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Ann Thorac Surg 2000;69:655-662
© 2000 The Society of Thoracic Surgeons

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Current Reviews

Myocardial laser revascularization: the controversy and the data

^a Department of Surgery, University of Pennsylvania Health System, Philadelphia, Pennsylvania, USA

Address reprint requests to Dr Bridges, Department of Surgery, Hospital of the University of Pennsylvania, 4 Silverstein, 3400 Spruce St, Philadelphia, PA 19104
e-mail: cbridges{at}mail.med.upenn.edu

	Abstract

Top Abstract Introduction Types of laser used... Evidence of angiogenesis Quantitative measurement of... Assessment of myocardial blood... Effect of TMR on... Denervation of myocardium Clinical results of TMR Percutaneous myocardial... Comment Addendum References

 
The clinical and experimental data relevant to the theoretical mechanisms and clinical results of laser myocardial revascularization are reviewed. Both transmyocardial and percutaneous approaches are considered. Both types result in a reduction in anginal symptoms in patients refractory to conventional therapy and are likely to act through common pathways. The proximate mechanisms for the transmyocardial revascularization effect most likely relate to myocardial inflammation, secondary stimulation of growth factors, and denervation of the myocardium.

	Introduction

Top Abstract Introduction Types of laser used... Evidence of angiogenesis Quantitative measurement of... Assessment of myocardial blood... Effect of TMR on... Denervation of myocardium Clinical results of TMR Percutaneous myocardial... Comment Addendum References

 
The idea of creating direct communications between the lumina of the left ventricle and the left ventricular (LV) myocardium originated in the classic description of myocardial sinusoids by Wearns and colleagues [1] in 1933. They described the sinusoids as "channels whose lumina are very irregular" with walls "made up of endothelium only or endothelium reinforced by a minimal amount of subendothelial connective tissue." Yet these myocardial "sinusoids" have largely evaded detection using modern histochemical and electron microscopic techniques [2]. Nonetheless, the concept of myocardial sinusoids is galvanized by extrapolation to more primitive vertebrate hearts such as the single-chambered hearts of hagfish and lampreys, which are supplied directly by blood from the ventricular cavity [3]. Although morphological studies of reptilian hearts such as those of the crocodile, snake, and alligator reveal a reasonably well developed coronary circulation [4], it has been postulated that the ventricles receive a substantial supply of blood directly from the ventricular lumen. In patients with pulmonary atresia and intact ventricular septum, proximal obstruction of the coronary arteries can result in a lumen-dependent perfusion of the myocardium [5].

Shortly after the classic description of myocardial microanatomy by Wearns and coauthors [1], a number of investigators began to develop new techniques for delivering oxygenated blood to the myocardium. Beck [6] attempted to increase blood flow by grafting omentum to the surface of the heart. Vineberg [7] sought to increase blood flow to the myocardium by grafting the mammary artery directly into the myocardium. Long-term follow-up of patients who have undergone the Vineberg procedure has demonstrated patent mammary artery grafts to the myocardium some 20 years after the procedure [8]. Several investigators attempted to deliver oxygenated blood to the myocardium by creating a mechanical connection between the LV myocardium and the LV lumen. Transmyocardial acupuncture was the approach taken by Sen [9], Pifarré [10], and their colleagues using acupuncture needles and by Massimo and Boffi [11] with T-shaped tubes. The success of the Vineberg and related procedures, however, was largely overshadowed by the development of coronary artery bypass grafting (CABG) techniques.

The modern rendition of this concept was proposed by Mirhoseini and Cayton [12], who used a 450-W industrial carbon dioxide (CO₂) laser in a canine model of acute ischemia to increase blood flow to the myocardium. Animals treated with laser revascularization had a 0% mortality rate after acute ligation of the left anterior descending coronary artery, whereas the mortality rate was greater than 83% in the control group. These animal experiments prompted Mirhoseini and associates [13] to perform laser revascularization clinically as an adjunct to CABG, and their results suggested the safety of the technique. The major limitation of their technique was that the CO₂ laser available for clinical use had only 80 W of power and required at least one complete cardiac cycle to complete creation of a transmyocardial channel. Therefore, the heart had to be stationary during channel creation. This limitation generally made it necessary to perform the procedure under conditions of ischemic arrest.

