of phenol) and in compliance with their acute results, they reported that "chronic TMLR does not alter cardiac afferent or efferent neuronal function." However, they also reported that "it does remodel the intrinsic cardiac nervous system such that the functional connectivity becomes obtunded." They concluded that this remodeling may account, at least in part, for the delayed symptomatic benefits in patients undergoing TMLR.

Besides these four papers, several abstracts have been published on denervation research, speaking for or against this mechanism. Kwong and colleagues [99] used the same techniques and follow-up time as in their previous study to investigate the effect of endocardial nontransmural laser channels on the innervation of canine hearts. Although the effect was less pronounced than with transmural TMR, they did find a loss of tyrosine hydroxylase and a decreased effect of epicardial application of bradykinin to MAP. The former can be explained by the fact that less myocardium is affected by endocardial TMR and the latter by the epicardial location of the sympathetic fibers (less damaged by endocardial TMR) or by the epicardial orientation of assessment. Le and colleagues [100] also performed endocardial Ho:YAG TMLR in a canine model. After an average of 10 weeks, they assessed dobutamine-induced changes in myocardial perfusion before and after treatment and their results indicated a lack of vasoconstriction after the treatment, which as they concluded was likely due to cardiac denervation.

Contrasting results were reported by Hughes and coworkers [101] who used a porcine model of hibernating myocardium and assessed the effect of CO2, Ho:YAG, and excimer TMLR after 6 months on histologic staining and protein concentration of tyrosine hydroxylase. In contrast to the results previously described by Kwong, they did not find any effect of TMLR on this sympathetic nerve-specific enzyme, regardless of the laser used. Unlike the other studies, however, only the amount of tyrosine hydroxylase in treated myocardium was measured and nervous functionality was not examined. Therefore a functional effect such as nervous remodeling suggested by Arora and colleagues [98] cannot be excluded. Finally, Minisi and colleagues [102] investigated the reflex responses of left ventricular nociceptors and sympathetic afferent fibers in response to epicardial and intracoronary bradykinin administration and found no significant change in these responses after Ho:YAG TMLR in canine hearts.

Because the denervation hypothesis is focused on the destruction of tissue instead of the healing response it might be reasoned that the device that creates the most extensive (thermal) damage is the most effective to induce denervation (provided that enough myocardium survives to enable effective contraction). Following this line of thought the most effective device seems to be the Ho:YAG laser [45], which has also been used in most studies. Varying results have been reported, however, making it difficult to define whether this is indeed the most effective device.

In conclusion, several assessment techniques have been used to measure the sympathetic nervous activity before and after TMR. From the eight experimental studies that have been reported (six using a Ho:YAG laser, one using RF energy, and one using CO2, Ho:YAG, and excimer laser), five have reported evidence of denervation or remodeling of the cardiac nervous system at 2 to 10 weeks after TMR [13, 95, 98–100]. Of the three studies that did not find any evidence of denervation, two used assessment acutely after TMR [97, 102] and one did not assess nervous functionality [101]. Thus experimental evidence for TMR-induced denervation is present although not in the acute phase. Denervation at longer follow-up is confirmed by the results of the only clinical study that has investigated denervation after TMLR. In this study, Al-Sheikh and colleagues [103] performed preoperative and postoperative PET imaging of myocardial sympathetic innervation in 8 Ho:YAG-treated patients. After 2 months, an increase in the size of innervation defects in 6 patients and a decrease in the size of innervation defects in 2 patients was demonstrated and they concluded that TMLR causes cardiac sympathetic denervation.

Other hypotheses
Placebo effect
The extreme discrepancies in TMR research, both within animal research and between animal and human research, have raised the thought that a placebo effect may play a role in the clinical improvement. As most TMR patients have a long history of treatment and have often been told that there are no more treatment possibilities, the option of TMR may create enormous hopes for treatment success, resulting in a (placebo) bias in results such as angina scores and quality of life. As a response, positive alteration in other factors such as optimization and adherence to medication regimes, improved diet, and appropriate rest and exercise might also contribute to an improvement after TMR. Furthermore, a possible placebo effect of the surgical procedure itself (usually a thoracotomy) may also play a role. Anecdotal evidence of clinical improvement in patients who only received thoracotomies or sternotomies without further treatment has been described in the past (references not retrieved). In our own practice, we have also seen a complete relief of angina immediately after surgery in a patient who was scheduled to receive CABG but ultimately only received a sternotomy because no grafts could be placed. Unfortunately, it is virtually impossible to clinically assess the importance of the surgical placebo effect as it is unethical to compare TMR and sham operations in humans in a controlled and blinded study. Furthermore the subjective nature of the placebo effect makes it also impossible to investigate this hypothesis in animal studies. Finally, although the placebo effect may contribute to the short-term clinical improvement after TMR, it is unlikely that it plays a role in the persisting, long-term improvement that has been described after TMR [104]. However, a combination of placebo and a consequent increase in exercise resulting in neovascularization should not be ruled out (see below).

