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Ann Thorac Surg 1999;67:423-431
© 1999 The Society of Thoracic Surgeons
a Cullen Cardiovascular Research Laboratories, Texas Heart Institute/St. Luke’s Episcopal Hospital, Houston, Texas, USA
b Department of Adult Cardiology, Texas Heart Institute/St. Luke’s Episcopal Hospital, Houston, Texas, USA
c Department of Cardiovascular Pathology, Texas Heart Institute/St. Luke’s Episcopal Hospital, Houston, Texas, USA
d Department of Cardiovascular Surgery, Texas Heart Institute, St. Luke’s Episcopal Hospital, Houston, Texas, USA
Accepted for publication June 30, 1998.
Address reprint requests to Dr Kadipasaoglu, Texas Heart Institute, MC 1-268, PO Box 20345, Houston, TX 77225-0345
e-mail: kkadison{at}biost1.thi.tmc.edu
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Abstract |
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 Top Abstract IntroductionMaterial and methodsResultsCommentAcknowledgmentsReferences |
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Methods. We used a continuous-wave, chopped CO2 laser (20 J/pulse, 15 ms/pulse) synchronized with the R wave; a holmium:yttrium aluminum garnet (Ho:YAG) laser (2 J/pulse, 250 µs/pulse, 5 Hz); and a xenon-chloride (excimer, Xe:Cl) laser (35 mJ/pulse, 20 ns/pulse, 30 Hz). Each laser was used 30 times as the sole modality in four consecutive pigs, yielding 120 channels.
Results. The average number of pulses needed to create a channel was 1, 11 ± 4, and 37 ± 8 for the CO2, Ho:YAG, and Xe:Cl lasers, respectively. All Ho:YAG and Xe:Cl channels had premature ventricular contractions. Ventricular tachycardia occurred in 70% of the Xe:Cl and 60% of the Ho:YAG channels. Only 36% of the CO2 channels had premature ventricular contractions, and only 3% of the CO2 channels had ventricular tachycardia (p < 0.001 versus Ho:YAG and Xe:Cl). Ho:YAG channels were highly irregular: each had a 0.6-mm-wide central zone surrounded by a ring of coagulation necrosis (diameter, 1.84 ± 0.67 mm) with effaced cellular architecture in a thin hemorrhagic zone. The Xe:Cl sections exhibited the same patterns on a smaller scale (diameter, 0.74 ± 0.18 mm). The CO2 channels were straight and well demarcated. The zone of structural and thermal damage extended over half the channel’s diameter, measuring 0.52 ± 0.25 mm.
Conclusions. During transmyocardial laser revascularization, the CO2 laser synchronized with the R wave is significantly less arrhythmogenic than the Ho:YAG and Xe:Cl lasers not synchronized with the R wave. In addition, the interaction of the CO2 laser with porcine cardiac tissue is significantly less traumatic than that of the Ho:YAG and the Xe:Cl lasers.
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Introduction |
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Despite the apparent clinical benefit of TMLR, some acute aspects of the technique, pertaining to its application and biologic tissue interaction, require further investigation. First, the arrhythmogenicity associated with irradiation of cardiac tissue at various intervals during the cardiac cycle has not been systematically investigated. Empirical observations during early animal experiments have suggested that if the laser is activated during repolarization of the myocardial cells (ie, during the T wave), the incidence of arrhythmic disturbances is increased, leading to an adverse outcome [2]. The arrhythmogenicity of the laser when fired during the T wave could be relevant to the choice of the laser source and the laser’s radiation pattern. Because the ablation speed in cardiovascular tissue is directly proportional to the pulse energy [3, 4], a laser with a sufficiently high pulse energy can create a channel with a single pulse. If this pulse is synchronized so as not to coincide with the T wave, arrhythmogenicity may be circumvented. At lower pulse energies (lower ablation speeds), however, delivery of multiple continuous pulse trains becomes necessary to create a TMLR channel. Because a number of these pulses will coincide with the T wave, arrhythmogenicity could become important. Thus, researchers need to determine whether multiple-pulse TMLR without electrocardiographic synchronization has a harmful effect on the electrical activity of the ventricle.
Another aspect of TMLR involves the effect of laser-induced acute tissue damage on the long-term patency of the channels. Early experiments in which channels were bored by means of needle acupuncture suggested that channel occlusion by scar tissue was caused by an extensive fibrous reaction secondary to mechanical damage [5]. More recent research into basic laser–tissue interactions has shown that the mechanical component, measured as acoustic tissue damage, increases in direct proportion to the peak power of the laser source [6]. The peak power of the laser pulse, defined as the laser energy delivered per unit time, increases significantly with a decreasing pulse duration. Therefore, with short-pulse lasers, the duration of the laser pulse may be one of the major determinants of the degree of initial tissue trauma and, hence, of the long-term patency of the laser channels.
