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What is the Optimal Channel Density for Transmyocardial Laser Revascularization?
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What is the Optimal Channel Density for Transmyocardial Laser Revascularization? Samdeep K. Mouli, BS, Jeffrey Fronza, BS, Rodney Greene, BS, Emmanuel S. Robert, MS, and Keith A. Horvath, MD Division of Cardiothoracic Surgery, The Feinberg School of Medicine, Northwestern University, Chicago, Illinois
Background. Transmyocardial laser revascularization (TMR) has demonstrated reproducible relief of angina in patients with end-stage coronary disease. However, the optimum dose or channel density has not been elucidated. Methods. Using a porcine model of chronic myocardial ischemia, 14 animals were treated with CO2 TMR and randomized as follows: group 1 was 1 channel per 2 cm2; group 2 was 1 channel per 1 cm2; and group 3 was 2 channels per 1 cm2. Left ventricular myocardial viability and function were assessed by magnetic resonance imaging (MRI) and echocardiography pretreatment, and repeated 6 weeks later. Results. The MRI assessment of group 1 (1 channel/2 cm2) and group 2 (1 channel/cm2) demonstrated similar improvement in segmental contractility posttreatment of 12.11% ⴞ 5.15% and 12.47% ⴞ 9.51%, respectively. In
contrast, group 3 (2 channels/cm2) showed significantly worse segmental contractility posttreatment: ⴚ18.52% ⴞ 7.16% (p ⴝ 0.01). Echocardiographic imaging revealed significant improvements in wall thickening in the ischemic zone for group 1 at 0.91 ⴞ 0.07 cm pretreatment versus 1.30 ⴞ 0.09 cm posttreatment, (p ⴝ 0.01); and for group 2 at 0.93 ⴞ 0.11 cm versus 1.42 ⴞ 0.18 cm, (p ⴝ 0.01). No significant improvement in wall thickening was seen in group 3 (0.84 ⴞ 0.06 cm versus 0.88 ⴞ 0.09 cm, p ⴝ n.s.). Conclusions. These data corroborate the empiric finding of an effective therapeutic dose range for TMR, 1 channel per 1 to 2 cm2. These results also demonstrate a detrimental effect when channel density is increased above the clinical standard of 1 channel per cm2 to a density of 2 channels per 1 cm2. (Ann Thorac Surg 2004;78:1326 –31) © 2004 by The Society of Thoracic Surgeons
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which TMR’s clinical benefit can be achieved. The purpose of this study was to determine the optimal channel density for CO2 TMR.
nd-stage coronary artery disease afflicts a growing number of patients whose diffuse stenoses are refractory to the traditional treatment modalities of coronary artery bypass grafting (CABG) and percutaneous coronary intervention (PCI). Transmyocardial laser revascularization (TMR) has evolved to treat these patients. Since 1993 more than 15,000 patients with chronic angina pectoris have been treated with TMR using a CO2 laser [1–12]. Clinical studies have demonstrated significant reduction in angina symptoms, decreased ischemia, improved myocardial function, and increased perfusion as a result of CO2 TMR therapy [1–12]. Previously we have experimentally demonstrated that this functional recovery may be due to a minimization of scar formation with a maximization of angiogenesis [13]. Several studies achieving these results reported a wide range of 25 to 48 TMR channels per patient. Empirically, most investigators employed a density of one channel per square centimeter (cm2) of ischemic myocardium [1–12]. Experimental evidence to determine the optimal CO2 TMR channel distribution is scant. Such work is necessary to delineate the therapeutic window within Accepted for publication April 14, 2004. Presented at the Fortieth Annual Meeting of The Society of Thoracic Surgeons, San Antonio, TX, Jan 26 –28, 2004. Address reprint requests to Dr Horvath, Division of Cardiothoracic Surgery, Northwestern University Medical School, 201 E Huron St, Galter 10-105, Chicago, IL 60611; e-mail: [email protected].
© 2004 by The Society of Thoracic Surgeons Published by Elsevier Inc
Material and Methods Operative Technique In order to mimic the clinical scenario, we employed a standard animal model of chronic myocardial ischemia [14, 15]. Seventeen Yorkshire pigs, weighing 12 to 15 kg, were preanesthetized with ketamine (15 mg/kg), acepromazine (0.15 mg/kg), and atropine (2 mg) intramuscularly, followed by brevital (11 mg/kg) IV. After intubation, anesthesia was maintained with isoflurane (0.5% to 2.0%; Abbott Laboratories, Chicago, IL) delivered in 60%/40% nitrous oxide. Bupivacaine (0.5 mL/kg) was infiltrated into the subcutaneous tissue along the incision to provide immediate postoperative analgesia. Buprenex (0.01 mg/kg) was given 30 minutes before the end of surgery and again every 12 hours for a minimum of 48 hours for postoperative analgesia. To reduce the risk of arrhythmias, bretylium (1 mg/kg) was administered intravenously and nitropaste (2 inches) was applied topically. The same anesthetic regimen was used for each of the three different surgical procedures that were performed. At the initial operation, using sterile technique, the heart was exposed through a small left thoracotomy, and 0003-4975/04/$30.00 doi:10.1016/j.athoracsur.2004.04.047
the pericardium was opened. The proximal left circumflex artery was dissected free, and an ameroid constrictor (Research Instruments SW, Escondido, CA) with an internal diameter of 2.5 mm was placed around the origin of the left circumflex artery. The pericardium and chest were then closed. The animals were allowed to recover and were ambulatory before leaving the operating room suite. They were monitored daily by a veterinarian and his staff as well as by the surgical team. Antibiotics were administered intramuscularly for 3 days postoperatively. Pain medications were also given intramuscularly until the animals were ambulating without difficulty and exhibiting normal activity levels. Adequate food and water were provided, and intakes, as well as weights, were measured daily. Five weeks following placement of the ameroid constrictor, immediately before TMR treatment (operation 2), the animals (now 50 to 60 kg), while anesthetized, were scanned on a 1.5-T Siemens Symphony Scanner (Siemens Medical Systems, Erlangen, Germany). Shortaxis images every 10 mm were performed to cover the entire left ventricular volume. The cine magnetic resonance images (MRI) provided evaluation of regional myocardial contractility, and demonstrated ischemic myocardium that was hypocontractile, and consistent with historical controls [13, 16, 17]. In addition, contrastenhanced MRI was used to confirm viability and rule out infarction. Animals received a clinically approved contrast agent intravenously (Magnevist, Abbott Laboratories; 0.2 mmol/kg weight; maximum rate of 10 mL/15 seconds), then MRI images were acquired at each of the cine short-axis locations. Cine MRI scanning was immediately followed by a second operation, through a larger left thoracotomy, where the pericardium was reopened and the heart was reexposed. Blood pressure and electrocardiographic monitoring was used. Rest and dobutamine stress epicardial echocardiography (7.5 MHz, model 128; Acuson Inc., Mountain View, CA) were performed to provide an assessment of the viability of the myocardium and to determine the extent of the ischemia. Data derived from this initial base line assessment was consistent with historical controls [13, 16, 17]. Dobutamine was administered intravenously starting at 5 g 䡠 kg⫺1 䡠 min⫺1 and titrated to a maximum infusion rate of 50 g 䡠 kg⫺1 䡠 min⫺1 to achieve a 100% increase in the resting heart rate. There was no significant difference in the resting heart rate at operation 2 or operation 3. Similarly there was no significant difference between the stress heart rates between operations 2 and 3. Mean arterial pressure demonstrated a modest increase with stress and there was no significant difference between the resting and stress blood pressure measurements for operation 2 versus operation 3. The 17 animals were randomized into one of three treatment groups before operation 2. Each animal underwent treatment to the circumflex territory (ischemic zone) with CO2 TMR (PLC Medical Systems, Franklin, MA). Group 1 received TMR treatment with a transmural channel density of one channel per 2 cm2, for a total of 10
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TMR channels. Group 2 had a channel distribution of one channel per square centimeter, for a total of 20 TMR channels. Group 3 received 2 channels per square centimeter in the ischemic zone, or 40 TMR channels. The total channel numbers mentioned above are absolute values without deviation. The thoracotomies were then closed and the animals were allowed to recover. The previously mentioned postoperative care was then reinstituted. Six weeks later (operation 3) animals had a repeat thoracotomy. At that time, they underwent repeat rest and dobutamine stress echocardiography, as well as repeat contrast-enhanced and cine MRI. In addition, postsacrifice tissue harvesting was done for each animal during which we identified the ameroid constrictor and demonstrated it to be fully constricted in every case.