With the advent of the 1,000-W CO₂ laser (PLC Systems, Franklin, MA), which was recently approved by the Food and Drug Administration for clinical use, transmyocardial channels can be created in approximately 40 ms—fast enough to successfully make transmural channels in a beating heart. At the same time that the high-powered CO₂ laser became available, experimental studies were conducted by Jeevanandam and coworkers using a thulium-holmium-chromium:yttrium-aluminum-garnet (YAG) laser [14] and using a holmium:YAG laser [15]. They demonstrated decreased mortality in dogs that underwent transmyocardial revascularization (TMR) after acute ligation of the left anterior descending coronary artery.

These technological advances and encouraging acute animal studies superimposed on the theoretical background provided by Wearns and coworkers [1], Beck [6], Vineberg [7], and others led to the development of clinical laser revascularization. Initially, the proposed mechanism of action of laser revascularization was the creation of connections between myocardial sinusoids and the LV lumen allowing oxygenated blood direct access from the LV lumen to the capillaries within the myocardium. This original hypothesis, the direct blood flow hypothesis, led to the development of laser revascularization but has largely been abandoned. In the majority of experimental studies and clinical postmortem studies, the channels became occluded with inflammatory tissue and necrotic debris and did not remain patent [16–29]. Few studies suggested evidence of long-term patency [30–32].

In addition, two theoretical arguments impugn the validity of the direct blood flow hypothesis. Pifarré and coauthors [10] proposed that blood flow from the LV lumen to the myocardium is a physiologic impossibility because intracavitary pressure is nearly always less than intramyocardial pressure. As the LV pressure is generated by contraction of the LV musculature, the pressure within the myocardial interstitium ought to exceed that within the LV lumen during systole and diastole. A second theoretical argument against the direct blood flow hypothesis is based on the fact that the total surface area of the transmyocardial channels represents less than 0.01% of the surface area of the capillaries within the LV myocardium and that therefore, any direct blood flow through these channels would contribute minimally to direct oxygen exchange [33]. Thus, in addition to overall channel patency, patent intersections with nearly all capillaries traversed would be required for substantial oxygen transport to the tissues to occur.

Yet clinical studies of TMR using a CO₂ laser or holmium:YAG laser and percutaneous myocardial revascularization (PMR) using a holmium:YAG laser have consistently demonstrated a marked reduction in anginal symptoms and, in most cases, an improvement in exercise tolerance and quality of life [29, 34–47]. This paradox has led to a search for the "true" mechanism of action of TMR.

The two leading proposed mechanisms of the TMR effect include laser-induced angiogenesis with improvement in regional myocardial blood flow and laser-induced denervation of the myocardium resulting in improvement in anginal symptoms without any improvement in oxygen delivery. A third, theoretical mechanism is that TMR improves intramyocardial blood flow distribution and thus obviates the need of direct communication of myocardial channels with the LV lumen. There is insufficient experimental evidence to support this last mechanism, however. Even if angiogenesis occurs, does it lead to a quantitatively significant increase in blood flow? Is any angiogenesis associated with laser revascularization a laser-specific phenomenon or a nonspecific inflammatory response?

I review the available literature in an attempt to answer these questions. The articles referenced were obtained through a search of the MEDLINE database (1966 to present) using keywords including TMR, laser, revascularization, transmyocardial, and TMLR, subject headings to which these terms were mapped, and logical combinations of these sets. Using the same database, I sought investigators active in the field. Additional references were obtained through direct communication with investigators. Manuscripts cited in the references retrieved were also reviewed.

