- Email: [email protected]
Current Perspectives on Direct Myocardial Revascularization 1
Current Perspectives on Direct Myocardial Revascularization Ran Kornowski,
MD,
Mun K. Hong,
MD,
and Martin B. Leon,
MD
Direct myocardial revascularization (DMR), either surgical or catheter-based, uses lasers to create channels between ischemic myocardium and the left ventricular cavity to improve perfusion and decrease angina. This technique can also be used to deliver drugs to the damaged tissue. Candidates include patients with chronic, severe, refractory angina and those unable to undergo conventional surgical revascularization or angioplasty because remaining conduits or acceptable target vessels are lacking. Although the mechanism of action of DMR is still not known, several theories have been proposed, including stimulated angiogenesis. Late sequelae also
remain to be determined. Channel characteristics differ depending on whether they were created by carbon dioxide or holmium/yttrium–aluminum– garnet (Ho: YAG) lasers. Catheter-based DMR obviates thoracotomy and anesthesia and, in systems that can create electromechanical maps, fluoroscopy. Phase I clinical trials are now under way to evaluate catheter-based DMR, with endpoints that include improvement in symptoms of angina, exercise capacity, and radionuclide myocardial perfusion. Q1998 by Excerpta Medica, Inc. Am J Cardiol 1998;81(7A):44E– 48E
irect myocardial revascularization (DMR) is a nonconventional therapy designed to elicit a therapeutic D response by creating direct communications between the
on this concept, as well as the naturally occurring myocardial sinusoids that supply important subendocardial perfusion in reptilian hearts, subsequent investigators tried to increase myocardial perfusion “directly” by augmenting blood flow into existing myocardial sinusoids or by creating new sinusoids. In 1935, Beck7 used the myopexy and omentoplexy approach. In the 1940s, Vineberg8 implanted the distal end of internal mammary arteries directly into canine myocardium and demonstrated myocardial “blush” as well as collateralization to the epicardial coronary arteries. Much later, Vineberg9 extended this approach to patients, comparing them to a control group treated medically. Both symptoms and survival improved with the implants, and their long-term patency and collateral supply function were documented. In 1950, Sen and his colleagues10 used blunt instruments to create transmural channels in canine hearts after coronary occlusion (“transmyocardial acupuncture”) and noted a significant improvement in survival and a reduction in myocardial infarct size in this model compared with controls. In 1969, Hershey and White11 used the “transmyocardial puncture tract” procedure in a patient to terminate intraoperative ventricular fibrillation secondary to global refractory ischemia. In 1983, Mirhoseini et al12,13 applied the surgical DMR technique using a CO2 laser to create transmyocardial channels as an adjunct to coronary artery bypass graft surgery in patients who could not be completely revascularized by conventional techniques. These investigators later reported less angina and greater myocardial perfusion in the treated regions.14,15 More recently, Frazier and Cooley1,2 used a similar surgical DMR approach with CO2 lasers as “sole therapy” and reported improved angina, increased exercise capacity, and enhanced subendocardial perfusion by positron emission tomographic scans for at least 12 months. Similar favorable results were reported by Horvath and Cohn3 when they applied surgical laser DMR techniques. Results on preliminary analysis of a randomized
ischemic myocardium and the left ventricular cavity. Also known as transmyocardial revascularization or transmyocardial laser revascularization, DMR can be classified according to the procedural technique (surgical vs catheter-based [percutaneous]), the route of myocardial access (epicardial vs endocardial), and the form of treatment being applied (channel-forming laser vs local pharmacotherapy). Surgical DMR creates intramyocardial channels using carbon dioxide (CO2) or holmium/ yttrium–aluminum– garnet (Ho:YAG) lasers using an epicardial approach. Catheter-based DMR generates endomyocardial channels from the left ventricular cavity to the subepicardial myocardium using short-pulsed lasers delivered through fiberoptic catheters. Both the surgical and catheter-based DMR can also be used to inject drugs directly into the ischemic myocardium. Previous animal studies and preliminary clinical trials of surgical DMR have indicated a significant reduction in angina severity, an improved quality of life, and improved myocardial perfusion in refractory coronary ischemic syndromes. 1–5 Catheterbased DMR may provide benefits equivalent to those of surgical DMR without the need for thoracotomy or general anesthesia.
HISTORICAL PERSPECTIVES ON SURGICAL DMR The concept of DMR dates back to the 1930s, when Wearn and his colleagues6 described “myocardial sinusoids” and “arterio-sinusoidal” vessels that seemed to connect the coronary arteries with the left ventricular chamber in human cadaveric hearts. Based From the Department of Cardiology, Department of Medicine, Washington Hospital Center, Washington, DC. Supported by a grant from the Cardiology Research Foundation, The Washington Cardiology Center, Washington, DC. Address for reprints: Martin B. Leon, MD, Washington Cardiology Center, 110 Irving Street, NW, Suite 4B-1, Washington, DC 20010.
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©1998 by Excerpta Medica, Inc. All rights reserved.
0002-9149/98/$19.00 PII S002-9149(98)00197-0
study to determine whether surgical CO2 laser revascularization is superior to optimal medical therapy in patients not amenable to conventional revascularization support the registry experience—i.e., symptoms and quality of life improved, and there was some evidence of enhanced myocardial perfusion in the treated areas.16 Of the patients randomized to surgical DMR, 67% showed a reduction in angina class of $2, compared with 6% in the medically treated group, and hospitalization for unstable angina was markedly decreased (13% post-DMR vs 72% with medical therapy). Interestingly, clinical efficacy persisted (i.e., angina threshold was decreased) for as long as 2 years after DMR, suggesting a permanent beneficial effect on myocardial perfusion. Nuclear studies, with analysis limited to the first 3 months thus far, showed a less impressive 15% reduction in reversible defects in the DMR group versus a 7% increase in reversible defects in the control group. Donovan et al17 used dobutamine stress echocardiography to study 12 patients treated with surgical CO2 laser DMR and found significant improvement in regional contractility in the treated segments. Recently, in a prospective randomized trial of surgical DMR using a Ho:YAG laser versus “best” medical therapy, Allen et al5 showed a significant improvement in angina class (85% vs 18%) and decreased hospitalizations compared with the medical group at 6 months; clinical benefit was sustained for up to 12 months.
PATIENT CANDIDATES FOR DMR To be a candidate for DMR, patients must meet the following criteria: (1) severe angina (functional class III or IV) despite optimal medical therapy; (2) poor candidate for catheter-based angioplasty due to high procedural risk or absence of acceptable target sites; and (3) poor candidate for surgical revascularization due a prohibitive risk or absence of acceptable target vessels and/or remaining surgical conduits. Currently, the major categories for clinical DMR investigations include patients with (1) degenerated saphenous vein grafts (especially in those with a patent internal mammary artery conduit); (2) diffuse coronary disease or small target vessels (e.g., diabetics); (3) incessant postangioplasty restenosis or recurrent diffuse in-stent restenosis; and (4) chronic total occlusions with either nonvisualized or poor distal vessels. Another potential use for DMR is as a “hybrid” procedure in nonrevascularizable territories during either coronary angioplasty or coronary artery bypass graft surgery—an indication that may ultimately constitute the largest patient cohort for DMR procedures. At present, patients with overt heart failure or very low left ventricular ejection fractions are excluded from most study protocols.