Magnetic Resonance Imaging Analysis Regional contractility, as measured by wall thickening, was determined by commercial software (Argus, Siemens) in 15 segments in the ischemic zone by the modified centerline method. The ischemic zone was defined as the region of the left ventricle perfused by the gradually occluded circumflex artery. Epicardial and endocardial contours were identified and percent wall thickening calculated. This measurement was performed for the short-axis image depicting the midpapillary region of the left ventricle, as well as one image above (10 mm) and one image below (10 mm) this region. With contrast enhancement, areas with an infarction appear hyperenhanced. Before randomization, animals with significant infarction were excluded from the study.
Echocardiographic Analysis The echocardiographic images were recorded onto a half-inch videotape. End-diastolic and end-systolic images were then digitized off-line from the videotape with a dedicated software package (Prism Lite for Windows, Version 5.14; Tomtec Imaging Systems, Broomfield, CO). The digitized images were spatially calibrated, and the endocardial contours were traced. The software then automatically calculated the wall motion along the 100 evenly distributed lines of site around the contour. By standard segmental contraction analysis, the mean wall motion score for each segment was obtained (48 segments for each short-axis image). Segmental contraction was defined as the change in wall thickness between systole and diastole as measured in centimeters. Magnetic resonance imaging and echocardiographic analysis was performed by an independent observer blinded to the treatment that the animals received. Segmental contraction was compared in all segments at all times using each animal as its own control. The changes in the treatment region were compared to the results seen in the region of the left ventricle not supplied by the circumflex artery. The latter region, the nonischemic zone, remains unaffected by the occlusion of the circumflex artery. The myocardium of this region should therefore remain unchanged between pretreatment and posttreatment. Thus, any difference demonstrated in the
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CARDIOVASCULAR Fig 1. Cine MRI results of regional contractility in the treated area for group 1 (1 channel/2 cm2) and group 2 (1 channel/cm2) demonstrated similar improvement in segmental contractility posttreatment of 12.11% ⫾ 5.15% and 12.47% ⫾ 9.51%, respectively. In contrast, group 3 (2 channels/cm2) did not show improvement posttreatment, with segmental contractility being significantly worse than baseline: ⫺18.52% ⫾ 7.16% (p ⫽ 0.01). Additionally, there was a significant difference for the posttreatment results between group 1 and group 2 versus group 3 (p ⫽ 0.01). ■ ⫽ 1 channel/2 cm2; 䊐 ⫽ 1 channel/ cm2; o ⫽ 2 channels/cm2. (MRI ⫽ magnetic resonance imaging; TMR ⫽ transmyocardial laser revascularization.)
treatment group between pretreatment and posttreatment can be attributed to the effects of TMR.
Statistical Analysis
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Cine MRI results of regional contractility in the treated area are depicted in Figure 1. Group 1 (1 channel/2 cm2) and group 2 (1 channel/cm2) demonstrated similar improvement in segmental contractility posttreatment of 12.11% ⫾ 5.15% and 12.47% ⫾ 9.51%, respectively. In contrast, group 3 (2 channels/cm2) did not show improvement posttreatment, with segmental contractility being significantly worse than baseline: ⫺18.52% ⫾ 7.16% (p ⫽ 0.01). Echocardiographic measurement of segmental wall motion in the ischemic zone at baseline and posttreatment for all three groups are depicted in Figure 2. The posttreatment resting function revealed significant improvements in wall thickening in the ischemic zone for group 1 at 0.91 ⫾ 0.07 cm pretreatment versus1.30 ⫾ 0.09 cm posttreatment, (p ⫽ 0.01); and for group 2 at 0.93 ⫾ 0.11 cm pretreatment versus 1.42 ⫾ 0.18 cm posttreatment (p ⫽ 0.01). Echocardiographic results demonstrated no significant improvement in wall thickening for group 3: 0.84 ⫾ 0.06 cm pretreatment versus 0.88 ⫾ 0.09 cm posttreatment, (p ⫽ not significant). Comparing functional improvement based on MRI and echocardiographic analysis, there was no significant difference between group 1 and group 2 (p ⫽ NS) after TMR. However, there was a significant difference for the posttreatment results between these groups versus group 3 (1 vs 3: p ⫽ 0.01; 2 vs 3: p ⫽ 0.01).
Comment Much work has been done to ascertain the exact mechanism of the clinical improvement seen with TMR. Angiogenesis, as a result of the healing response to tissue
Continuous data are presented as a mean ⫾ standard error. Changes in contractility were assessed using a paired t-test for each treatment group. A Bonferroni correction was used as needed for repeated measures over time. All statistical tests were two-tailed, and p value less than 0.05 was regarded as statistically significant.
Results A total of 14 animals were originally enrolled in this study and randomized among the three treatment groups. Three of these animals, specifically from group 3, died before final analysis. Therefore additional animals were enrolled to compensate for the deaths observed in group 3. Seventeen animals were treated in total, however only 14 survived until final analysis. The 14 animals were divided into the three groups: group 1 (n ⫽ 5), group 2 (n ⫽ 4), group 3 (n ⫽ 5). The segmental wall motion after placement of the ameroid constrictor (operation 2) demonstrated hypokinesis of the ischemic zone myocardium subtended by occlusion. There was no change in wall motion after operation 2 in the nonischemic zone. There was no significant difference in the baseline resting function for all animals (p ⫽ not significant [NS]) at operation 2, and these results are consistent with historic controls [16].
Fig 2. Echocardiography results revealed significant improvements in wall thickening in the ischemic zone for group 1 at 0.91 ⫾ 0.07 cm pretreatment versus 1.30 ⫾ 0.09 cm posttreatment (p ⫽ 0.01); and for group 2 at 0.93 ⫾ 0.11 cm pretreatment versus 1.42 ⫾ 0.18 cm posttreatment (p ⫽ 0.01). Echocardiographic results demonstrated no significant improvement in wall thickening for group 3 (0.84 ⫾ 0.06 cm pretreatment versus 0.88 ⫾ 0.09 cm posttreatment; p ⫽ not significant [n.s.]). In addition there was a significant difference for the posttreatment results between group 1 and 2 versus group 3 (p ⫽ 0.01). 䊐 ⫽ pretreatment; ■ ⫽ posttreatment.