Thus, an analysis of the relative arrhythmogenicity and trauma-inducing potential of various laser sources currently available for TMLR would be important, because it could affect perioperative arrhythmic complications and increase long-term efficacy. In the present study, we assessed the incidence of arrhythmias and the amount of tissue damage associated with three different lasers during TMLR in normal porcine hearts: the high-energy, long-pulse CO2 laser and the low-energy, short-pulse holmium:yttrium aluminum garnet (Ho:YAG) and xenon-chloride (excimer, Xe:Cl) lasers.
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Material and methods |
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TopAbstractIntroductionMaterial and methodsResultsCommentAcknowledgmentsReferences |
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Animal preparation, surgery, and instrumentation
Domestic pigs weighing approximately 56.2 to 67.5 kg were acclimatized and quarantined for at least 1 week before undergoing surgical intervention. After the animals had fasted overnight, a preanesthetic regimen was induced with acepromazine maleate (0.11 to 0.22 mg/kg intramuscularly, not exceeding a total dose of 15 mg) and atropine sulfate (0.05 mg/kg intramuscularly, premixed in the syringe). An ear vein was catheterized, and general anesthesia with ketamine hydrochloride (20 mg/kg intravenously) was started 10 minutes after the preanesthetic injection. The animals were then intubated, and anesthesia was maintained throughout the operation by means of an isoflurane and oxygen mixture.
Each animal was positioned on its right side on an electrocoagulation electrode and a warming blanket to maintain its body temperature at 41°C. The body temperature was monitored nasally. Surface electrocardiographic electrodes were applied, and the electrocardiographic waveform during and after the laser procedure was recorded on a computerized data collection and analysis system (Dataflow; Crystal Biotech, Northborough, MA). Intravenous catheters were placed in the left jugular vein for further infusion of medications and in the carotid artery for monitoring the arterial pressure. A left thoracotomy was performed in the fourth intercostal space. The pericardium was exposed and cut in a T shape, and the heart was isolated in a pericardial cradle. To prevent muscle spasms, pancuronium bromide (0.1 mg/kg intravenously) was given for one time only. After creation of the laser channels, the experiment was terminated by injecting the unconscious animal intravenously with a euthanizing agent (Beuthanasia solution Delmarva Laboratories Inc, Midlothian, VA).
Transmyocardial laser revascularization modalities
We used a high-energy CO2 laser (Heart Laser; PLC Medical Systems, Inc), a Ho:YAG laser (Laser Photonics, Sunnyvale, CA), and an Xe:Cl laser (Advanced Interventional Systems, Scottsdale, AZ).
Activation of the CO2 laser was adjusted to coincide with the electrocardiographic R wave, and pulses were delivered at 25 J. Because this laser’s average output power is fixed at 800 W, this pulse energy setting corresponded to a pulse duration of 31 ms. The pulses were separated from each other by at least 1 minute to achieve adequate hemostasis. In a separate set of experiments, CO2 laser emission was set to coincide with the T wave. The Ho:YAG laser was set to a pulse energy of 2 J/pulse and a pulsing frequency of 5 Hz. The Xe:Cl laser was set to an output energy of 0.035 J/pulse and a pulsing frequency of 30 Hz. The pulse duration of the Ho:YAG and the Xe:Cl lasers was fixed at 250 x 10-3 ms and 20 x 10-9 ms, respectively. These settings corresponded to peak powers of 8,000 W for the Ho:YAG laser and 175 x 103 W for the Xe:Cl laser. Both lasers were coupled to a silica fiber (outer diameter, 600 µm), and laser ablation was continued with gentle forward pressure until the full thickness of the myocardium was penetrated. In some additional cases, the fiber was advanced without activating the laser, to assess the arrhythmogenicity of the fiber alone. In other cases, the laser was activated during both forward motion (toward the ventricular cavity) and backward motion of the fiber.
Histologic studies
Porcine hearts subjected to TMLR in vivo were flushed with 2 L of 4°C physiologic saline (retrograde through the cannulated thoracic aorta, at 40 mm Hg) and then with 1 L of 10% buffered formalin. Each heart was removed and photographed, and transmural sections of laser tracks were taken for microscopic evaluation. A minimum of four blocks from representative areas of each heart were examined grossly and microscopically. Sections for microscopic studies were processed using standard paraffin-embedding techniques. Five-micrometer paraffin-embedded sections were stained with hematoxylin and eosin. Slides were coded and examined. After all sections were evaluated, the descriptions were collated by type of laser.