SUGGESTED MECHANISMS FOR EFFECTS OF DMR Despite extensive investigations, the mechanism of beneficial DMR effects is still unknown.18 Initially, it was postulated that blood flow through the patent
channels would provide continued myocardial perfusion similar to the endocardial perfusion seen in normal alligator hearts.19 However, data are conflicting as to the long-term patency of these laser channels. Initial animal studies suggested patency of the channels, and anecdotal autopsy studies support the feasibility of chronic channel patency20,21; other animal studies and autopsy reports actively refute these findings.22–27 Another intriguing possibility is the stimulation of angiogenesis by laser-induced myocardial injury, leading to an increases myocardial perfusion. Recent reports from animal studies have demonstrated neovascularization and increased collateral flow, which may contribute to increased perfusion and myocardial salvage.28 –33 Unfortunately, there are no simple methods to evaluate the physiologic significance of these new vessels. A third proposed mechanism to explain the acute symptomatic relief observed after DMR is damage to myocardial nerve fibers, resulting in an “anesthetic effect” without altered intramyocardial perfusion.34 It is also plausible that a combination of these potential mechanisms may be at work, with initial improvement due to cardiac nerve damage along with some increase in local myocardial perfusion via patent channels and more chronic improvement in perfusion as a result of neovascularization. Finally, late consequences of the creation of laser channels are unknown. Specifically, it remains to be determined whether laser-induced myocardial damage and fibrosis increase the risk for cardiac arrhythmias and late mortality.
LASER–MYOCARDIAL TISSUE INTERACTIONS Despite the preliminary use of different laser sources and energies to create intramyocardial channels, the laser–tissue interactions associated with DMR have been poorly characterized. A “laser system” is defined by its wavelength and operating parameters, including pulse duration, energy density, and repetition rate.35–39 Each system has a distinctive histopathologic “signature” and biologic response. For example, the CO2 laser produces confined photothermal ablative effects, with a thin zone of adjacent thermal injury and precise channel borders (Figure 1A).36,37 However, the CO2 laser cannot be transmitted by conventional fiberoptics and cannot be used for catheter-based DMR applications. Unlike the “purely” ablative CO2 laser, the short-pulsed (Ho:YAG or excimer) lasers, which can be transmitted via silicabased fibers, cause photothermal and predominantly photoacoustic (“shock-wave”) tissue effects. These are manifested as large zones of collateral tissue injury and irregular channel borders (Figure 1B),38 which differ greatly from the CO2 laser channels. In studying the laser myocardial tissue interactions using different Ho:YAG laser outputs, we have found that modifying the lasing parameters (e.g., number of pulses, energy per pulse, and laser fiber configuration) can alter tissue responses dramatically and predictably (Figure 2).39 Although the ideal channel morphology for DMR is unknown, specific laser–tissue interactions must be A SYMPOSIUM: INTERVENTIONAL VASCULAR MEDICINE
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FIGURE 1. Histologic features on close-up horizontal section myocardial channels in canine hearts corresponding to different laser sources. A: Carbon dioxide (CO2) laser channel representing “pure” ablation, with a thin zone of adjacent thermal injury and precise channel borders. B: Holmium/yttrium–aluminum– garnet (Ho:YAG) laser channel having irregular channel borders and collateral tissue injury zone, with dissection planes extending into natural interstitial spaces owing to profound photoacoustic effect. (Original magnification 3160.)
FIGURE 2. Impact of total laser output on myocardial channel dimensions using holmium/yttrium–aluminum– garnet (Ho:YAG) laser in porcine hearts. Note the increase in channel length and collateral thermal injury (white zone) with use of 2 joules 3 4 pulses (A) compared with 2 joules 3 1 pulse (B). Arrows denote the endocardial surface.
FIGURE 3. Representative case of percutaneous direct myocardial revascularization (DMR) using a new diagnostic and guidance-electromechanical navigational system in a patient with severe angina and unsuccessful prior angioplasty. A: Dual-isotope nuclear study indicating reversible perfusion defects in the posterolateral myocardial territory (arrows). B: Coronary angiogram (right anterior oblique projection) showing chronic total occlusion of the left circumflex artery and its marginal tributaries (arrow). C: Left lateral projection of endocardial voltage map after percutaneous DMR procedure in the posterolateral zone. Laser sites were tagged on the map in real time (brown dots) to show the exact endocardial location and precise distances of the laser channels. The map colors (blue, green, and yellow) represent the extent of endocardial voltage potentials (>10 mV), signifying myocardial viability in the treated zones.
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carefully evaluated for each laser source to design the optimal parameters for catheter-based DMR.
THE CATHETER-BASED APPROACH FOR DMR If surgical DMR can improve ischemic symptoms, percutaneous DMR may (1) provide equal benefit without the need for a thoracotomy or general anesthesia; (2) enable access to areas not approachable using surgical DMR (e.g., the ventricular septum and posterior wall); and (3) provide an opportunity for multiple treatment sessions using a “less invasive” approach.40,41 It is hypothesized that catheter-based DMR could generate smaller channels from the left ventricular cavity to the subepicardial myocardium using a Ho:YAG laser with collateral injury zones comparable in total volume to the surgical DMR channels created using a CO2 laser. For “optimal” catheter-based DMR, the system would require integrating catheter guidance with an ablative laser system that uses the “most appropriate” laser parameters. Most importantly, the percutaneous approach must ensure the delivery of penetrating energy to prespecified viable treatment zones without causing (1) perforation or other undesirable tissue effects (e.g., thrombosis, particulate debris, infarction); (2) ventricular dysrhythmias; (3) heart motion effects; and (4) “channel-on-channel” phenomena. The catheter design for percutaneous DMR is rapid evolving. It should include a laser fiber and should permit access to all endocardial zones, which would require adequate torque response, tip deflection, and endocardial contact stability as well as a tip configuration that minimizes surface trauma.