injury caused by laser ablation, may play a pivotal role in achieving this clinical benefit. However, the injury that induces angiogenesis must not be so great as to cause more harm to the myocardium than good. If the injury produced by the laser destroys tissue such that the resulting scar is vascularized but acontractile, it will be at the expense of functional improvement for the patient. In addition to forming new blood vessels that increase myocardial perfusion, obtaining functional recovery of the ischemic myocardium is essential. Such functional recovery has been demonstrated both experimentally and clinically after laser TMR [16, 18, 19]. Experiments in a large animal model of chronic ischemia have demonstrated reduction in infarct size, as well as an improvement in myocardial contractility after CO2 TMR [2–3]. Further study has revealed histologic evidence of angiogenesis after TMR treatment [20 –23]. In previous studies, we have demonstrated that the functional improvement seen was likely a result of angiogenesis through the upregulation of vascular endothelial growth factor [16, 24]. Despite several previous studies designed to elucidate the mechanism behind TMR’s benefit, little has been done to elaborate a dosage response curve for this procedure. The current clinical dosage standard for CO2 TMR remains at 1 channel per cm2; however data demonstrating that this is the optimal channel density for the patient was lacking. The results of the present TMR study demonstrate a significant improvement with a channel density of 1 channel per 2 cm2 to 1 channel per cm2, as demonstrated by an improvement in myocardial contractility posttreatment. The data also reveals an upward limit for the therapeutic range of TMR, with a significant detrimental effect when channel density is increased to 2 channels per cm2. Here the damage due to the laser exceeded any possible therapeutic benefit, causing severe deterioration in myocardial function. It should also be noted that 3 animals that received TMR treatment of 2 channels per cm2 died shortly before sacrifice. Previous work also attempted to define a dose response for TMR, albeit applying a considerably different laser [25]. The XeCl (excimer) laser has a markedly different tissue effect than CO2 TMR. It was concluded that excimer TMR enhances perfusion as a result of an induced angiogenic response, which correlated with the total channel number. This study differed from the current study in several ways. As outlined, the goal of the current study was to determine the relationship between channel density and the subsequent therapeutic response for CO2 TMR, an infrared laser that creates channels by thermal ablation. The previous study examined the effect of total channel number for the excimer laser, an ultraviolet laser that produces tissue damage by the dissociation of molecular bonds [26]. The inherent wavelength difference between CO2 and excimer lasers, and resultant difference in laser-tissue interaction, explains the difference in dosage-response observed between the two therapeutic approaches. Additionally, the previous study assessed outcomes using perfusion and
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histologic analysis rather than functional contractility data. As stated by the study’s authors, such data cannot be extrapolated to a high-energy laser such as CO2 TMR. A key limitation of the present work is that the results did not reveal a lower threshold at which functional angiogenesis occurs. Furthermore, the design of this study utilized a consistent laser energy level for each treatment group, while channel density was varied. Determining the optimal laser energy level while keeping the channel density within the established therapeutic window could provide a more complete dose response effect, and requires further study. Establishment of an optimal channel density is essential for any therapeutic intervention. Thus, the data derived from this study not only confirms the functional benefit of standard TMR channel density, but also helps establish the therapeutic limit of this surgical intervention. This research was supported by the National Institutes of Health 5R01HL064868 – 04.
References 1. Mirhoseini M, Cayton MM, Shelgikar S, Fisher JC. Clinical report: laser myocardial revascularization. Lasers Surg Med 1986;6:459 –61. 2. Horvath KA, Smith WJ, Laurence RG, et al. Improved shortand long-term recovery after an acute myocardial infarct treated by transmyocardial laser revascularization. Surg Forum 1993;44:220 –2. 3. Horvath KA, Smith WJ, Laurence RG, Appleyard RF, Cohn LH. Recovery and viability of an acute myocardial infarct after transmyocardial laser revascularization. J Am Coll Cardiol 1995;25:158 –63. 4. Frazier OH, Cooley DA, Kadipasaglu KA, et al. Myocardial revascularization with laser: preliminary findings. Circulation 1995;92(Suppl 2):1158 –65. 5. Horvath KA, Mannting FR, Cummings N, Shernan SK, Cohn LH. Transmyocardial laser revascularization: operative techniques and clinical results at two years. J Thorac Cardiovasc Surg 1996;4:1047–53. 6. Maisch B, Funck R, Herzum MD, et al. Does transmyocardial laser revascularization influence prognosis in endstage coronary artery disease? Circulation 1996;94(Suppl 1):295. 7. Horvath KA, Cohn LC, Cooley DA, et al. Transmyocardial revascularization: results of a multi-center trial using TLR as sole therapy for end stage coronary artery disease. J Thorac Cardiovasc Surg 1997;113:645–54. 8. Schofield PM, Sharples LD, Caine N, et al. Transmyocardial laser revascularization in patients with refractory angina: a randomized controlled trial. Lancet 1999;353:519 –24. 9. Horvath KA, Aranki SF, Cohn LH, et al. Sustained angina relief 5 years after transmyocardial laser revascularization with a CO2 laser. Circulation 2001;104(suppl 1):I-81–84. 10. Frazier OH, March RJ, Horvath KA. Transmyocardial revascularization with a carbon dioxide laser in patients with end-stage coronary artery disease. N Engl J Med 1999;341: 1021–8. 11. Aaberge L, Nordstrand K, Dragsund M, et al. Transmyocardial revascularization with CO2 laser in patients with refractory angina pectoris. Clinical results from the Norwegian randomized trial. J Am Coll Cardiol 2000;35:1170 –7. 12. Aaberge L, Rootwelt K, Blomhoff S, Saatvedt K, Abdelnoor M, Forfang K. Continued symptomatic improvement three to five years after transmyocardial revascularization with CO2 laser. A late clinical follow-up of the Norwegian ran-
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domized trial with transmyocardial revascularization. J Am Coll Cardiol 2002;39:1588 –93. Horvath KA, Belkind N, Wu I, et al. Functional comparison of transmyocardial revascularization by mechanical, and laser means. Ann Thorac Surg 2001;72:1997–2002. O’Konski MS, White FC, Longhurst JC, Roth DM, Bloor CM. Ameroid constriction of the proximal left circumflex coronary artery in swine. Am J Cardiovasc Pathol 1987;1:69 –77. Roth DM, Maruoka Y, Rogers J, White FC, Longhurst JC, Bloor CM. Development of coronary collateral circulation in left circumflex ameroid-occluded swine myocardium. Am J Physiol 1987;253(5 Pt 2):H1279 –88. Horvath KA, Greene R, Belkind N, Kane B, McPherson DD, Fullerton DA. Left ventricular functional improvement after transmyocardial laser revascularization. Ann Thorac Surg 1998;66:721–5. Horvath KA, Chiu E, Dipen CM, et al. Up-regulation of vascular endothelial growth factor mRNA, and angiogenesis after transmyocardial laser revascularization. Ann Thorac Surg 1999;68:825. Horvath KA, Kim RJ, Judd RM, Parker MA, Fullerton DA. Contrast enhanced MRI assessment of microinfarction after transmyocardial laser revascularization (abstr). Circulation 2000;102:II-765. Donovan CL, Landolfo KP, Lowe JE, Clements F, Coleman RB, Ryan T. Improvement in inducible ischemia during dobutamine stress echocardiography after transmyocardial
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laser revascularization in patients with refractory angina pectoris. J Am Coll Cardiol 1997;30:607–12. Fisher PE, Kohmoto T, DeRosa CM, Spotnitz HM, Smith CR, Burkhoff D. Histologic analysis of transmyocardial channels: comparison of CO2 and holmium:YAG lasers. Ann Thorac Surg 1997;64:466 –72. Kohmoto T, Fisher PE, Gu A, Smith CR, De Rosa C, Burkhoff D. Physiology, histology, and two week morphology of acute myocardial channels made with a CO2 laser. Ann Thorac Surg 1997;63:1275–83. Burkhoff D, Fisher PE, Apfelbaum M, Kohmoto T, DeRosa CM, Smith CR. Histologic appearance of transmyocardial laser channels after 4 1/2 weeks. Ann Thorac Surg 1996;61: 1532–5. Yamamoto N, Khomoto T, Gu A, De Rosa C, Smith CR, Burkhoff D. Angiogenesis is enhanced in ischemic canine myocardium by transmyocardial laser revascularization. J Am Coll Cardiol 1998;31:1426 –33. Hughes GC, Lowe JE, Kypson AP, et al. Neovascularization after transmyocardial laser revascularization in a model of chronic ischemia. Ann Thorac Surg 1998;66:2029 –36. Hamawy AH, Yee LY, Samy SA, et al. Transmyocardial laser revascularization dose response: enhanced perfusion in a porcine model as a function of channel density. Ann Thorac Surg 2001;72:817–22. Hughes GC, Kypson AP, Annex BH, et al. Induction of angiogenesis after TMR: a comparison of holmium:YAG, CO2, and excimer lasers. Ann Thorac Surg 2000;70:504 –9.