	Types of laser used for laser revascularization

Top Abstract Introduction Types of laser used... Evidence of angiogenesis Quantitative measurement of... Assessment of myocardial blood... Effect of TMR on... Denervation of myocardium Clinical results of TMR Percutaneous myocardial... Comment Addendum References

 
The major features of laser light are that it is monochromatic (consisting of a single color or wavelength), it has a small divergence (resulting in a small beam and high energy per unit area), and the light waves are generally in phase. Together, these three properties make laser light coherent, which distinguishes it from all other types of light. Early use of the CO₂ laser (wavelength = 10.6 µm) for TMR was based on its clinical availability and the relative absence of thermal injury caused by this wavelength. Subsequently, PLC Systems engineered a high-power CO₂ laser specifically for TMR. Since that time, a variety of wavelengths have been proposed for clinical TMR in addition to that of the CO₂ laser, including holmium:YAG (wavelength = 2.1 µm) and excimer (wavelength = 193 nm, 248 nm, or 308 nm) [48] lasers. The CO₂ and holmium:YAG lasers create transmyocardial channels through the vaporization of the water component of the tissue. The excimer laser creates channels through direct breakage of covalent bonds, a process known as photoablation [48].

Of the two lasers used most commonly clinically, the CO₂ and the holmium:YAG, the CO₂ laser energy is more efficiently absorbed by water molecules [48]. As the energy per pulse of the CO₂ system is on the order of 40 Js, whereas the pulse energy of the holmium:YAG laser used clinical is typically 2 to 5 Js, several pulses are required to generate a transmural channel with the holmium:YAG laser. That laser, therefore, requires delivery during several cardiac cycles to create a single channel. Excimer and holmium:YAG laser energy, in contrast to CO₂ laser energy, can be delivered through a flexible fiber. This delivery system allows creation of a single channel using several pulses. The holmium:YAG laser has recently been adapted to the performance of TMR using a percutaneous approach, an approach that is not possible with the CO₂ laser [43, 46, 47].

The erbium:YAG laser (wavelength = 2.94 µm) is another solid-state laser similar in engineering aspects to the holmium:YAG laser. In contrast to the holmium:YAG laser, the erbium:YAG laser corresponds almost precisely to the absorption peak for water (3 µm) [48]. Thus, the erbium:YAG laser should allow creation of transmural myocardial channels with greater efficiency than the CO₂ or holmium:YAG laser and with less thermal damage. This laser has been used as a highly efficient and precise ablator and cutter in orthopedic and skin surface applications [48] but has not been used for TMR.

	Evidence of angiogenesis

Top Abstract Introduction Types of laser used... Evidence of angiogenesis Quantitative measurement of... Assessment of myocardial blood... Effect of TMR on... Denervation of myocardium Clinical results of TMR Percutaneous myocardial... Comment Addendum References

 
In a porcine model of chronic ischemia 4 weeks after TMR, evidence of TMR–induced stimulation of angiogenesis within channels was demonstrated by Zlotnick and associates [28]. In a normal canine model, Kohmoto and coworkers [24] similarly demonstrated several weeks after laser revascularization, immunohistochemical evidence of new blood vessel formation within channels and extending to 0.5 cm from the outer circumference of the channels. In both of these studies, however, all channels were closed. Recent experimental studies in normal and ischemic canine, porcine, and ovine models have demonstrated that myocardial laser injury leads to an increase in the density of arterial vessels [16, 19, 21–25, 27, 49–51]. In contrast, Whittaker and colleagues [52] found no increase in capillary density 2 months after TMR.