CATHETER NAVIGATIONAL CONTROL DURING DMR Navigational control of the distal tip of the laser catheter is necessary to achieve optimal laser–tissue contact at “vulnerable” treatment zones as well as to prevent repetitive, same-site laser firing that may increase the risk of perforation. Conventional catheter navigational modalities, such as biplane fluoroscopy and echocardiography, are limited by (1) their 2-dimensional endocardial representation; (2) nonoptimal echocardiographic resolution at the catheter tip– endocardial interface; (3) the inability to identify “vulnerable” viable treatment zones on-line; and (4) the inability to predict channel-on-channel laser firing, which may contribute to perforation. A novel navigational platform for catheter-based DMR has been derived from a new diagnostic and guidance-navigational system called Biosense.42,43 This device utilizes electromagnetic field energy to direct catheters in 3-dimensional space to create electromechanical maps without the need for fluoroscopy.42,43 These maps would then be used to identify viable target zones for DMR based on intracardiac electrical and contractility signals. The catheter system is integrated with a laser to perform the DMR procedure at precise locations within the left ventricle. The exact channel location is indicated in real time on
the electromechanical map (Figure 3).44 It remains to be established whether such precise localized treatment directed to viable myocardial zones would enhance therapeutic benefit and improve procedural safety of the catheter-based DMR procedure.
CATHETER-BASED DMR CLINICAL TRIALS: CURRENT STATUS Three commercially available catheter-based laser DMR systems are now being evaluated in Phase I clinical trials (CardioGenesis, Sunnyvale, CA; Eclipse, Sunnyvale, CA; Biosense/Johnson & Johnson; Tirat-Hacarmel, Israel). The energy source for all 3 systems is a Ho:YAG laser with differing energy parameters, fiber diameters, and catheter design. These Phase I registries were designed to prove the safety and feasibility of percutaneous DMR and will be followed by randomized controlled clinical trials. Although study cohorts will initially include patients with chronic refractory ischemia, “hybrid” procedures combined with routine angioplasty will probably follow. The clinical endpoints in all trials are improvements in symptomatic angina and in exercise capacity and radionuclide myocardial perfusion.
FUTURE DIRECTIONS Since beneficial DMR effects might not require long-term channel patency, different energy sources (such as radiofrequency ablation45) might be used to elicit a similar myocardial response without actual channel formation. A novel approach that may have an important application in the treatment of cardiovascular disease has been the use of recombinant genes or growth factors injected directly into the myocardium. Animal studies have proved the feasibility of introducing recombinant genes into cardiomyocytes by direct intramyocardial injection.46,47 Thus, DMR may be used in the future to elicit pharmacologic enhancement of naturally occurring angiogenic responses in the ischemic myocardium.48
CONCLUSIONS Both surgical and catheter-based DMR may be considered provocational treatment modalities for patients with chronic refractory ischemia who are no longer candidates for percutaneous transluminal coronary angioplasty or coronary artery bypass graft surgery. Although the clinical data are compelling for surgical DMR, more rigorous assessment of objective endpoints is still required to render definitive conclusions. Catheter-based DMR is truly in its infancy. Hurdles that still confront clinical investigators include further catheter development, improved guidance systems, predictable energy delivery, and acute complications. There are serious gaps in our understanding of the optimal channel size and channel density as well as the ideal energy source to produce desired tissue responses. Before DMR will be accepted as a viable therapeutic alternative in patients with severe ischemic heart disease, the mechanisms underlying the observed clinical benefits must be explored further and the dichotomy between clinical A SYMPOSIUM: INTERVENTIONAL VASCULAR MEDICINE
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responses and objective endpoint assessments must be resolved. 1. Frazier OH, Cooley DA, Kadipasaoglu KA, Pehlivanoglu S, Kindenmeir M,
Barasch E, Conger JL, Wilansky S, Moore WH. Myocardial revascularization with laser. Preliminary findings. Circulation 1995;92(suppl II):II-58 –II-65. 2. Cooley DA, Frazier OH, Kadipasaoglu KA, Kindenmeir MH, Pehlivanoglu S, Kolff JW, Wilansky S, Moore WH. Transmyocardial laser revascularization: clinical experience with twelve-month follow-up. J Thorac Cardiovasc Surg 1996;111:791–799. 3. Horvath KA, Mannting F, Cummings N, Shernan SK, Cohn LH. Transmyocardial laser revascularization: operative techniques and clinical results at two years. J Thorac Cardiovasc Surg 1996;111:1047–1053. 4. Boyce SW, Cooke RH, Aranki S, Cohn LH, Cooley DA, Crew J, Fontana G, Fraizer OH, Griffith B, Landolfo KP, Lansing AM, Lowe JE, Lytle BW, March RJ, Mirhoseini M, Smith CR. Quality of life following transmyocardial revascularization using the heart laser: randomized study results. (Abstr.) J Am Coll Cardiol 1997;29 (suppl A):105A. 5. Allen KB, Fudge TL, Selinger SL, Dowling RD. Prospective randomized multicenter trial of transmyocardial revascularization versus maximal medical management in patients with class IV angina. (Abstr.) Circulation 1997;96(suppl I):I-564. 6. Wearn JT, Mettier SR, Klumpp TG, Zschiesche LJ. The nature of the vascular communications between the coronary arteries and the chambers of the heart. Am Heart J 1933;9:143–164. 7. Beck CS. The development of a new blood supply to the heart by operation. Ann Surg 1935;102:801– 813. 8. Vineberg AM. Development of an anastomosis between the coronary vessels and a transplanted internal mammary artery. Can Med Assoc J 1946;55:117–119. 9. Vineberg A. Evidence that revascularization by ventricular–internal mammary artery implants increases longevity. J Thorac Cardiovasc Surg 1975;70:381–397. 10. Sen PK, Udwadia TE, Kinare SG, Parulkar GB. Transmyocardial acupuncture: a new approach to myocardial revascularization. J Thorac Cardiovasc Surg 1965;50:181–189. 11. Hershey JE, White M. Transmyocardial puncture revascularization. Geriatrics 1969;101–108. 12. Mirhoseini M, Muckerheide M, Cayton MM. Transventricular revascularization by laser. Lasers Surg Med 1982;2:187–198. 13. Mirhoseini M, Fisher JC, Cayton MM. Myocardial revascularization by laser: a clinical report. Lasers Surg Med 1983;3:241–245. 14. Mirhoseini M, Cayton MM, Shelgikar S, Fisher JC. Clinical report: laser myocardial revascularization. Lasers Surg Med 1986;6:459 – 461. 15. Mirhoseini M, Shelgikar S, Cayton MM. New concepts in revascularization of the myocardium. Ann Thorac Surg 1988;45:415– 420. 16. Boyce S, Aranki S, Cohn L, Cooley D, Crew J, Fontana G, Frazier OH, Griffith B, Landolfo K, Lansing A, Lowe J, Lytle B, March R, Mirhoseini M, Smith C. Transmyocardial laser revascularization using the heart laser system. US clinical experience, phases 2 and 3. Presented at Transcatheter Cardiovascular Therapeutic 9th Annual Symposium, September 24 –28, 1997, Washington, DC. 17. Donovan CL, Landolfo KP, Lowe JE, Clements F, Coleman RB, Ryan T. Improvement in inducible ischemia during dobutamine stress echocardiography after transmyocardial laser revascularization in patients with refractory angina pectoris. J Am Coll Cardiol 1997;30:607– 612. 18. Whittaker P, Kloner RA. Transmural channels as a source of blood flow to ischemic myocardium? Insights from the reptilian heart. Circulation 1997;95: 1357–1359. 19. Kohmoto T, Argenziano M, Yamamoto N, Vliet KA, Gu A, DeRosa CM, Fisher PE, Spotnitz HM, Burkhoff D, Smith CR. Assessment of transmyocardial perfusion in alligator hearts. Circulation 1997;95:1585–1591. 20. Mirhoseini M, Shelgikar S, Cayton MM. Clinical and histological evaluation of laser myocardial revascularization. J Clin Laser Med Surg 1990;9:73–78. 21. Cooley DA, Frazier OH, Kadipasaoglu KA, Pehlivanoglu S, Shannon RL, Angelini P. Transmyocardial laser revascularization: anatomic evidence of longterm channel patency. Tex Heart Inst J 1994;21:220 –224. 22. 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;61:1532–1535. 23. Gassler N, Wintzer HO, Stubbe HM, Wullbrand A, Helmchen U. Transmyocardial laser revascularization. Histologic features in human nonresponder myocardium. Circulation 1997;95:371–375. 24. Leszek R, Rainer M, Adolfo B, Dirk G, Christian BG. Transmyocardial laser revascularization: lack of channel patency in an experimental pig model. (Abstr.) Circulation 1996;94(suppl I):I-476.