DISCUSSION DR KEITH ALLEN (Indianapolis, IN): You are to be congratulated for an excellent study. Whatever field you choose after medical school, I am sure you will do well. I really have just an observation. We previously reported that there appears to be better angina relief with increasing number of channels. However, I have always cautioned users of TMR that too many channels may not be a good thing. I think the data that you have generated really reinforces that idea. It is very easy to place these channels, particularly when you are doing CABG/TMR, and you have to be cognizant of how many channels you are placing, particularly in a patient that has reduced LV function. DR MOULI: Thank you for your comments. DR VALLUVAN JEEVANANDAM (Chicago, IL): I think one of the compelling things about this study as opposed to most studies which just look at angina relief is that this actually shows an improvement in wall motion abnormalities in that segment. So I have two questions for you. First of all, you looked at the circumflex distribution, and infarction in the circumflex distribution is usually associated with mitral regurgitation. Did you see any mitral regurgitation in the study? And the other thing is, did you take a group where you infarcted the circumflex, did not do TMR on them, and do you have any comparative data on that group of patients in terms of wall motion abnormalities? DR MOULI: In reference to your second question, from historical studies, we have had control groups that were not treated with TMR and compared them to TMR-treated groups, and there was a significant difference in wall motion post-treatment after TMR compared to the control groups. In reference to your first question, I am not sure whether we
have looked at mitral regurgitation, because this was a porcine model of chronic ischemia not infarction. DR JEEVANANDAM: Maybe Keith can answer that question. DR KEITH A. HORVATH (Chicago, IL): There was no evidence of significant mitral regurgitation on the echoes or the MRIs. This model does not induce mitral insufficiency. It basically establishes a collateral-dependent ischemic area, and unless you have infarction or that you overstress the animals, you are not going to see much in the way of mitral regurgitation. DR EDGAR PINEDA (Clearwater, MN): My question is you looked at this in the short term, the results were in the short term, the echo and the wall motion. Could it be possible that in the long term, as we know, the effect of revascularization on neoformation takes 6 to 8 weeks, that actually there is going to be an improvement more severe than you see in group 1 and group 2? DR MOULI: Could you repeat the question? DR PINEDA: In group 3, there is an impaired ventricular function when you did the echo and you did the MRI, but have you looked at that 6 or 8 weeks after and compared and seen if that impaired function persists, or is it the opposite, the results are better than group 1 and 2? DR MOULI: Group 1 and 2, especially group 2, represents a historical model that we have used in the past, and we have demonstrated in past studies that the improvement seen continues in the long-term. DR PINEDA: I mean in group 3, the one that you put two lesions per square centimeter and you have decreased function.
DR MOULI: Group 3 would require further evaluation, but I am sure there would not be any improvement for group 3, and it would probably continue to deteriorate. DR PINEDA: Why do you say that?
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DR MOULI: In that particular group, several animals died even before we instituted a follow-up scan due to the damage inflicted on the myocardium. In general, for that group the loss of function is pretty significant, and I think that speaks for itself.
The Thoracic Surgery Foundation for Research and Education Grants, Fellowships, and Career Development Awards The Thoracic Surgery Foundation for Research and Education (TSFRE) was founded to bring together the research and education support efforts of the four major societies in cardiothoracic surgery in the United States: The American Association for Thoracic Surgery (AATS), The Society of Thoracic Surgeons (STS), the Southern Thoracic Surgical Association (STSA), and the Western Thoracic Surgical Association (WTSA). Because of its close and continuing relationship with organized cardiothoracic surgery, TSFRE attracts the highest quality research award applicants and truly outstanding reviewers. Any surgeon who meets the eligibility requirements is invited to submit an application. Research grants will be judged separately from research fellowship applications. In general, top-scoring applications in each category will receive priority with respect to funding. Multiple fellowship applications under the sponsorship of an individual mentor, or multiple grant applications from a single institution will be accepted and reviewed, as long as there is no significant scientific overlap. Only under extraordinary circumstances will the TSFRE fund simultaneous awards to a single institution. This year, TSFRE is proud to offer the following awards to the most promising cardiothoracic surgeon-scientists: The Nina Starr Braunwald Research Fellowship Support of up to $35,000 a year for up to 2 years for young women in academic cardiac surgery who have not yet completed surgical training. Deadline: November 1 The Nina Starr Braunwald Career Development Award Support of up to $35,000 a year for up to 2 years for women in academic cardiac surgery who are in the early stages of their faculty career (within 5 years of completion of training). Deadline: November 1 TSFRE Research Grants Operational support of original research efforts by cardiothoracic surgeons who have completed their formal training, and who are seeking initial support and recognition for their research program. Awards of up to $30,000 a year for up to 2 years are made each year to support the work of an early-career cardiothoracic surgeon (within 5 years of first faculty appointment). Deadline: November 1 TSFRE Research Fellowships Support of up to $35,000 a year for up to 2 years for surgical residents who have not yet completed cardiothoracic surgical training. Deadline: November 1 © 2004 by The Society of Thoracic Surgeons Published by Elsevier Inc
TSFRE Career Development Awards Salary support of up to $50,000 a year for up to 2 years for applicants who have completed their residency training and who wish to pursue investigative careers in cardiothoracic surgery. Deadline: November 1 TSFRE/NHLBI Mentored Clinical Scientist Development Award (TSFRE/NHLBI MCSDA) K08 or K23 Support to outstanding clinician research scientists who are committed to a career in cardiothoracic surgery research and have the potential to develop into independent investigators. The award is $150,000 a year ($75,000 from TSFRE and $75,000 from NHLBI) plus $25,000 indirect support from the NHLBI and supports a 3-, 4-, or 5-year period of didactic training and supervised research experience. Deadline: May 31 TSFRE/NCI Mentored Clinical Scientist Development Award (TSFRE/NCI MCSDA) K08 or K23 Support to outstanding clinically trained professionals who are committed to a career in laboratory or fieldbased research and have the potential to develop into independent investigators. The award is $150,000 a year ($75,000 from TSFRE and $75,000 from NCI) plus $30,000 indirect support from the NCI and supports a 5-year period of supervised research that integrates didactic studies with laboratory or clinically based research. Deadline: February 1 and October 1 The American Association for Thoracic Surgery Awards Support of $75,000 for 1 year through the Evarts A. Graham Memorial Traveling Fellowship to a non-North American young cardiothoracic surgeon future international leader for further development in the United States. The AATS also provides $50,000 a year for 2 years of support for young cardiothoracic surgeons committed to pursuing an academic career in cardiothroacic surgery through the AATS Research Scholarship. Deadline: July 1 Applications will be available online only this year and can be found at www.tsfre.org. For more information, please address inquiries to: Chair, Research Committee The Thoracic Surgery Foundation for Research and Education 900 Cummings Center, Suite 221-U Beverly, MA 01915l Telephone: (978) 927-8330 Ann Thorac Surg 2004;78:1331
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What is the Optimal Channel Density for Transmyocardial Laser Revascularization? Samdeep K. Mouli, BS, Jeffrey Fronza, BS, Rodney Greene, BS, Emmanuel S. Robert, MS, and Keith A. Horvath, MD Division of Cardiothoracic Surgery, The Feinberg School of Medicine, Northwestern University, Chicago, Illinois