Experimental design and data analysis
The electrocardiographic and systemic arterial waveforms during and after the lasing procedure were recorded on the data analysis system. Each heart was treated with a single laser modality, so that 30 channels were created in the anterolateral aspect of the myocardium. To eliminate interanimal variability, the same laser modality was used on 4 consecutive animals (total, 120 channels for each laser modality). The experiments were performed in an acute setting.
The results of the experiments were evaluated separately for each laser modality. Premature ventricular contractions (PVCs), ventricular tachycardia (VT), and other changes in cardiac rhythm, as recorded by continuous electrocardiography, were classified as events. Premature ventricular contractions were differentiated from other changes by the accompanying compensatory pause. Runs of three or more PVCs in a row were classified as a VT episode. The number of events per channel was analyzed from analog and digital tracings recorded during TMLR. Table 1 shows the total number of events per channel and the classification of these events for each laser modality.
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[ = p (1 - p)], of the binomial distribution of the outcomes (arrhythmia or no arrhythmia) with each laser modality. For an acceptable standard error of 10% around the mean proportion, p, of occurrence of arrhythmias with each laser modality, the minimum number, n, of laser pulses that should be delivered with each laser modality was calculated with the following formula:
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= 0.05). Carrying on the calculation gives n = 96, which means that to detect a significant difference between the arrhythmic effects of each laser modality, at least 96 channels should be created with each modality. To preserve regional myocardial structural integrity, we refrained from creating more than 30 channels per animal. Because each laser modality was used on 4 different animals to account for interanimal variability, a total of 120 channels were created with each laser modality in a total of 4 animals. This arrangement gave us an additional margin of safety of 120/96 = 1.25, or 25% above the minimum number of channels required for statistical significance.
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Results |
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Arrhythmia experiments
During creation of the 120 channels with the Ho:YAG laser, a total of 431 events were recorded in 117 channels (98%), at an average rate of 3.68 events per channel (Table 1). All but one of the events were PVCs, occurring in 116 channels (97%). In 74 cases, distributed among 68 channels (60%), the PVCs occurred in runs of three or more, qualifying for classification as VT. The PVCs and VT episodes consistently occurred when the laser was activated, regardless of the direction of motion of the catheter, as long as the fiber was in contact with the myocardial tissue (Fig 1A). A brief pause in the generation of arrhythmias occurred when the fiber tip was fired into the blood within the ventricular cavity (Fig 1A). The laser fiber itself was also arrhythmogenic: by simply poking the transmural channel without firing the laser, we elicited arrhythmias in some cases (Fig 1B).
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When the CO2 laser was synchronized with the R wave, 164 arrhythmic events were recorded in 70 channels (60%), for an average of 2.34 events per channel (p < 0.01 versus the Ho:YAG and Xe:Cl lasers, Table 1). Of the 164 events, 87 (53%) were associated with changes that did not involve a PVC-type morphology, but rather, consisted of a transient, minimal elevation of the signal voltage or duration (Fig 1D); 77 events (47%) involved a PVC-type morphology. In four instances, the PVCs progressed to a nonsustained episode of VT. The 77 PVCs occurred in 43 channels (36%), and the four VT episodes occurred in four channels (3%) (p < 0.001 versus the Ho:YAG and Xe:Cl lasers). The remaining 50 channels (42%) were arrhythmia-free (Fig 1E). When the CO2 laser was fired during the T wave, 332 events were recorded. Of the 120 channels, 103 (86%) were associated with at least one event, and the average number of events per channel was 3.22 (p < 0.001 versus the CO2 laser fired during the R wave). Of the 332 events, 325 (98%), occurring in 97 channels (81%), involved PVC-type morphology (p < 0.01 versus the CO2 fired during the R wave). A total of 26 VT episodes were observed in 18 channels (15%). This was significantly less compared with the Ho:YAG- and Xe:Cl-induced VT episodes (p < 0.01).
In Figure 2, the results of the arrhythmia experiments are presented in graphic form with respect to the number of events per channel (Fig 2A) and the percentage of channels that had an event (Fig 2B).
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The extent of damage in each zone varied according to the laser used. Table 2 shows the cumulative width of the various laser zones observed on light microscopy. Volumetric damage to the tissues was calculated from the single-dimensional measurements, assuming the presence of cylindrical channels in a 20-mm-thick myocardium.