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25. Berwing K, Bauer EP, Strasser R, Klovekorn WP, Reuthebuch O, Bertschmann W. Functional evidence of long-term channel patency after transmyocardial laser revascularization. (Abstr.) Circulation 1997;96(suppl I):I-564. 26. Kohmoto T, Fisher PE, Gu A, Zhu SM, Yano OJ, Spotnitz HM, Smith CR, Burkhoff D. Does blood flow through Holmium: YAG transmyocardial laser channels? Ann Thorac Surg 1996;61:861– 868. 27. Whittaker P, Kloner RA, Przyklenk K. Laser-mediated transmural myocardial channels do not salvage acutely ischemic myocardium. J Am Coll Cardiol 1993;22:302–309. 28. Kohmoto T, Fisher PE, DeRosa C, Smith CR, Burkhoff D. Evidence of angiogenesis in regions treated with transmyocardial laser revascularization. (Abstr.) Circulation 1996;94(suppl I):I-294. 29. Almanza O, Wassmer P, Moreno CA, Revail S, Sanchez JH, Ochsner J, Murgo JP, Cheirif J. Laser transmyocardial revascularization (LTMR) improves myocardial blood flow via collaterals. (Abstr.) J Am Coll Cardiol 1997;29(suppl A):99A. 30. Yamamoto N, Kohmoto T, Gu A, Derosa C, Smith CR, Burkhoff D. Transmyocardial revascularization enhances angiogenesis in a canine model of chronic ischemia. (Abstr.) Circulation 1997;96(suppl I):I-563. 31. Malekan R, Reynolds C, Kelley ST, Suzuki Y, Bridges CR. Angiogenesis in transmyocardial laser revascularization: a nonspecific response to injury. (Abstr.) Circulation 1997;96(suppl I):I-564. 32. Whittaker P, Rakusan K, Kloner RA. Transmural channels can protect ischemic tissue. Assessment of long-term myocardial response to laser- and needle-made channels. Circulation 1996;93:143–152. 33. Horvath KA, Smith WJ, Laurence RG, Schoen FJ, Appleyard RF, Cohn LH. Recovery and viability of an acute myocardial infarct after transmyocardial laser revascularization. J Am Coll Cardiol 1995;25:258 –263. 34. Kwong KF, Kanellopoulos GK, Schuessler RB, Saffitz JE, Sundt TM. Endocardial laser treatment incompletely denervates canine myocardium. (Abstr.) Circulation 1997;96(suppl I):I-565. 35. Leon MB, Bonner RF. Recent trends and future directions in laser angioplasty. In: Topol EJ, ed. Textbook of Interventional Cardiology. 1994:903–916. 36. Cummins L, Nauenberg M. Thermal effects of laser radiation in biologic tissue. Biophys J 1983;43:99 –102. 37. Deeckelbaum LI, Isner JM, Donaldson REF, Laliberte SM, Clarke RH, Salem DN. Use of pulsed energy delivery to minimize tissue injury resulting from carbon dioxide laser irradiation to cardiovascular tissues. J Am Coll Cardiol 1986;7:898 –908. 38. Van Leeuwen TG, Motamedi M, Meertens JH, Motamedi M, Post MJ, Borst C. Origin of arterial wall dissections induced by pulsed excimer and mid-infrared laser ablation in the pig. J Am Coll Cardiol 1992;19:1610 –1618. 39. Kornowski R, Hong MH, Haudenschild CC, Leon MB. Potentially hazardous effects of high-power holmium:YAG lasers during direct myocardial revascularization in porcine hearts. (Abstr.) Am J Cardiol 1997;80(suppl 7A):14S. 40. Kim CB, Kasten R, Javier M, Hayase M, Walton AS, Billingham ME, Kernoff R, Oesterle SN. Percutaneous methods of laser transmyocardial revascularization. Cathet Cardiovasc Diag 1997;40:223–228. 41. Oesterle S, Schuler G, Lauer B, Reifart N. Percutaneous myocardial laser revascularization: Initial human experience. (Abstr.) Circulation 1997;96(suppl I):I-218. 42. Ben-Haim SA, Osadchy D, Schuster I, Gepstein L, Hayam G, Josephson ME. Nonfluoroscopic, in vivo navigation and mapping technology. Nat Med 1996;2: 1393–1395. 43. Gepstein L, Hayam G, Ben-Haim SA. A novel method for non-fluoroscopic catheter based electroanatomical mapping of the heart: in vitro and in vivo accuracy results. Circulation 1997;95:1611–1622. 44. Shpun S, Hayam G, Gepstein L, Ben-Haim SA. Accurate non-fluoroscopic guidance of percutaneous myocardial revascularization with holmium/yttrium– aluminum– garnet laser in the canine left ventricle. (Abstr.) J Invas Cardiol 1997;9(suppl C):41C. 45. Weber HP, Heinze A, Enders S, Ruprecht L, Unsold E. Laser versus radiofrequency catheter ablation of ventricular myocardium in dogs: a comparative test. Cardiology 1997;88:346 –352. 46. Von Harsdorf R, Schott RJ, Shen YT, Vanter SF, Mahdavi V, Nadal-Ginard B. Gene injection into canine myocardium as a useful model for studying gene expression in the heart of large mammals. Circ Res 1993;72:688 – 695. 47. French BA, Mazur W, Geske R, Bolli R. Direct in vivo gene transfer into porcine myocardium using replication-deficient adenoviral vectors. Circulation 1994;90:2414 –2424. 48. Waltenberger J. Modulation of growth factor action. Implication for the treatment of cardiovascular diseases. Circulation 1997;96:4083– 4094.