Background. Transmyocardial laser revascularization (TMR) has demonstrated reproducible relief of angina in patients with end-stage coronary disease. However, the optimum dose or channel density has not been elucidated. Methods. Using a porcine model of chronic myocardial ischemia, 14 animals were treated with CO2 TMR and randomized as follows: group 1 was 1 channel per 2 cm2; group 2 was 1 channel per 1 cm2; and group 3 was 2 channels per 1 cm2. Left ventricular myocardial viability and function were assessed by magnetic resonance imaging (MRI) and echocardiography pretreatment, and repeated 6 weeks later. Results. The MRI assessment of group 1 (1 channel/2 cm2) and group 2 (1 channel/cm2) demonstrated similar improvement in segmental contractility posttreatment of 12.11% ⴞ 5.15% and 12.47% ⴞ 9.51%, respectively. In
contrast, group 3 (2 channels/cm2) showed significantly worse segmental contractility posttreatment: ⴚ18.52% ⴞ 7.16% (p ⴝ 0.01). Echocardiographic imaging revealed significant improvements in wall thickening in the ischemic zone for group 1 at 0.91 ⴞ 0.07 cm pretreatment versus 1.30 ⴞ 0.09 cm posttreatment, (p ⴝ 0.01); and for group 2 at 0.93 ⴞ 0.11 cm versus 1.42 ⴞ 0.18 cm, (p ⴝ 0.01). No significant improvement in wall thickening was seen in group 3 (0.84 ⴞ 0.06 cm versus 0.88 ⴞ 0.09 cm, p ⴝ n.s.). Conclusions. These data corroborate the empiric finding of an effective therapeutic dose range for TMR, 1 channel per 1 to 2 cm2. These results also demonstrate a detrimental effect when channel density is increased above the clinical standard of 1 channel per cm2 to a density of 2 channels per 1 cm2. (Ann Thorac Surg 2004;78:1326 –31) © 2004 by The Society of Thoracic Surgeons
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which TMR’s clinical benefit can be achieved. The purpose of this study was to determine the optimal channel density for CO2 TMR.
nd-stage coronary artery disease afflicts a growing number of patients whose diffuse stenoses are refractory to the traditional treatment modalities of coronary artery bypass grafting (CABG) and percutaneous coronary intervention (PCI). Transmyocardial laser revascularization (TMR) has evolved to treat these patients. Since 1993 more than 15,000 patients with chronic angina pectoris have been treated with TMR using a CO2 laser [1–12]. Clinical studies have demonstrated significant reduction in angina symptoms, decreased ischemia, improved myocardial function, and increased perfusion as a result of CO2 TMR therapy [1–12]. Previously we have experimentally demonstrated that this functional recovery may be due to a minimization of scar formation with a maximization of angiogenesis [13]. Several studies achieving these results reported a wide range of 25 to 48 TMR channels per patient. Empirically, most investigators employed a density of one channel per square centimeter (cm2) of ischemic myocardium [1–12]. Experimental evidence to determine the optimal CO2 TMR channel distribution is scant. Such work is necessary to delineate the therapeutic window within Accepted for publication April 14, 2004. Presented at the Fortieth Annual Meeting of The Society of Thoracic Surgeons, San Antonio, TX, Jan 26 –28, 2004. Address reprint requests to Dr Horvath, Division of Cardiothoracic Surgery, Northwestern University Medical School, 201 E Huron St, Galter 10-105, Chicago, IL 60611; e-mail: [email protected].
© 2004 by The Society of Thoracic Surgeons Published by Elsevier Inc
Material and Methods Operative Technique In order to mimic the clinical scenario, we employed a standard animal model of chronic myocardial ischemia [14, 15]. Seventeen Yorkshire pigs, weighing 12 to 15 kg, were preanesthetized with ketamine (15 mg/kg), acepromazine (0.15 mg/kg), and atropine (2 mg) intramuscularly, followed by brevital (11 mg/kg) IV. After intubation, anesthesia was maintained with isoflurane (0.5% to 2.0%; Abbott Laboratories, Chicago, IL) delivered in 60%/40% nitrous oxide. Bupivacaine (0.5 mL/kg) was infiltrated into the subcutaneous tissue along the incision to provide immediate postoperative analgesia. Buprenex (0.01 mg/kg) was given 30 minutes before the end of surgery and again every 12 hours for a minimum of 48 hours for postoperative analgesia. To reduce the risk of arrhythmias, bretylium (1 mg/kg) was administered intravenously and nitropaste (2 inches) was applied topically. The same anesthetic regimen was used for each of the three different surgical procedures that were performed. At the initial operation, using sterile technique, the heart was exposed through a small left thoracotomy, and 0003-4975/04/$30.00 doi:10.1016/j.athoracsur.2004.04.047
the pericardium was opened. The proximal left circumflex artery was dissected free, and an ameroid constrictor (Research Instruments SW, Escondido, CA) with an internal diameter of 2.5 mm was placed around the origin of the left circumflex artery. The pericardium and chest were then closed. The animals were allowed to recover and were ambulatory before leaving the operating room suite. They were monitored daily by a veterinarian and his staff as well as by the surgical team. Antibiotics were administered intramuscularly for 3 days postoperatively. Pain medications were also given intramuscularly until the animals were ambulating without difficulty and exhibiting normal activity levels. Adequate food and water were provided, and intakes, as well as weights, were measured daily. Five weeks following placement of the ameroid constrictor, immediately before TMR treatment (operation 2), the animals (now 50 to 60 kg), while anesthetized, were scanned on a 1.5-T Siemens Symphony Scanner (Siemens Medical Systems, Erlangen, Germany). Shortaxis images every 10 mm were performed to cover the entire left ventricular volume. The cine magnetic resonance images (MRI) provided evaluation of regional myocardial contractility, and demonstrated ischemic myocardium that was hypocontractile, and consistent with historical controls [13, 16, 17]. In addition, contrastenhanced MRI was used to confirm viability and rule out infarction. Animals received a clinically approved contrast agent intravenously (Magnevist, Abbott Laboratories; 0.2 mmol/kg weight; maximum rate of 10 mL/15 seconds), then MRI images were acquired at each of the cine short-axis locations. Cine MRI scanning was immediately followed by a second operation, through a larger left thoracotomy, where the pericardium was reopened and the heart was reexposed. Blood pressure and electrocardiographic monitoring was used. Rest and dobutamine stress epicardial echocardiography (7.5 MHz, model 128; Acuson Inc., Mountain View, CA) were performed to provide an assessment of the viability of the myocardium and to determine the extent of the ischemia. Data derived from this initial base line assessment was consistent with historical controls [13, 16, 17]. Dobutamine was administered intravenously starting at 5 g 䡠 kg⫺1 䡠 min⫺1 and titrated to a maximum infusion rate of 50 g 䡠 kg⫺1 䡠 min⫺1 to achieve a 100% increase in the resting heart rate. There was no significant difference in the resting heart rate at operation 2 or operation 3. Similarly there was no significant difference between the stress heart rates between operations 2 and 3. Mean arterial pressure demonstrated a modest increase with stress and there was no significant difference between the resting and stress blood pressure measurements for operation 2 versus operation 3. The 17 animals were randomized into one of three treatment groups before operation 2. Each animal underwent treatment to the circumflex territory (ischemic zone) with CO2 TMR (PLC Medical Systems, Franklin, MA). Group 1 received TMR treatment with a transmural channel density of one channel per 2 cm2, for a total of 10
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TMR channels. Group 2 had a channel distribution of one channel per square centimeter, for a total of 20 TMR channels. Group 3 received 2 channels per square centimeter in the ischemic zone, or 40 TMR channels. The total channel numbers mentioned above are absolute values without deviation. The thoracotomies were then closed and the animals were allowed to recover. The previously mentioned postoperative care was then reinstituted. Six weeks later (operation 3) animals had a repeat thoracotomy. At that time, they underwent repeat rest and dobutamine stress echocardiography, as well as repeat contrast-enhanced and cine MRI. In addition, postsacrifice tissue harvesting was done for each animal during which we identified the ameroid constrictor and demonstrated it to be fully constricted in every case.