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Comment |
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TopAbstractIntroductionMaterial and methodsResultsCommentAcknowledgmentsReferences |
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We have been using the CO2 laser in clinical trials since June 1993. We therefore had access to it for experimental studies. However, despite our requests, we were not able to obtain the Ho:YAG or the Xe:Cl laser hardware directly from the manufacturer of a clinically used model. Therefore, we substituted alternative commercial models for these laser modalities. Our understanding was that the nature of the laser–tissue interactions would not be affected so long as the clinically important variables, ie, the respective wavelengths (308 nm and 2,010 nm), delivery systems (600-µm optical silica fibers), and settings for pulse energy and repetition rate (see Methods) were kept identical to current clinical specifications. It should be noted, however, that there is at least one manufactured Ho:YAG modality that is undergoing clinical evaluation and that is gated to the R wave. Therefore, the conclusions drawn from the present results may not apply to this modality.
The first factor of interest in this study was the rate of generation of complex arrhythmias associated with the creation of a single channel using the three different laser modalities. When the CO2, Ho:YAG, and Xe:Cl lasers were fired during the cardiac repolarization period (ie, during the T wave), all three lasers caused a high incidence of PVC arrhythmias (98%, 100%, and 100%, respectively). The incidence of VT, however, was significantly higher with the Ho:YAG (60%) and Xe:Cl (70%) instruments than with the CO2 laser (15%). This finding suggests that complex ventricular arrhythmias may be influenced by the type of laser when firing of the laser is not synchronized to occur away from the T wave. The incidence of VT with the CO2 laser was further reduced when that laser was fired during the depolarization period (R wave). This fact supports our initial hypothesis that arrhythmias during ablation are influenced by the time of lasing with respect to the cardiac cycle.
The hearts of patients undergoing TMLR are vulnerable to arrhythmias [11]. The presence of scar tissue or periinfarct ischemia is a well-known risk factor for reentrant ventricular tachyarrhythmias [12]. Because extracorporeal cardiopulmonary support is not used, the duration of TMLR is shortened; nevertheless, left-side volume overload and circumferential ventricular stress, which often accompany ischemic cardiomyopathy, predispose these patients to ventricular and supraventricular arrhythmias.
In the initial 35-patient series treated at our hospital (which reflects our early experience in using TMLR with a CO2 laser [13, 14] either as sole therapy or as an adjunct to coronary artery bypass grafting between July 1993 and July 1995), 28 patients had a history of major arrhythmias such as frequent PVCs and runs of VT, pacemaker-dependent syncope, or cardiac arrest at baseline. After TMLR, 17 (61%) of these patients had one or more arrhythmic sequelae, 7 of which proved fatal despite the aggressive use of various antiarrhythmic agents. Only 3 (11%) of the 28 patients had no arrhythmias postoperatively. In 9 (32%) of the 28 patients with a history of major arrhythmias, the postoperative arrhythmias were similar to those seen at baseline. The 7 patients without a history of arrhythmias at baseline had no postoperative complications. The increased perioperative incidence of arrhythmic complications in patients predisposed to arrhythmia suggests that TMLR exacerbates the electrical vulnerability of the myocardium, even when the operation is performed with the least arrhythmogenic modality (the CO2 laser synchronized with the R wave). Thus, the threat of arrhythmias is a major limitation to the more widespread application of TMLR. Use of optimal laser ablation parameters and synchronization with the cardiac cycle are highly important. In light of our findings, TMLR should be done with extreme caution when the nonsynchronized laser modalities are used. In the current randomized phase of the clinical TMLR trials, patients with a history of major arrhythmias are excluded.
The second factor of interest in our study was the relative extent of the tissue damage caused by the currently available TMLR laser modalities. The thermal and acoustic damage that surrounded the transmyocardial channel was significantly greater with the Ho:YAG and Xe:Cl lasers than with the CO2 laser. It is important to note that we did not test to determine whether the difference in arrhythmogenic effect with the three lasers was causally related to the different amount of tissue damage that each laser created in our heart model. However, as discussed below, the trauma-inducing capacity may arguably govern the long-term patency of the laser channels. The damage imparted to the target tissue was considerably less with the CO2 laser than with the other two laser modalities. The damage was predominantly thermal in the immediate vicinity of the channels and structural in the outlying layers. The gross appearance of the channels closely reflected the geometry of channels created in tissue phantoms observed under fast video cinegrams [15]. The extent of the damage was also in agreement with the acute effects that Fisher and associates [16] observed in CO2- and Ho:YAG-treated cardiac tissue.