VOL. 81 (7A)
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MD,
Mun K. Hong,
MD,
and Martin B. Leon,
MD
Direct myocardial revascularization (DMR), either surgical or catheter-based, uses lasers to create channels between ischemic myocardium and the left ventricular cavity to improve perfusion and decrease angina. This technique can also be used to deliver drugs to the damaged tissue. Candidates include patients with chronic, severe, refractory angina and those unable to undergo conventional surgical revascularization or angioplasty because remaining conduits or acceptable target vessels are lacking. Although the mechanism of action of DMR is still not known, several theories have been proposed, including stimulated angiogenesis. Late sequelae also
remain to be determined. Channel characteristics differ depending on whether they were created by carbon dioxide or holmium/yttrium–aluminum– garnet (Ho: YAG) lasers. Catheter-based DMR obviates thoracotomy and anesthesia and, in systems that can create electromechanical maps, fluoroscopy. Phase I clinical trials are now under way to evaluate catheter-based DMR, with endpoints that include improvement in symptoms of angina, exercise capacity, and radionuclide myocardial perfusion. Q1998 by Excerpta Medica, Inc. Am J Cardiol 1998;81(7A):44E– 48E
irect myocardial revascularization (DMR) is a nonconventional therapy designed to elicit a therapeutic D response by creating direct communications between the
on this concept, as well as the naturally occurring myocardial sinusoids that supply important subendocardial perfusion in reptilian hearts, subsequent investigators tried to increase myocardial perfusion “directly” by augmenting blood flow into existing myocardial sinusoids or by creating new sinusoids. In 1935, Beck7 used the myopexy and omentoplexy approach. In the 1940s, Vineberg8 implanted the distal end of internal mammary arteries directly into canine myocardium and demonstrated myocardial “blush” as well as collateralization to the epicardial coronary arteries. Much later, Vineberg9 extended this approach to patients, comparing them to a control group treated medically. Both symptoms and survival improved with the implants, and their long-term patency and collateral supply function were documented. In 1950, Sen and his colleagues10 used blunt instruments to create transmural channels in canine hearts after coronary occlusion (“transmyocardial acupuncture”) and noted a significant improvement in survival and a reduction in myocardial infarct size in this model compared with controls. In 1969, Hershey and White11 used the “transmyocardial puncture tract” procedure in a patient to terminate intraoperative ventricular fibrillation secondary to global refractory ischemia. In 1983, Mirhoseini et al12,13 applied the surgical DMR technique using a CO2 laser to create transmyocardial channels as an adjunct to coronary artery bypass graft surgery in patients who could not be completely revascularized by conventional techniques. These investigators later reported less angina and greater myocardial perfusion in the treated regions.14,15 More recently, Frazier and Cooley1,2 used a similar surgical DMR approach with CO2 lasers as “sole therapy” and reported improved angina, increased exercise capacity, and enhanced subendocardial perfusion by positron emission tomographic scans for at least 12 months. Similar favorable results were reported by Horvath and Cohn3 when they applied surgical laser DMR techniques. Results on preliminary analysis of a randomized
ischemic myocardium and the left ventricular cavity. Also known as transmyocardial revascularization or transmyocardial laser revascularization, DMR can be classified according to the procedural technique (surgical vs catheter-based [percutaneous]), the route of myocardial access (epicardial vs endocardial), and the form of treatment being applied (channel-forming laser vs local pharmacotherapy). Surgical DMR creates intramyocardial channels using carbon dioxide (CO2) or holmium/ yttrium–aluminum– garnet (Ho:YAG) lasers using an epicardial approach. Catheter-based DMR generates endomyocardial channels from the left ventricular cavity to the subepicardial myocardium using short-pulsed lasers delivered through fiberoptic catheters. Both the surgical and catheter-based DMR can also be used to inject drugs directly into the ischemic myocardium. Previous animal studies and preliminary clinical trials of surgical DMR have indicated a significant reduction in angina severity, an improved quality of life, and improved myocardial perfusion in refractory coronary ischemic syndromes. 1–5 Catheterbased DMR may provide benefits equivalent to those of surgical DMR without the need for thoracotomy or general anesthesia.
HISTORICAL PERSPECTIVES ON SURGICAL DMR The concept of DMR dates back to the 1930s, when Wearn and his colleagues6 described “myocardial sinusoids” and “arterio-sinusoidal” vessels that seemed to connect the coronary arteries with the left ventricular chamber in human cadaveric hearts. Based From the Department of Cardiology, Department of Medicine, Washington Hospital Center, Washington, DC. Supported by a grant from the Cardiology Research Foundation, The Washington Cardiology Center, Washington, DC. Address for reprints: Martin B. Leon, MD, Washington Cardiology Center, 110 Irving Street, NW, Suite 4B-1, Washington, DC 20010.
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©1998 by Excerpta Medica, Inc. All rights reserved.
0002-9149/98/$19.00 PII S002-9149(98)00197-0
study to determine whether surgical CO2 laser revascularization is superior to optimal medical therapy in patients not amenable to conventional revascularization support the registry experience—i.e., symptoms and quality of life improved, and there was some evidence of enhanced myocardial perfusion in the treated areas.16 Of the patients randomized to surgical DMR, 67% showed a reduction in angina class of $2, compared with 6% in the medically treated group, and hospitalization for unstable angina was markedly decreased (13% post-DMR vs 72% with medical therapy). Interestingly, clinical efficacy persisted (i.e., angina threshold was decreased) for as long as 2 years after DMR, suggesting a permanent beneficial effect on myocardial perfusion. Nuclear studies, with analysis limited to the first 3 months thus far, showed a less impressive 15% reduction in reversible defects in the DMR group versus a 7% increase in reversible defects in the control group. Donovan et al17 used dobutamine stress echocardiography to study 12 patients treated with surgical CO2 laser DMR and found significant improvement in regional contractility in the treated segments. Recently, in a prospective randomized trial of surgical DMR using a Ho:YAG laser versus “best” medical therapy, Allen et al5 showed a significant improvement in angina class (85% vs 18%) and decreased hospitalizations compared with the medical group at 6 months; clinical benefit was sustained for up to 12 months.
PATIENT CANDIDATES FOR DMR To be a candidate for DMR, patients must meet the following criteria: (1) severe angina (functional class III or IV) despite optimal medical therapy; (2) poor candidate for catheter-based angioplasty due to high procedural risk or absence of acceptable target sites; and (3) poor candidate for surgical revascularization due a prohibitive risk or absence of acceptable target vessels and/or remaining surgical conduits. Currently, the major categories for clinical DMR investigations include patients with (1) degenerated saphenous vein grafts (especially in those with a patent internal mammary artery conduit); (2) diffuse coronary disease or small target vessels (e.g., diabetics); (3) incessant postangioplasty restenosis or recurrent diffuse in-stent restenosis; and (4) chronic total occlusions with either nonvisualized or poor distal vessels. Another potential use for DMR is as a “hybrid” procedure in nonrevascularizable territories during either coronary angioplasty or coronary artery bypass graft surgery—an indication that may ultimately constitute the largest patient cohort for DMR procedures. At present, patients with overt heart failure or very low left ventricular ejection fractions are excluded from most study protocols.