Other than the studies by Malekan [19], Chu [21], Whittaker [52], and their coworkers, most studies demonstrating TMR–induced angiogenesis can be criticized for lacking an appropriate mechanical injury control. Mack and colleagues [50] attempted to provide such a control by comparing angiogenesis resulting from a "channel" produced by the laser fiber alone (no laser energy) with angiogenesis from a channel created with laser energy. Although these investigators demonstrated a greater degree of angiogenesis after laser-related injury, the experiment is lacking a valid control because the degree of myocardial injury is greater in the presence of laser energy and its associated thermal effects. Four weeks after TMR, Malekan and coauthors [19] found precisely the same degree of new arterial blood vessel formation after creating channels of equal diameter using a power drill or a CO₂ laser in an ovine model. More recently, Chu and associates [21] demonstrated in a chronically ischemic porcine model that sufficient needle injury to the myocardium and TMR lead to similar degrees of stimulation of vascular endothelial growth factor (VEGF) expression and angiogenesis. Horvath and colleagues [49] showed that TMR leads to induction of VEGF gene expression and elevated tissue levels of VEGF messenger ribonucleic acid but failed to provide an appropriate mechanical injury control. The available evidence, therefore, suggests that TMR–induced angiogenesis is likely to be a nonspecific response of the myocardium to injury. Certainly, a laser-specific angiogenic response has never been identified.

	Quantitative measurement of myocardial blood flow

Top Abstract Introduction Types of laser used... Evidence of angiogenesis Quantitative measurement of... Assessment of myocardial blood... Effect of TMR on... Denervation of myocardium Clinical results of TMR Percutaneous myocardial... Comment Addendum References

 
The injection of radioactive or fluorescent microspheres, usually into the left atrium, followed by withdrawal at a predetermined rate and measurement of tissue concentrations of the injected spheres represents the most widely accepted method for quantitative tissue blood flow estimation [53]. If TMR improves myocardial blood flow through any of the proposed mechanisms, an increase in regional blood flow should be demonstrable using microsphere-based techniques. In most animal studies where microspheres have been used to measure regional myocardial blood flow after TMR, an increase in regional flow has not been demonstrated [23, 54–58]. Cayton and colleagues [54] did show, however, an improvement in endocardial blood flow and in the ratio of endocardial to epicardial blood flow using a microsphere technique after CO₂ laser TMR in a porcine model of acute coronary ischemia.

Lutter and associates [58] also studied a porcine model of acute coronary ischemia and found no change in regional blood flow after CO₂ laser TMR. Also using CO₂ laser TMR, Mirhoseini and Cayton [59] reported an increase in regional myocardial blood flow in a chronic porcine model using magnetic resonance imaging techniques for the measurement of myocardial blood flow. These blood flow–imaging techniques are new and promising but incompletely validated. In a canine model of chronic ischemia, Yamamoto and coworkers [26], using a holmium:YAG laser, demonstrated no increase in regional blood flow at rest in TMR–treated animals compared with controls. In contrast, regional blood flow was 40% higher in TMR–treated animals than controls during stress. The conflicting results of these studies suggest that TMR by both the holmium:YAG laser and the CO₂ laser does not improve blood flow acutely or at rest but may improve coronary blood flow in the setting of chronic ischemia, particularly during stress.

	Assessment of myocardial blood flow using nuclear imaging

Top Abstract Introduction Types of laser used... Evidence of angiogenesis Quantitative measurement of... Assessment of myocardial blood... Effect of TMR on... Denervation of myocardium Clinical results of TMR Percutaneous myocardial... Comment Addendum References

 
In contrast to experimental studies, clinical studies of TMR have relied primarily on nuclear perfusion/function imaging for estimation of the effect of TMR on myocardial regional perfusion. The techniques employed have included technetium 99m sestamibi scanning, thallium 201 single-photon emission computed tomography, or positron emission tomography [29, 35, 36, 38, 39, 41, 42, 44, 45, 60]. Horvath and coauthors [39] in 1997 reported a summary of the results in 200 patients at eight hospitals in the United States who underwent TMR using the PLC Systems 1,000-W CO₂ laser. In that series, scans were performed with either technetium 99m sestamibi or thallium 201 and were obtained at baseline and at 3, 6, and 12 months after TMR. The LV free wall and septum were each divided into 12 segments. Scans were read by observers blinded to patient information including the timing of the scan. At 6 and 12 months, the authors found a significant decrease in the number of segments in the LV free wall with reversible defects after TMR. They also found a decrease in the number of segments in the septum with reversible defects (TMR not performed), but this difference failed to reach significance. There was no significant change in the number of segments with fixed defects in either the septum or the LV free wall. In an earlier study of 20 patients at their own institution, this group [41] reported similar results using exclusively technetium 99m sestamibi imaging techniques, results implying that TMR improved regional perfusion of ischemic myocardium.