Magnetic Resonance Imaging Analysis Regional contractility, as measured by wall thickening, was determined by commercial software (Argus, Siemens) in 15 segments in the ischemic zone by the modified centerline method. The ischemic zone was defined as the region of the left ventricle perfused by the gradually occluded circumflex artery. Epicardial and endocardial contours were identified and percent wall thickening calculated. This measurement was performed for the short-axis image depicting the midpapillary region of the left ventricle, as well as one image above (10 mm) and one image below (10 mm) this region. With contrast enhancement, areas with an infarction appear hyperenhanced. Before randomization, animals with significant infarction were excluded from the study.
Echocardiographic Analysis The echocardiographic images were recorded onto a half-inch videotape. End-diastolic and end-systolic images were then digitized off-line from the videotape with a dedicated software package (Prism Lite for Windows, Version 5.14; Tomtec Imaging Systems, Broomfield, CO). The digitized images were spatially calibrated, and the endocardial contours were traced. The software then automatically calculated the wall motion along the 100 evenly distributed lines of site around the contour. By standard segmental contraction analysis, the mean wall motion score for each segment was obtained (48 segments for each short-axis image). Segmental contraction was defined as the change in wall thickness between systole and diastole as measured in centimeters. Magnetic resonance imaging and echocardiographic analysis was performed by an independent observer blinded to the treatment that the animals received. Segmental contraction was compared in all segments at all times using each animal as its own control. The changes in the treatment region were compared to the results seen in the region of the left ventricle not supplied by the circumflex artery. The latter region, the nonischemic zone, remains unaffected by the occlusion of the circumflex artery. The myocardium of this region should therefore remain unchanged between pretreatment and posttreatment. Thus, any difference demonstrated in the
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CARDIOVASCULAR Fig 1. Cine MRI results of regional contractility in the treated area for group 1 (1 channel/2 cm2) and group 2 (1 channel/cm2) demonstrated similar improvement in segmental contractility posttreatment of 12.11% ⫾ 5.15% and 12.47% ⫾ 9.51%, respectively. In contrast, group 3 (2 channels/cm2) did not show improvement posttreatment, with segmental contractility being significantly worse than baseline: ⫺18.52% ⫾ 7.16% (p ⫽ 0.01). Additionally, there was a significant difference for the posttreatment results between group 1 and group 2 versus group 3 (p ⫽ 0.01). ■ ⫽ 1 channel/2 cm2; 䊐 ⫽ 1 channel/ cm2; o ⫽ 2 channels/cm2. (MRI ⫽ magnetic resonance imaging; TMR ⫽ transmyocardial laser revascularization.)
treatment group between pretreatment and posttreatment can be attributed to the effects of TMR.
Statistical Analysis
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Cine MRI results of regional contractility in the treated area are depicted in Figure 1. Group 1 (1 channel/2 cm2) and group 2 (1 channel/cm2) demonstrated similar improvement in segmental contractility posttreatment of 12.11% ⫾ 5.15% and 12.47% ⫾ 9.51%, respectively. In contrast, group 3 (2 channels/cm2) did not show improvement posttreatment, with segmental contractility being significantly worse than baseline: ⫺18.52% ⫾ 7.16% (p ⫽ 0.01). Echocardiographic measurement of segmental wall motion in the ischemic zone at baseline and posttreatment for all three groups are depicted in Figure 2. The posttreatment resting function revealed significant improvements in wall thickening in the ischemic zone for group 1 at 0.91 ⫾ 0.07 cm pretreatment versus1.30 ⫾ 0.09 cm posttreatment, (p ⫽ 0.01); and for group 2 at 0.93 ⫾ 0.11 cm pretreatment versus 1.42 ⫾ 0.18 cm posttreatment (p ⫽ 0.01). Echocardiographic results demonstrated no significant improvement in wall thickening for group 3: 0.84 ⫾ 0.06 cm pretreatment versus 0.88 ⫾ 0.09 cm posttreatment, (p ⫽ not significant). Comparing functional improvement based on MRI and echocardiographic analysis, there was no significant difference between group 1 and group 2 (p ⫽ NS) after TMR. However, there was a significant difference for the posttreatment results between these groups versus group 3 (1 vs 3: p ⫽ 0.01; 2 vs 3: p ⫽ 0.01).
Comment Much work has been done to ascertain the exact mechanism of the clinical improvement seen with TMR. Angiogenesis, as a result of the healing response to tissue
Continuous data are presented as a mean ⫾ standard error. Changes in contractility were assessed using a paired t-test for each treatment group. A Bonferroni correction was used as needed for repeated measures over time. All statistical tests were two-tailed, and p value less than 0.05 was regarded as statistically significant.
Results A total of 14 animals were originally enrolled in this study and randomized among the three treatment groups. Three of these animals, specifically from group 3, died before final analysis. Therefore additional animals were enrolled to compensate for the deaths observed in group 3. Seventeen animals were treated in total, however only 14 survived until final analysis. The 14 animals were divided into the three groups: group 1 (n ⫽ 5), group 2 (n ⫽ 4), group 3 (n ⫽ 5). The segmental wall motion after placement of the ameroid constrictor (operation 2) demonstrated hypokinesis of the ischemic zone myocardium subtended by occlusion. There was no change in wall motion after operation 2 in the nonischemic zone. There was no significant difference in the baseline resting function for all animals (p ⫽ not significant [NS]) at operation 2, and these results are consistent with historic controls [16].
Fig 2. Echocardiography results revealed significant improvements in wall thickening in the ischemic zone for group 1 at 0.91 ⫾ 0.07 cm pretreatment versus 1.30 ⫾ 0.09 cm posttreatment (p ⫽ 0.01); and for group 2 at 0.93 ⫾ 0.11 cm pretreatment versus 1.42 ⫾ 0.18 cm posttreatment (p ⫽ 0.01). Echocardiographic results demonstrated no significant improvement in wall thickening for group 3 (0.84 ⫾ 0.06 cm pretreatment versus 0.88 ⫾ 0.09 cm posttreatment; p ⫽ not significant [n.s.]). In addition there was a significant difference for the posttreatment results between group 1 and 2 versus group 3 (p ⫽ 0.01). 䊐 ⫽ pretreatment; ■ ⫽ posttreatment.