SUGGESTED MECHANISMS FOR EFFECTS OF DMR Despite extensive investigations, the mechanism of beneficial DMR effects is still unknown.18 Initially, it was postulated that blood flow through the patent
channels would provide continued myocardial perfusion similar to the endocardial perfusion seen in normal alligator hearts.19 However, data are conflicting as to the long-term patency of these laser channels. Initial animal studies suggested patency of the channels, and anecdotal autopsy studies support the feasibility of chronic channel patency20,21; other animal studies and autopsy reports actively refute these findings.22–27 Another intriguing possibility is the stimulation of angiogenesis by laser-induced myocardial injury, leading to an increases myocardial perfusion. Recent reports from animal studies have demonstrated neovascularization and increased collateral flow, which may contribute to increased perfusion and myocardial salvage.28 –33 Unfortunately, there are no simple methods to evaluate the physiologic significance of these new vessels. A third proposed mechanism to explain the acute symptomatic relief observed after DMR is damage to myocardial nerve fibers, resulting in an “anesthetic effect” without altered intramyocardial perfusion.34 It is also plausible that a combination of these potential mechanisms may be at work, with initial improvement due to cardiac nerve damage along with some increase in local myocardial perfusion via patent channels and more chronic improvement in perfusion as a result of neovascularization. Finally, late consequences of the creation of laser channels are unknown. Specifically, it remains to be determined whether laser-induced myocardial damage and fibrosis increase the risk for cardiac arrhythmias and late mortality.
LASER–MYOCARDIAL TISSUE INTERACTIONS Despite the preliminary use of different laser sources and energies to create intramyocardial channels, the laser–tissue interactions associated with DMR have been poorly characterized. A “laser system” is defined by its wavelength and operating parameters, including pulse duration, energy density, and repetition rate.35–39 Each system has a distinctive histopathologic “signature” and biologic response. For example, the CO2 laser produces confined photothermal ablative effects, with a thin zone of adjacent thermal injury and precise channel borders (Figure 1A).36,37 However, the CO2 laser cannot be transmitted by conventional fiberoptics and cannot be used for catheter-based DMR applications. Unlike the “purely” ablative CO2 laser, the short-pulsed (Ho:YAG or excimer) lasers, which can be transmitted via silicabased fibers, cause photothermal and predominantly photoacoustic (“shock-wave”) tissue effects. These are manifested as large zones of collateral tissue injury and irregular channel borders (Figure 1B),38 which differ greatly from the CO2 laser channels. In studying the laser myocardial tissue interactions using different Ho:YAG laser outputs, we have found that modifying the lasing parameters (e.g., number of pulses, energy per pulse, and laser fiber configuration) can alter tissue responses dramatically and predictably (Figure 2).39 Although the ideal channel morphology for DMR is unknown, specific laser–tissue interactions must be A SYMPOSIUM: INTERVENTIONAL VASCULAR MEDICINE
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FIGURE 1. Histologic features on close-up horizontal section myocardial channels in canine hearts corresponding to different laser sources. A: Carbon dioxide (CO2) laser channel representing “pure” ablation, with a thin zone of adjacent thermal injury and precise channel borders. B: Holmium/yttrium–aluminum– garnet (Ho:YAG) laser channel having irregular channel borders and collateral tissue injury zone, with dissection planes extending into natural interstitial spaces owing to profound photoacoustic effect. (Original magnification 3160.)
FIGURE 2. Impact of total laser output on myocardial channel dimensions using holmium/yttrium–aluminum– garnet (Ho:YAG) laser in porcine hearts. Note the increase in channel length and collateral thermal injury (white zone) with use of 2 joules 3 4 pulses (A) compared with 2 joules 3 1 pulse (B). Arrows denote the endocardial surface.
FIGURE 3. Representative case of percutaneous direct myocardial revascularization (DMR) using a new diagnostic and guidance-electromechanical navigational system in a patient with severe angina and unsuccessful prior angioplasty. A: Dual-isotope nuclear study indicating reversible perfusion defects in the posterolateral myocardial territory (arrows). B: Coronary angiogram (right anterior oblique projection) showing chronic total occlusion of the left circumflex artery and its marginal tributaries (arrow). C: Left lateral projection of endocardial voltage map after percutaneous DMR procedure in the posterolateral zone. Laser sites were tagged on the map in real time (brown dots) to show the exact endocardial location and precise distances of the laser channels. The map colors (blue, green, and yellow) represent the extent of endocardial voltage potentials (>10 mV), signifying myocardial viability in the treated zones.
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carefully evaluated for each laser source to design the optimal parameters for catheter-based DMR.
THE CATHETER-BASED APPROACH FOR DMR If surgical DMR can improve ischemic symptoms, percutaneous DMR may (1) provide equal benefit without the need for a thoracotomy or general anesthesia; (2) enable access to areas not approachable using surgical DMR (e.g., the ventricular septum and posterior wall); and (3) provide an opportunity for multiple treatment sessions using a “less invasive” approach.40,41 It is hypothesized that catheter-based DMR could generate smaller channels from the left ventricular cavity to the subepicardial myocardium using a Ho:YAG laser with collateral injury zones comparable in total volume to the surgical DMR channels created using a CO2 laser. For “optimal” catheter-based DMR, the system would require integrating catheter guidance with an ablative laser system that uses the “most appropriate” laser parameters. Most importantly, the percutaneous approach must ensure the delivery of penetrating energy to prespecified viable treatment zones without causing (1) perforation or other undesirable tissue effects (e.g., thrombosis, particulate debris, infarction); (2) ventricular dysrhythmias; (3) heart motion effects; and (4) “channel-on-channel” phenomena. The catheter design for percutaneous DMR is rapid evolving. It should include a laser fiber and should permit access to all endocardial zones, which would require adequate torque response, tip deflection, and endocardial contact stability as well as a tip configuration that minimizes surface trauma.