These results notwithstanding, most investigators [29, 35, 36, 38, 42, 45, 60] have not demonstrated an increase in regional myocardial blood flow after TMR. Frazier and colleagues [38] reported the results in 21 patients studied using thallium 201 imaging 3 and 6 months after TMR with the same CO₂ laser system as that of Horvath and coworkers [39, 41] and found no difference in the number of myocardial segments with perfusion defects. Using positron emission tomographic scanning, Frazier and associates [36, 38] did report a 10% to 20% increase in the ratio of subendocardial to subepicardial perfusion 3 and 6 months after TMR. In a controlled, randomized trial comparing CO₂ laser TMR with medical therapy, Schofield and associates [29] found no significant difference between groups in the number of myocardial segments with reversible ischemia at any time up to 12 months after initiation of therapy. Krabatsch and coauthors [42] examined 171 patients after TMR and could not demonstrate an increase in regional perfusion, and Milano and associates [45] found that at a mean follow-up of 10 months after holmium:YAG laser TMR in 16 patients, there was no significant change in the number of segments with reversible ischemia.

	Effect of TMR on myocardial function

Top Abstract Introduction Types of laser used... Evidence of angiogenesis Quantitative measurement of... Assessment of myocardial blood... Effect of TMR on... Denervation of myocardium Clinical results of TMR Percutaneous myocardial... Comment Addendum References

 
Most experimental studies of both CO₂ and holmium:YAG laser TMR in models of acute and chronic coronary ischemia have not performed detailed evaluations of myocardial function. In experimental models of ischemia after TMR, improvement in regional or global LV function has not been consistently demonstrated [15, 20, 32, 61, 62]. Horvath and colleagues [32] studied sheep 30 days after an acute infarction where CO₂ laser TMR was performed acutely and found an improvement in regional contractility in those regions treated with TMR compared with controls. In a porcine model of chronic ischemia, he and his group [61] also demonstrated an improvement in regional LV function after TMR. In a canine model of acute infarction, Yano and associates [15] noted an improvement in preload-recruitable stroke work acutely after TMR. In contrast, using an ovine model, Malekan and coworkers [20] performed CO₂ laser TMR immediately prior to creation of an anteroapical infarction in sheep and found no change in myocardial function and no attenuation of adverse remodeling up to 8 weeks after TMR compared with the control group. Most clinical studies do not demonstrate an increase in ejection fraction after TMR [29, 36–38, 42, 45], although an improvement in dobutamine hydrochloride stress–induced regional wall motion abnormalities has been demonstrated in several clinical studies after CO₂ laser TMR [36–38].

	Denervation of myocardium

Top Abstract Introduction Types of laser used... Evidence of angiogenesis Quantitative measurement of... Assessment of myocardial blood... Effect of TMR on... Denervation of myocardium Clinical results of TMR Percutaneous myocardial... Comment Addendum References

 
Kwong and coworkers [63] studied the effects of holmium:YAG laser TMR on myocardial afferent nerve fibers in a canine model. Both phenol (known to destroy nerve fibers) and TMR abolished the hypotensive response to topical application of bradykinin (a potent algesic) to the myocardium, thus implying interruption of subepicardial visceral afferent neural signals. Using an immunoblotting technique, these authors also demonstrated a loss of the neural-specific enzyme tyrosine hydroxylase after TMR treatment or phenol application but not after sham operations (controls). Stoll and colleagues [64] studied the effects of holmium:YAG laser TMR in a nonischemic porcine model using C-11-hydroxyephedrine positron emission tomographic scanning. Transmyocardial revascularization induced significant innervation defects extending beyond the treatment zone. Their data suggest that TMR destroys nerve fibers traversing the laser-treated areas as well as those arising from these areas.