Other
Through the years, several other hypotheses for the mechanism of action have also been suggested. They include scar production leading to an improved cardiac compliance and efficacy [40, 55, 105], myocardial destruction resulting in a redistribution of blood flow and improved oxygenation of surviving myocardium [78], a photo-acoustically induced change of conduction of ischemic myocardium resulting in improved contractility and function [106], and a combination of mechanisms. Additionally, another mechanism has been suggested that might play a role in the long-term relief of anginal pain: TMR relieves angina acutely by any of the working mechanisms suggested above, followed by an increase in exercise in individual patients, resulting in an increase of shear stress in myocardial vessels and stimulation of arterial growth in the myocardium. Although they have been suggested as mechanisms, little or no research has been performed to make a funded statement on the clinical significance of any of these hypotheses.


   Conclusion
Top
 Abstract
 Introduction
 Methods of channel creation
 Hypotheses of working mechanisms...
 Conclusion
Acknowledgments
 References
 
Despite the controversy and the many questions that have surrounded transmyocardial revascularization in the past 35 years, the demonstrated relief of angina after TMR still captures the interest of clinical and basic researchers around the world. A number of books have been written [8, 45, 106, 107] and for several years the number of publications on TMR has risen steadily, peaking in 1999, the year in which the first randomized clinical trials [108–111] were published (Fig 1). The recently observed sharp decrease (in 2000 and 2001) may have several reasons. On the one hand it is a reflection of a procedure maturing from experimental to routine (based on the results of five randomized clinical trials), and on the other hand it could be an indication that the lack of an accepted mechanism and the consequent continuing controversy is decreasing the interest of clinicians and scientists. This controversy surrounding TMR is furthermore due to the discrepancy between general improvement of subjective factors (eg, angina and quality of life) and varying results of objective factors (eg, perfusion and exercise tests). In the five randomized clinical TMLR trials that have been published, using either a CO2 [110–112] or Ho:YAG laser [108, 109], clinical improvement in angina (defined as a decrease after 1 year of at least two angina classes) was found in 58% of a total of 402 patients who received stand-alone TMLR versus 11% in a total of 272 control patients (excluding crossovers). Given that all patients had severe angina and were not eligible for other revascularization procedures, this result (in combination with the improvement in quality of life) is impressive. However, as mentioned, the results of objective variables have been much less evident, with for instance only one of the five studies (using CO2 TMLR) reporting significantly improved perfusion after treatment [110] and two out of four studies (one study did not assess exercise tolerance) reporting a significant increase in exercise tolerance [108, 109]. This variation in objective clinical results emphasizes the need for objective experimental studies that have been described in this paper.

When attempting to answer the question "what have we learned," we have to conclude that the patent channels hypothesis has lost interest and credibility, and we believe that there is enough evidence to reject this hypothesis. For both the angiogenesis and denervation hypotheses, supporting experimental evidence has been given and it is therefore likely that both mechanisms play a role. However, the angiogenesis hypothesis loses some support when reviewed in combination with the clinical findings because of the clinical inability to demonstrate reproducible improved perfusion. The experimental denervation evidence is supported by the one clinical study investigating this hypothesis. However, more clinical studies must be performed before a firm statement can be made.

In spite of the sometimes large discrepancies between studies, the experimental research that has been performed in the past 35 years has provided important insights into the various hypotheses that have been suggested for the working mechanism of TMR. However, although this research has contributed to our understanding it has not yet led to the final elucidation of the problem. We believe that continued clinical research on the hypotheses is essential to obtain a complete understanding of the working mechanism of TMR, and that this will ultimately provide the best possibility to optimize TMR as a last-resort treatment for angina pectoris. Whether the reclining interest in TMR research will lead to a slow death or a general acceptance of the treatment remains to be seen.


   Acknowledgments
Top
 Abstract
 Introduction
 Methods of channel creation
 Hypotheses of working mechanisms...
 Conclusion
 Acknowledgments
References
 
The authors wish to thank the Dutch Heart Foundation for its financial support (grant number 97–196).


   References
Top
 Abstract
 Introduction
 Methods of channel creation
 Hypotheses of working mechanisms...
 Conclusion
 Acknowledgments
 References
 

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