CATHETER NAVIGATIONAL CONTROL DURING DMR Navigational control of the distal tip of the laser catheter is necessary to achieve optimal laser–tissue contact at “vulnerable” treatment zones as well as to prevent repetitive, same-site laser firing that may increase the risk of perforation. Conventional catheter navigational modalities, such as biplane fluoroscopy and echocardiography, are limited by (1) their 2-dimensional endocardial representation; (2) nonoptimal echocardiographic resolution at the catheter tip– endocardial interface; (3) the inability to identify “vulnerable” viable treatment zones on-line; and (4) the inability to predict channel-on-channel laser firing, which may contribute to perforation. A novel navigational platform for catheter-based DMR has been derived from a new diagnostic and guidance-navigational system called Biosense.42,43 This device utilizes electromagnetic field energy to direct catheters in 3-dimensional space to create electromechanical maps without the need for fluoroscopy.42,43 These maps would then be used to identify viable target zones for DMR based on intracardiac electrical and contractility signals. The catheter system is integrated with a laser to perform the DMR procedure at precise locations within the left ventricle. The exact channel location is indicated in real time on
the electromechanical map (Figure 3).44 It remains to be established whether such precise localized treatment directed to viable myocardial zones would enhance therapeutic benefit and improve procedural safety of the catheter-based DMR procedure.
CATHETER-BASED DMR CLINICAL TRIALS: CURRENT STATUS Three commercially available catheter-based laser DMR systems are now being evaluated in Phase I clinical trials (CardioGenesis, Sunnyvale, CA; Eclipse, Sunnyvale, CA; Biosense/Johnson & Johnson; Tirat-Hacarmel, Israel). The energy source for all 3 systems is a Ho:YAG laser with differing energy parameters, fiber diameters, and catheter design. These Phase I registries were designed to prove the safety and feasibility of percutaneous DMR and will be followed by randomized controlled clinical trials. Although study cohorts will initially include patients with chronic refractory ischemia, “hybrid” procedures combined with routine angioplasty will probably follow. The clinical endpoints in all trials are improvements in symptomatic angina and in exercise capacity and radionuclide myocardial perfusion.
FUTURE DIRECTIONS Since beneficial DMR effects might not require long-term channel patency, different energy sources (such as radiofrequency ablation45) might be used to elicit a similar myocardial response without actual channel formation. A novel approach that may have an important application in the treatment of cardiovascular disease has been the use of recombinant genes or growth factors injected directly into the myocardium. Animal studies have proved the feasibility of introducing recombinant genes into cardiomyocytes by direct intramyocardial injection.46,47 Thus, DMR may be used in the future to elicit pharmacologic enhancement of naturally occurring angiogenic responses in the ischemic myocardium.48
CONCLUSIONS Both surgical and catheter-based DMR may be considered provocational treatment modalities for patients with chronic refractory ischemia who are no longer candidates for percutaneous transluminal coronary angioplasty or coronary artery bypass graft surgery. Although the clinical data are compelling for surgical DMR, more rigorous assessment of objective endpoints is still required to render definitive conclusions. Catheter-based DMR is truly in its infancy. Hurdles that still confront clinical investigators include further catheter development, improved guidance systems, predictable energy delivery, and acute complications. There are serious gaps in our understanding of the optimal channel size and channel density as well as the ideal energy source to produce desired tissue responses. Before DMR will be accepted as a viable therapeutic alternative in patients with severe ischemic heart disease, the mechanisms underlying the observed clinical benefits must be explored further and the dichotomy between clinical A SYMPOSIUM: INTERVENTIONAL VASCULAR MEDICINE
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responses and objective endpoint assessments must be resolved. 1. Frazier OH, Cooley DA, Kadipasaoglu KA, Pehlivanoglu S, Kindenmeir M,
Barasch E, Conger JL, Wilansky S, Moore WH. Myocardial revascularization with laser. Preliminary findings. Circulation 1995;92(suppl II):II-58 –II-65. 2. Cooley DA, Frazier OH, Kadipasaoglu KA, Kindenmeir MH, Pehlivanoglu S, Kolff JW, Wilansky S, Moore WH. Transmyocardial laser revascularization: clinical experience with twelve-month follow-up. J Thorac Cardiovasc Surg 1996;111:791–799. 3. Horvath KA, Mannting F, Cummings N, Shernan SK, Cohn LH. Transmyocardial laser revascularization: operative techniques and clinical results at two years. J Thorac Cardiovasc Surg 1996;111:1047–1053. 4. Boyce SW, Cooke RH, Aranki S, Cohn LH, Cooley DA, Crew J, Fontana G, Fraizer OH, Griffith B, Landolfo KP, Lansing AM, Lowe JE, Lytle BW, March RJ, Mirhoseini M, Smith CR. Quality of life following transmyocardial revascularization using the heart laser: randomized study results. (Abstr.) J Am Coll Cardiol 1997;29 (suppl A):105A. 5. Allen KB, Fudge TL, Selinger SL, Dowling RD. Prospective randomized multicenter trial of transmyocardial revascularization versus maximal medical management in patients with class IV angina. (Abstr.) Circulation 1997;96(suppl I):I-564. 6. Wearn JT, Mettier SR, Klumpp TG, Zschiesche LJ. The nature of the vascular communications between the coronary arteries and the chambers of the heart. Am Heart J 1933;9:143–164. 7. Beck CS. The development of a new blood supply to the heart by operation. Ann Surg 1935;102:801– 813. 8. Vineberg AM. Development of an anastomosis between the coronary vessels and a transplanted internal mammary artery. Can Med Assoc J 1946;55:117–119. 9. Vineberg A. Evidence that revascularization by ventricular–internal mammary artery implants increases longevity. J Thorac Cardiovasc Surg 1975;70:381–397. 10. Sen PK, Udwadia TE, Kinare SG, Parulkar GB. Transmyocardial acupuncture: a new approach to myocardial revascularization. J Thorac Cardiovasc Surg 1965;50:181–189. 11. Hershey JE, White M. Transmyocardial puncture revascularization. Geriatrics 1969;101–108. 12. Mirhoseini M, Muckerheide M, Cayton MM. Transventricular revascularization by laser. Lasers Surg Med 1982;2:187–198. 13. Mirhoseini M, Fisher JC, Cayton MM. Myocardial revascularization by laser: a clinical report. Lasers Surg Med 1983;3:241–245. 14. Mirhoseini M, Cayton MM, Shelgikar S, Fisher JC. Clinical report: laser myocardial revascularization. Lasers Surg Med 1986;6:459 – 461. 15. Mirhoseini M, Shelgikar S, Cayton MM. New concepts in revascularization of the myocardium. Ann Thorac Surg 1988;45:415– 420. 16. Boyce S, Aranki S, Cohn L, Cooley D, Crew J, Fontana G, Frazier OH, Griffith B, Landolfo K, Lansing A, Lowe J, Lytle B, March R, Mirhoseini M, Smith C. Transmyocardial laser revascularization using the heart laser system. US clinical experience, phases 2 and 3. Presented at Transcatheter Cardiovascular Therapeutic 9th Annual Symposium, September 24 –28, 1997, Washington, DC. 17. Donovan CL, Landolfo KP, Lowe JE, Clements F, Coleman RB, Ryan T. Improvement in inducible ischemia during dobutamine stress echocardiography after transmyocardial laser revascularization in patients with refractory angina pectoris. J Am Coll Cardiol 1997;30:607– 612. 18. Whittaker P, Kloner RA. Transmural channels as a source of blood flow to ischemic myocardium? Insights from the reptilian heart. Circulation 1997;95: 1357–1359. 19. Kohmoto T, Argenziano M, Yamamoto N, Vliet KA, Gu A, DeRosa CM, Fisher PE, Spotnitz HM, Burkhoff D, Smith CR. Assessment of transmyocardial perfusion in alligator hearts. Circulation 1997;95:1585–1591. 20. Mirhoseini M, Shelgikar S, Cayton MM. Clinical and histological evaluation of laser myocardial revascularization. J Clin Laser Med Surg 1990;9:73–78. 21. Cooley DA, Frazier OH, Kadipasaoglu KA, Pehlivanoglu S, Shannon RL, Angelini P. Transmyocardial laser revascularization: anatomic evidence of longterm channel patency. Tex Heart Inst J 1994;21:220 –224. 22. 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;61:1532–1535. 23. Gassler N, Wintzer HO, Stubbe HM, Wullbrand A, Helmchen U. Transmyocardial laser revascularization. Histologic features in human nonresponder myocardium. Circulation 1997;95:371–375. 24. Leszek R, Rainer M, Adolfo B, Dirk G, Christian BG. Transmyocardial laser revascularization: lack of channel patency in an experimental pig model. (Abstr.) Circulation 1996;94(suppl I):I-476.