Ablation of cardiovascular tissue with laser energy is governed not only by the thermal- and light-distribution characteristics of the tissue but also by the nonadjustable settings of the laser pulse. The important parameters of the laser pulse are its energy, duration, and frequency. For a given amount of energy delivered per laser pulse, the peak power (energy over time) will increase with a decrease in the pulse duration. Therefore, with ultrashort pulses, the peak power will be very high, even at a relatively low pulse energy. The higher the peak power, the faster the rate at which the pulse energy is delivered to the tissue. Any excess energy not used for active ablation is used to heat the tissue, and that heat should eventually dissipate by means of conductive processes. If a high pulse frequency, however, causes heat to build up within a confined tissue space faster than it can be dissipated, water vapor bubbles will form. The explosive collapse of these bubbles will send shock waves through the adjacent tissue layers. As this acoustic effect radiates from the ablation site in all directions, it will rip the tissue apart and superimpose a considerable structural component on the already existing thermal damage [6].
On histomorphometric analysis of our CO2 laser-treated tissues, the combined thermal and structural components of the laser-induced damage extended through a zone of 0.52 ± 0.25 mm on each side of the channel in planar cross-sections (Table 2). Assuming that the laser channels had a cylindrical geometry in a 20-mm-thick porcine myocardium, the volume of damaged myocardium was calculated as 1.49 ± 1.03 cm3, excluding the channel volume itself. The total volume of damaged tissue was calculated as 1.87 ± 0.72 cm3 for the Xe:Cl laser and 8.46 ± 5.35 cm3 for the Ho:YAG laser. Therefore, these two lasers respectively produced 25% and 568% more volumetric damage than did the CO2 laser. If the intensity of the fibrous repair process is indeed proportional to the extent of the damage, the tissue reaction to Ho:YAG and Xe:Cl laser ablation will be that much greater than the reaction to CO2 laser ablation. Therefore, unlike TMLR with the CO2 laser [17], TMLR with the Ho:YAG and Xe:Cl lasers may not be compatible with long-term channel patency; according to one untested theory, however, it may enhance angiogenesis [18].
In conclusion, compared with the high-energy CO2 laser, the lower energy Ho:YAG and Xe:Cl lasers that were not synchronized to the subject’s electrocardiogram were more arrhythmogenic owing to the necessity of delivering multiple pulses per TMLR channel. Also, the Ho:YAG and Xe:Cl lasers, which have a shorter pulse duration than the CO2 device, were more traumatic to cardiovascular tissue, possibly owing to the development of high peak powers. One way to minimize these adverse reactions may be to synchronize activation of the Ho:YAG and Xe:Cl lasers with the subject’s electrocardiographic waveform. Whether the comparative effects observed in our animal model can be extrapolated to the clinical setting is a question that should be evaluated in controlled, multicenter, clinical trials.
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Acknowledgments |
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TopAbstractIntroductionMaterial and methodsResultsCommentAcknowledgmentsReferences |
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This work was partially supported by PLC Systems, Inc., Franklin, MA.
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References |
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TopAbstractIntroductionMaterial and methodsResultsCommentAcknowledgmentsReferences |
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This article has been cited by other articles:
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  K. A. Horvath and Y. Zhou Transmyocardial Laser Revascularization and Extravascular Angiogenetic Techniques to Increase Myocardial Blood Flow Card. Surg. Adult, January 1, 2008; 3(2008): 733 - 752. [Full Text]
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M. Ruel, R. A. Kelly, and F. W. Sellke Therapeutic Angiogenesis, Transmyocardial Laser Revascularization, and Cell Therapy Card. Surg. Adult, January 1, 2003; 2(2003): 715 - 750. [Full Text]
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 K. A. Horvath, S. F. Aranki, L. H. Cohn, R. J. March, O. H. Frazier, K. A. Kadipasaoglu, S. W. Boyce, B. W. Lytle, K. P. Landolfo, J. E. Lowe, et al. Sustained Angina Relief 5 Years After Transmyocardial Laser Revascularization With a CO2 Laser Circulation, September 18, 2001; 104 (2009): I-81 - I-84. [Abstract] [Full Text] [PDF]
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 L. Y. Lee, M. F. O'Hara, E. B. Finnin, R. Hachamovitch, M. Szulc, P. D. Kligfield, P. M. Okin, O. W. Isom, and T. K. Rosengart Transmyocardial laser revascularization with excimer laser: clinical results at 1 year Ann. Thorac. Surg., August 1, 2000; 70(2): 498 - 503. [Abstract] [Full Text] [PDF]
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