	Clinical results of TMR

Top Abstract Introduction Types of laser used... Evidence of angiogenesis Quantitative measurement of... Assessment of myocardial blood... Effect of TMR on... Denervation of myocardium Clinical results of TMR Percutaneous myocardial... Comment Addendum References

 
Many of the clinical studies of holmium:YAG and CO₂ laser TMR have been discussed here. The most consistent finding of all of the studies performed to date is that TMR results in a significant improvement in angina class using the Canadian Cardiovascular Society scoring system, and many of these studies also demonstrate an increase in exercise capacity after TMR [29, 34–47]. The early mortality after TMR is a strong function of the preoperative status of the patients with increased mortality for patients with unstable angina or reduced ejection fraction [44]. Preoperative placement of an intraaortic balloon pump has been shown to decrease mortality after TMR for patients with reduced ventricular function [44]. There appears to be a learning curve with TMR; at a given institution, the mortality decreases with time, perhaps the result of both better selection and improvements in technique [42].

Schofield and coworkers [29] randomly assigned 188 patients with refractory angina to TMR or medical management in randomized study comparing CO₂ laser TMR with medical therapy. In contrast to the previous uncontrolled studies suggesting the beneficial effects of this form of therapy [36, 38, 39, 41], this study was striking for its failure to demonstrate a significant improvement in myocardial perfusion or mortality after TMR. At 12 months, the Canadian Cardiovascular Society angina score decreased by at least two classes in only 25% of patients in contrast to 75% of patients in the series of Horvath and colleagues [39]. There was no significant difference in treadmill exercise time or distance at 12 months. The perioperative mortality rate was 5% in the TMR group, and subsequent 12-month mortality was similar in both groups, thus resulting in a higher total 12-month mortality rate of 11% in the TMR group versus 4% in the medically treated patients. Although the difference in mortality failed to reach significance, the lack of demonstrable benefit led the authors to conclude that the TMR procedure could not be advocated.

Allen and associates [34] reported in 1998 the early results of a prospective, randomized multicenter trial of holmium:YAG laser TMR combined with CABG versus CABG alone for 221 patients with ungraftable myocardial segments. In this study, the ungraftable areas were treated with TMR in the TMR + CABG arm and were left ungrafted in the CABG alone arm. The authors reported a significant reduction in the perioperative mortality rate (0.9% versus 7.0%) in the patients treated with TMR. This result is somewhat curious, however, as the mortality rate in the TMR + CABG group was substantially lower than the predicted mortality rate for these same patients (8.8%) for CABG alone [34]. In contrast, an earlier report by the same group [35] concerning a prospective, randomized multicenter trial of holmium:YAG laser TMR versus medical therapy in 160 patients for the treatment of refractory class IV angina revealed no change in reversible or fixed defects by thallium 201 imaging and no significant difference in 12-month mortality (14.8% for TMR versus 13.3% for medical therapy). Other than mortality, TMR–specific complications include arrhythmias, LV dysfunction, and cerebral microembolization, but long-term sequelae appear to be rare [29, 36, 38, 39, 41].

Newer proposed clinical applications for TMR include the treatment of graft vasculopathy after cardiac transplantation. Although theoretically appealing, the benefits of TMR for such treatment have not been established [65, 66]. A number of groups [34, 67, 68] have reported the combination of TMR with standard or minimally invasive CABG. With the exception of the study by Allen and associates [34], these studies have not shown a beneficial effect of TMR with respect to survival; the numbers of patients have been small, and the confounding effects of concomitant CABG cannot be ascertained. In most surgical studies of TMR, the LV free wall has been approached through a left thoracotomy. There have been several reports of the performance of TMR using thoracoscopy. These early reports suggest that the technique can be performed safely and adequately through this approach [69].