injury caused by laser ablation, may play a pivotal role in achieving this clinical benefit. However, the injury that induces angiogenesis must not be so great as to cause more harm to the myocardium than good. If the injury produced by the laser destroys tissue such that the resulting scar is vascularized but acontractile, it will be at the expense of functional improvement for the patient. In addition to forming new blood vessels that increase myocardial perfusion, obtaining functional recovery of the ischemic myocardium is essential. Such functional recovery has been demonstrated both experimentally and clinically after laser TMR [16, 18, 19]. Experiments in a large animal model of chronic ischemia have demonstrated reduction in infarct size, as well as an improvement in myocardial contractility after CO2 TMR [2–3]. Further study has revealed histologic evidence of angiogenesis after TMR treatment [20 –23]. In previous studies, we have demonstrated that the functional improvement seen was likely a result of angiogenesis through the upregulation of vascular endothelial growth factor [16, 24]. Despite several previous studies designed to elucidate the mechanism behind TMR’s benefit, little has been done to elaborate a dosage response curve for this procedure. The current clinical dosage standard for CO2 TMR remains at 1 channel per cm2; however data demonstrating that this is the optimal channel density for the patient was lacking. The results of the present TMR study demonstrate a significant improvement with a channel density of 1 channel per 2 cm2 to 1 channel per cm2, as demonstrated by an improvement in myocardial contractility posttreatment. The data also reveals an upward limit for the therapeutic range of TMR, with a significant detrimental effect when channel density is increased to 2 channels per cm2. Here the damage due to the laser exceeded any possible therapeutic benefit, causing severe deterioration in myocardial function. It should also be noted that 3 animals that received TMR treatment of 2 channels per cm2 died shortly before sacrifice. Previous work also attempted to define a dose response for TMR, albeit applying a considerably different laser [25]. The XeCl (excimer) laser has a markedly different tissue effect than CO2 TMR. It was concluded that excimer TMR enhances perfusion as a result of an induced angiogenic response, which correlated with the total channel number. This study differed from the current study in several ways. As outlined, the goal of the current study was to determine the relationship between channel density and the subsequent therapeutic response for CO2 TMR, an infrared laser that creates channels by thermal ablation. The previous study examined the effect of total channel number for the excimer laser, an ultraviolet laser that produces tissue damage by the dissociation of molecular bonds [26]. The inherent wavelength difference between CO2 and excimer lasers, and resultant difference in laser-tissue interaction, explains the difference in dosage-response observed between the two therapeutic approaches. Additionally, the previous study assessed outcomes using perfusion and
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histologic analysis rather than functional contractility data. As stated by the study’s authors, such data cannot be extrapolated to a high-energy laser such as CO2 TMR. A key limitation of the present work is that the results did not reveal a lower threshold at which functional angiogenesis occurs. Furthermore, the design of this study utilized a consistent laser energy level for each treatment group, while channel density was varied. Determining the optimal laser energy level while keeping the channel density within the established therapeutic window could provide a more complete dose response effect, and requires further study. Establishment of an optimal channel density is essential for any therapeutic intervention. Thus, the data derived from this study not only confirms the functional benefit of standard TMR channel density, but also helps establish the therapeutic limit of this surgical intervention. This research was supported by the National Institutes of Health 5R01HL064868 – 04.
References 1. Mirhoseini M, Cayton MM, Shelgikar S, Fisher JC. Clinical report: laser myocardial revascularization. Lasers Surg Med 1986;6:459 –61. 2. Horvath KA, Smith WJ, Laurence RG, et al. Improved shortand long-term recovery after an acute myocardial infarct treated by transmyocardial laser revascularization. Surg Forum 1993;44:220 –2. 3. Horvath KA, Smith WJ, Laurence RG, Appleyard RF, Cohn LH. Recovery and viability of an acute myocardial infarct after transmyocardial laser revascularization. J Am Coll Cardiol 1995;25:158 –63. 4. Frazier OH, Cooley DA, Kadipasaglu KA, et al. Myocardial revascularization with laser: preliminary findings. Circulation 1995;92(Suppl 2):1158 –65. 5. Horvath KA, Mannting FR, Cummings N, Shernan SK, Cohn LH. Transmyocardial laser revascularization: operative techniques and clinical results at two years. J Thorac Cardiovasc Surg 1996;4:1047–53. 6. Maisch B, Funck R, Herzum MD, et al. Does transmyocardial laser revascularization influence prognosis in endstage coronary artery disease? Circulation 1996;94(Suppl 1):295. 7. Horvath KA, Cohn LC, Cooley DA, et al. Transmyocardial revascularization: results of a multi-center trial using TLR as sole therapy for end stage coronary artery disease. J Thorac Cardiovasc Surg 1997;113:645–54. 8. Schofield PM, Sharples LD, Caine N, et al. Transmyocardial laser revascularization in patients with refractory angina: a randomized controlled trial. Lancet 1999;353:519 –24. 9. Horvath KA, Aranki SF, Cohn LH, et al. Sustained angina relief 5 years after transmyocardial laser revascularization with a CO2 laser. Circulation 2001;104(suppl 1):I-81–84. 10. Frazier OH, March RJ, Horvath KA. Transmyocardial revascularization with a carbon dioxide laser in patients with end-stage coronary artery disease. N Engl J Med 1999;341: 1021–8. 11. Aaberge L, Nordstrand K, Dragsund M, et al. Transmyocardial revascularization with CO2 laser in patients with refractory angina pectoris. Clinical results from the Norwegian randomized trial. J Am Coll Cardiol 2000;35:1170 –7. 12. Aaberge L, Rootwelt K, Blomhoff S, Saatvedt K, Abdelnoor M, Forfang K. Continued symptomatic improvement three to five years after transmyocardial revascularization with CO2 laser. A late clinical follow-up of the Norwegian ran-
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domized trial with transmyocardial revascularization. J Am Coll Cardiol 2002;39:1588 –93. Horvath KA, Belkind N, Wu I, et al. Functional comparison of transmyocardial revascularization by mechanical, and laser means. Ann Thorac Surg 2001;72:1997–2002. O’Konski MS, White FC, Longhurst JC, Roth DM, Bloor CM. Ameroid constriction of the proximal left circumflex coronary artery in swine. Am J Cardiovasc Pathol 1987;1:69 –77. Roth DM, Maruoka Y, Rogers J, White FC, Longhurst JC, Bloor CM. Development of coronary collateral circulation in left circumflex ameroid-occluded swine myocardium. Am J Physiol 1987;253(5 Pt 2):H1279 –88. Horvath KA, Greene R, Belkind N, Kane B, McPherson DD, Fullerton DA. Left ventricular functional improvement after transmyocardial laser revascularization. Ann Thorac Surg 1998;66:721–5. Horvath KA, Chiu E, Dipen CM, et al. Up-regulation of vascular endothelial growth factor mRNA, and angiogenesis after transmyocardial laser revascularization. Ann Thorac Surg 1999;68:825. Horvath KA, Kim RJ, Judd RM, Parker MA, Fullerton DA. Contrast enhanced MRI assessment of microinfarction after transmyocardial laser revascularization (abstr). Circulation 2000;102:II-765. Donovan CL, Landolfo KP, Lowe JE, Clements F, Coleman RB, Ryan T. Improvement in inducible ischemia during dobutamine stress echocardiography after transmyocardial
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laser revascularization in patients with refractory angina pectoris. J Am Coll Cardiol 1997;30:607–12. Fisher PE, Kohmoto T, DeRosa CM, Spotnitz HM, Smith CR, Burkhoff D. Histologic analysis of transmyocardial channels: comparison of CO2 and holmium:YAG lasers. Ann Thorac Surg 1997;64:466 –72. Kohmoto T, Fisher PE, Gu A, Smith CR, De Rosa C, Burkhoff D. Physiology, histology, and two week morphology of acute myocardial channels made with a CO2 laser. Ann Thorac Surg 1997;63:1275–83. Burkhoff D, Fisher PE, Apfelbaum M, Kohmoto T, DeRosa CM, Smith CR. Histologic appearance of transmyocardial laser channels after 4 1/2 weeks. Ann Thorac Surg 1996;61: 1532–5. Yamamoto N, Khomoto T, Gu A, De Rosa C, Smith CR, Burkhoff D. Angiogenesis is enhanced in ischemic canine myocardium by transmyocardial laser revascularization. J Am Coll Cardiol 1998;31:1426 –33. Hughes GC, Lowe JE, Kypson AP, et al. Neovascularization after transmyocardial laser revascularization in a model of chronic ischemia. Ann Thorac Surg 1998;66:2029 –36. Hamawy AH, Yee LY, Samy SA, et al. Transmyocardial laser revascularization dose response: enhanced perfusion in a porcine model as a function of channel density. Ann Thorac Surg 2001;72:817–22. Hughes GC, Kypson AP, Annex BH, et al. Induction of angiogenesis after TMR: a comparison of holmium:YAG, CO2, and excimer lasers. Ann Thorac Surg 2000;70:504 –9.