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25. Berwing K, Bauer EP, Strasser R, Klovekorn WP, Reuthebuch O, Bertschmann W. Functional evidence of long-term channel patency after transmyocardial laser revascularization. (Abstr.) Circulation 1997;96(suppl I):I-564. 26. Kohmoto T, Fisher PE, Gu A, Zhu SM, Yano OJ, Spotnitz HM, Smith CR, Burkhoff D. Does blood flow through Holmium: YAG transmyocardial laser channels? Ann Thorac Surg 1996;61:861– 868. 27. Whittaker P, Kloner RA, Przyklenk K. Laser-mediated transmural myocardial channels do not salvage acutely ischemic myocardium. J Am Coll Cardiol 1993;22:302–309. 28. Kohmoto T, Fisher PE, DeRosa C, Smith CR, Burkhoff D. Evidence of angiogenesis in regions treated with transmyocardial laser revascularization. (Abstr.) Circulation 1996;94(suppl I):I-294. 29. Almanza O, Wassmer P, Moreno CA, Revail S, Sanchez JH, Ochsner J, Murgo JP, Cheirif J. Laser transmyocardial revascularization (LTMR) improves myocardial blood flow via collaterals. (Abstr.) J Am Coll Cardiol 1997;29(suppl A):99A. 30. Yamamoto N, Kohmoto T, Gu A, Derosa C, Smith CR, Burkhoff D. Transmyocardial revascularization enhances angiogenesis in a canine model of chronic ischemia. (Abstr.) Circulation 1997;96(suppl I):I-563. 31. Malekan R, Reynolds C, Kelley ST, Suzuki Y, Bridges CR. Angiogenesis in transmyocardial laser revascularization: a nonspecific response to injury. (Abstr.) Circulation 1997;96(suppl I):I-564. 32. Whittaker P, Rakusan K, Kloner RA. Transmural channels can protect ischemic tissue. Assessment of long-term myocardial response to laser- and needle-made channels. Circulation 1996;93:143–152. 33. Horvath KA, Smith WJ, Laurence RG, Schoen FJ, Appleyard RF, Cohn LH. Recovery and viability of an acute myocardial infarct after transmyocardial laser revascularization. J Am Coll Cardiol 1995;25:258 –263. 34. Kwong KF, Kanellopoulos GK, Schuessler RB, Saffitz JE, Sundt TM. Endocardial laser treatment incompletely denervates canine myocardium. (Abstr.) Circulation 1997;96(suppl I):I-565. 35. Leon MB, Bonner RF. Recent trends and future directions in laser angioplasty. In: Topol EJ, ed. Textbook of Interventional Cardiology. 1994:903–916. 36. Cummins L, Nauenberg M. Thermal effects of laser radiation in biologic tissue. Biophys J 1983;43:99 –102. 37. Deeckelbaum LI, Isner JM, Donaldson REF, Laliberte SM, Clarke RH, Salem DN. Use of pulsed energy delivery to minimize tissue injury resulting from carbon dioxide laser irradiation to cardiovascular tissues. J Am Coll Cardiol 1986;7:898 –908. 38. Van Leeuwen TG, Motamedi M, Meertens JH, Motamedi M, Post MJ, Borst C. Origin of arterial wall dissections induced by pulsed excimer and mid-infrared laser ablation in the pig. J Am Coll Cardiol 1992;19:1610 –1618. 39. Kornowski R, Hong MH, Haudenschild CC, Leon MB. Potentially hazardous effects of high-power holmium:YAG lasers during direct myocardial revascularization in porcine hearts. (Abstr.) Am J Cardiol 1997;80(suppl 7A):14S. 40. Kim CB, Kasten R, Javier M, Hayase M, Walton AS, Billingham ME, Kernoff R, Oesterle SN. Percutaneous methods of laser transmyocardial revascularization. Cathet Cardiovasc Diag 1997;40:223–228. 41. Oesterle S, Schuler G, Lauer B, Reifart N. Percutaneous myocardial laser revascularization: Initial human experience. (Abstr.) Circulation 1997;96(suppl I):I-218. 42. Ben-Haim SA, Osadchy D, Schuster I, Gepstein L, Hayam G, Josephson ME. Nonfluoroscopic, in vivo navigation and mapping technology. Nat Med 1996;2: 1393–1395. 43. Gepstein L, Hayam G, Ben-Haim SA. A novel method for non-fluoroscopic catheter based electroanatomical mapping of the heart: in vitro and in vivo accuracy results. Circulation 1997;95:1611–1622. 44. Shpun S, Hayam G, Gepstein L, Ben-Haim SA. Accurate non-fluoroscopic guidance of percutaneous myocardial revascularization with holmium/yttrium– aluminum– garnet laser in the canine left ventricle. (Abstr.) J Invas Cardiol 1997;9(suppl C):41C. 45. Weber HP, Heinze A, Enders S, Ruprecht L, Unsold E. Laser versus radiofrequency catheter ablation of ventricular myocardium in dogs: a comparative test. Cardiology 1997;88:346 –352. 46. Von Harsdorf R, Schott RJ, Shen YT, Vanter SF, Mahdavi V, Nadal-Ginard B. Gene injection into canine myocardium as a useful model for studying gene expression in the heart of large mammals. Circ Res 1993;72:688 – 695. 47. French BA, Mazur W, Geske R, Bolli R. Direct in vivo gene transfer into porcine myocardium using replication-deficient adenoviral vectors. Circulation 1994;90:2414 –2424. 48. Waltenberger J. Modulation of growth factor action. Implication for the treatment of cardiovascular diseases. Circulation 1997;96:4083– 4094.
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