	Percutaneous myocardial revascularization (PMR)

Top Abstract Introduction Types of laser used... Evidence of angiogenesis Quantitative measurement of... Assessment of myocardial blood... Effect of TMR on... Denervation of myocardium Clinical results of TMR Percutaneous myocardial... Comment Addendum References

 
The newest approach to laser myocardial revascularization is to perform the technique percutaneously using the arterial route to gain access to the LV lumen in direct analogy to cardiac catheterization. The term percutaneous myocardial revascularization, or PMR, has been used rather than TMR both to distinguish this technique and to indicate that PMR—unlike TMR—purposely avoids the creation of transmyocardial channels [43, 46, 47]. In the PMR technique, the holmium:YAG laser has been used primarily, as the CO₂ laser energy cannot be transmitted through a flexible fiber. The percutaneous devices used for PMR are designed so that the channels created from the endocardial side of the LV wall do not completely reach the epicardial surface. This design minimizes the probability of LV wall perforation and the possibility of pericardial tamponade, an infrequent but reported complication of PMR [43, 46].

The early results of PMR indicate that the reduction in anginal symptoms is similar to that with TMR with an average reduction of two angina classes after the procedure [43, 46]. There is also a similar degree of improvement in exercise duration [43]. The rare complication of pericardial tamponade has been managed conservatively or with pericardiocentesis [46], although in one reported case [43], surgical intervention was necessary. The question of the mechanism of the observed reduction in anginal symptoms remains unanswered with this technique, however. As with available clinical studies of holmium:YAG laser TMR [35, 45], holmium:YAG laser PMR has not been shown to increase regional myocardial perfusion by thallium 201 perfusion imaging [43].

	Comment

Top Abstract Introduction Types of laser used... Evidence of angiogenesis Quantitative measurement of... Assessment of myocardial blood... Effect of TMR on... Denervation of myocardium Clinical results of TMR Percutaneous myocardial... Comment Addendum References

 
The mechanism of the clinical effects of TMR has not been established. Although Kohmoto and associates [70] demonstrated that direct blood flow to the endocardium may be quantitatively important in alligator hearts, quantitatively important direct blood flow has not been demonstrated after TMR [23]. Both clinical autopsy studies and experimental studies have rarely identified patent channels after TMR. On the basis of all these data and the theoretical arguments against it, the direct blood flow hypothesis must be rejected.

Transmyocardial revascularization may stimulate angiogenesis, but this effect is likely to represent a nonspecific result of myocardial injury. The fact that TMR causes myocardial injury has been postulated to account for the increased mortality observed in patients with impaired LV function or hemodynamic instability and limited reserve [44]. Experimental studies demonstrate that the holmium:YAG laser results in a greater degree of myocardial tissue damage than the CO₂ laser [25, 52, 71]. Because PMR is currently performed using the holmium:YAG laser [43, 46, 47], any deleterious effects caused by irreversible tissue damage may be most pronounced using this technique.

The inflammatory response to TMR–induced myocardial injury is the most cogent hypothesis for TMR–induced angiogenesis. This hypothesis is bolstered by the fact that both CO₂ and holmium:YAG lasers induce angiogenesis but are known to have widely divergent effects on tissue [22, 23, 25, 48, 70, 71]. The actual impact of the induced vasculogenesis on blood flow is not clear given the conflicting perfusion studies already cited. These equivocal data underscore the limits of imaging technology in patients with diffuse coronary artery disease. The results are further confounded by the ability of myocardial leukocytes to take up fluorine-18-2-deoxyglucose detected by positron emission tomographic scans [72]. Regardless of the etiology of the angiogenic stimulus, the studies demonstrating an improvement in regional wall motion during dobutamine-induced stress suggest that in some patients, functionally significant increases in perfusion can occur [36–38].