DISCUSSION DR KEITH ALLEN (Indianapolis, IN): You are to be congratulated for an excellent study. Whatever field you choose after medical school, I am sure you will do well. I really have just an observation. We previously reported that there appears to be better angina relief with increasing number of channels. However, I have always cautioned users of TMR that too many channels may not be a good thing. I think the data that you have generated really reinforces that idea. It is very easy to place these channels, particularly when you are doing CABG/TMR, and you have to be cognizant of how many channels you are placing, particularly in a patient that has reduced LV function. DR MOULI: Thank you for your comments. DR VALLUVAN JEEVANANDAM (Chicago, IL): I think one of the compelling things about this study as opposed to most studies which just look at angina relief is that this actually shows an improvement in wall motion abnormalities in that segment. So I have two questions for you. First of all, you looked at the circumflex distribution, and infarction in the circumflex distribution is usually associated with mitral regurgitation. Did you see any mitral regurgitation in the study? And the other thing is, did you take a group where you infarcted the circumflex, did not do TMR on them, and do you have any comparative data on that group of patients in terms of wall motion abnormalities? DR MOULI: In reference to your second question, from historical studies, we have had control groups that were not treated with TMR and compared them to TMR-treated groups, and there was a significant difference in wall motion post-treatment after TMR compared to the control groups. In reference to your first question, I am not sure whether we
have looked at mitral regurgitation, because this was a porcine model of chronic ischemia not infarction. DR JEEVANANDAM: Maybe Keith can answer that question. DR KEITH A. HORVATH (Chicago, IL): There was no evidence of significant mitral regurgitation on the echoes or the MRIs. This model does not induce mitral insufficiency. It basically establishes a collateral-dependent ischemic area, and unless you have infarction or that you overstress the animals, you are not going to see much in the way of mitral regurgitation. DR EDGAR PINEDA (Clearwater, MN): My question is you looked at this in the short term, the results were in the short term, the echo and the wall motion. Could it be possible that in the long term, as we know, the effect of revascularization on neoformation takes 6 to 8 weeks, that actually there is going to be an improvement more severe than you see in group 1 and group 2? DR MOULI: Could you repeat the question? DR PINEDA: In group 3, there is an impaired ventricular function when you did the echo and you did the MRI, but have you looked at that 6 or 8 weeks after and compared and seen if that impaired function persists, or is it the opposite, the results are better than group 1 and 2? DR MOULI: Group 1 and 2, especially group 2, represents a historical model that we have used in the past, and we have demonstrated in past studies that the improvement seen continues in the long-term. DR PINEDA: I mean in group 3, the one that you put two lesions per square centimeter and you have decreased function.
DR MOULI: Group 3 would require further evaluation, but I am sure there would not be any improvement for group 3, and it would probably continue to deteriorate. DR PINEDA: Why do you say that?
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DR MOULI: In that particular group, several animals died even before we instituted a follow-up scan due to the damage inflicted on the myocardium. In general, for that group the loss of function is pretty significant, and I think that speaks for itself.
The Thoracic Surgery Foundation for Research and Education Grants, Fellowships, and Career Development Awards The Thoracic Surgery Foundation for Research and Education (TSFRE) was founded to bring together the research and education support efforts of the four major societies in cardiothoracic surgery in the United States: The American Association for Thoracic Surgery (AATS), The Society of Thoracic Surgeons (STS), the Southern Thoracic Surgical Association (STSA), and the Western Thoracic Surgical Association (WTSA). Because of its close and continuing relationship with organized cardiothoracic surgery, TSFRE attracts the highest quality research award applicants and truly outstanding reviewers. Any surgeon who meets the eligibility requirements is invited to submit an application. Research grants will be judged separately from research fellowship applications. In general, top-scoring applications in each category will receive priority with respect to funding. Multiple fellowship applications under the sponsorship of an individual mentor, or multiple grant applications from a single institution will be accepted and reviewed, as long as there is no significant scientific overlap. Only under extraordinary circumstances will the TSFRE fund simultaneous awards to a single institution. This year, TSFRE is proud to offer the following awards to the most promising cardiothoracic surgeon-scientists: The Nina Starr Braunwald Research Fellowship Support of up to $35,000 a year for up to 2 years for young women in academic cardiac surgery who have not yet completed surgical training. Deadline: November 1 The Nina Starr Braunwald Career Development Award Support of up to $35,000 a year for up to 2 years for women in academic cardiac surgery who are in the early stages of their faculty career (within 5 years of completion of training). Deadline: November 1 TSFRE Research Grants Operational support of original research efforts by cardiothoracic surgeons who have completed their formal training, and who are seeking initial support and recognition for their research program. Awards of up to $30,000 a year for up to 2 years are made each year to support the work of an early-career cardiothoracic surgeon (within 5 years of first faculty appointment). Deadline: November 1 TSFRE Research Fellowships Support of up to $35,000 a year for up to 2 years for surgical residents who have not yet completed cardiothoracic surgical training. Deadline: November 1 © 2004 by The Society of Thoracic Surgeons Published by Elsevier Inc
TSFRE Career Development Awards Salary support of up to $50,000 a year for up to 2 years for applicants who have completed their residency training and who wish to pursue investigative careers in cardiothoracic surgery. Deadline: November 1 TSFRE/NHLBI Mentored Clinical Scientist Development Award (TSFRE/NHLBI MCSDA) K08 or K23 Support to outstanding clinician research scientists who are committed to a career in cardiothoracic surgery research and have the potential to develop into independent investigators. The award is $150,000 a year ($75,000 from TSFRE and $75,000 from NHLBI) plus $25,000 indirect support from the NHLBI and supports a 3-, 4-, or 5-year period of didactic training and supervised research experience. Deadline: May 31 TSFRE/NCI Mentored Clinical Scientist Development Award (TSFRE/NCI MCSDA) K08 or K23 Support to outstanding clinically trained professionals who are committed to a career in laboratory or fieldbased research and have the potential to develop into independent investigators. The award is $150,000 a year ($75,000 from TSFRE and $75,000 from NCI) plus $30,000 indirect support from the NCI and supports a 5-year period of supervised research that integrates didactic studies with laboratory or clinically based research. Deadline: February 1 and October 1 The American Association for Thoracic Surgery Awards Support of $75,000 for 1 year through the Evarts A. Graham Memorial Traveling Fellowship to a non-North American young cardiothoracic surgeon future international leader for further development in the United States. The AATS also provides $50,000 a year for 2 years of support for young cardiothoracic surgeons committed to pursuing an academic career in cardiothroacic surgery through the AATS Research Scholarship. Deadline: July 1 Applications will be available online only this year and can be found at www.tsfre.org. For more information, please address inquiries to: Chair, Research Committee The Thoracic Surgery Foundation for Research and Education 900 Cummings Center, Suite 221-U Beverly, MA 01915l Telephone: (978) 927-8330 Ann Thorac Surg 2004;78:1331
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