If induction of vascular growth factor production is indeed the proximate mechanism of any TMR effect on angiogenesis, TMR may be an expensive and relatively inefficient means of achieving this end. In several studies, direct administration of recombinant proteins encoding basic fibroblast growth factor [73], VEGF [27], and hepatocyte growth factor [74] has been combined with TMR. Gene therapy using adenovirus encoding VEGF [75] or profilin [27] has also been used in conjunction with TMR. In general, administration of basic fibroblast growth factor, VEGF, or hepatocyte growth factor or adenovirus encoding VEGF leads to a greater angiogenic response than TMR alone [73–75]. Although the authors of these studies have made a case for a synergistic effect of TMR, they either omitted a control group with recombinant growth factor or gene therapy alone [73, 74] or demonstrated that TMR alone had no significant salutary effects [75].

A balanced interpretation of the available literature suggests that both holmium:YAG and CO₂ laser TMR and PMR, by analogy, can largely be demystified as techniques that cause inflammation of the myocardium and some degree of myocardial injury. Holmium:YAG laser TMR has also been shown to destroy afferent cardiac nerve fibers. Nonetheless, it is possible that a carefully controlled degree of inflammation may lead to a salutary angiogenic response and some improvement in blood flow through the induction of angiogenic factors. If this hypothesis is correct, then do these treatment modalities have a role in the treatment of patients with intractable medically refractory angina pectoris not amenable to CABG and percutaneous transluminal coronary angioplasty? If angina relief is the primary objective and mortality is not increased, the answer may be affirmative. If denervation is the primary mechanism of angina reduction, however, there is concern that late mortality may increase because of the absence of an effective warning system for myocardial oxygen supply–demand mismatch. The failure of two published randomized trials [29, 35] comparing TMR with medical therapy to demonstrate a survival benefit of TMR is worthy of concern, and longer-term follow-up of these patients is essential, as the trend suggests that mortality may actually increase after TMR. In any case, careful patient selection must be used, and alternative more direct, more effective, and perhaps less costly methods of achieving these results should be investigated.

	Addendum

Top Abstract Introduction Types of laser used... Evidence of angiogenesis Quantitative measurement of... Assessment of myocardial blood... Effect of TMR on... Denervation of myocardium Clinical results of TMR Percutaneous myocardial... Comment Addendum References

 
Since this article was accepted for publication, two perspective controlled, multicenter, randomized trials of TMR were published. In a study by Frazier and colleagues [76], 91 patients were assigned to undergo TMR and 101 patients received continued medical treatment. At 12 months, angina had improved by at least two Canadian Cardovascular Society (CCS) classes in 72% of the patients assigned to TMR and in only 13% of the patients assigned to medical treatment. There was no statistically significant difference in survival at 12 months. There was a 20% improvement in myocardial perfusion in the TMR group in contrast to a 27% worsening of myocardial perfusion in the medical treatment group as assessed by Thallium-201 single photon emission computed tomography. In the study by Allen and associates [77], 275 patients with medically refractory Class IV angina were randomly assigned to receive TMR followed by continued medical therapy or medical therapy alone. The improvements in CCS angina class and indices of quality of life were similar to those in the study by Frazier and colleagues [76]. However, Allen and coworkers [77], found no change in myocardial perfusion between the two treatment groups.

These authors are to be congratulated for assembling a large volume of randomized, clinical data to evaluate this technology. Although the improvement in myocardial perfusion demonstrated by Frazier and colleagues [76] is encouraging, the failure of the study by Allen and associates [77] and the randomized trial published by Schofield and coworkers [29] to show statistically significant improvement in perfusion after TMR is of concern. These studies used different types of lasers, the study by Allen and colleagues [77] utilizing the Holmium: YAG and the studies by Frazier and coworkers [76] and Schofield and colleagues [29] using the carbon dioxide laser. As discussed in the editorial published in the same issue of the New England Journal of Medicine as the studies by the former two authors, the improvement in angina appears to be out of proportion to any demonstrable improvement in myocardial perfusion [78]. Taken together these studies confirm that the actual mechanism of TMR-included angina relief remains controversial.

	References

Top Abstract Introduction Types of laser used... Evidence of angiogenesis Quantitative measurement of... Assessment of myocardial blood... Effect of TMR on... Denervation of myocardium Clinical results of TMR Percutaneous myocardial... Comment Addendum References

 

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