Acute effects of argon laser on human atherosclerotic plaque

Transcription

1 Acute effects of argon laser on human atherosclerotic plaque Peter F. Lawrence, M.D., David J. Dries, M.D., Farhad Moatamed, M.D., and John Dixon, M.D., Salt Lake City, Utah Although the laser has been demonstrated to vaporize coronary artery plaque, there is little information about its ability to resect or vaporize the range of plaques present in peripheral vessels. This study attempts to determine the ability of the argon laser to resect all grades of atherosclerotic plaque, the risk Of perforation during plaque resection, the effects on surrounding arteries, and the effect of different transmission media (air, saline solution, and blood) on the delivery of laser energy to the vessel. Seventy-five adult human cadaveric aortic specimens with a range of atherosclerosis from grossly normal artery to extensive calcification with ulceration were exposed to variable energy densities (200 to >20,000 J/cm 2) within 48 hours of harvesting. Specimens were examined grossly for the visual effects of laser and microscopically after preparation with hematoxylin-eosin, trichrome, and/or Verhoeff's elastin stains. Our results indicate that normal arteries and noncalcified plaques absorb laser energy and are vaporized. As the atherosclerosis becomes more complex with calcification, calcified regions are not vaporized and cannot be resected. In normal arteries and noncalcified plaque, perforation times were less than 5 seconds. Where palpable calcification was present in atherosclerotic lesions, average perforation time was doubled. In some vessels areas of calcification prevented wall perforation, but areas of snbintimal hemorrhage perforated rapidly because of the selective absorption of laser energy by the red color of hemorrhagic tissue. These results remain the same when saline solution is used as a transmission media, although the amount of energy required to achieve the effects is increased. A blood medium absorbs most of the energy and markedly delays the resection of the plaque and perforation of the artery. Our experience indicates that the use of the argon laser, in an air or saline medium, has potential for the resection of noncalcified atherosclerotic plaques. Effects on the atherosclerotic vessel wall become less predictable as the plaque becomes heterogeneous with calcification and hemorrhage. (J VAsc SURG 1984; 1: ) Laser angioplasty has been proposed as a technique to resect atherosclerotic plaquey -3 Enthusiasm for this procedure is based on the ability of some lasers to deliver laser energy through a small flexible catheter, the ability to vaporize and resect tissue, and the potential for selective absorption of the laser energy by atherosclerotic plaque. Although most studies have investigated the effect of the laser on coronary arteries, 4,~ large peripheral arteries are more easily approached percutaneously and may also be optimal vessels for laser angioplasty. Of the lasers that are clinically available, the argon laser has been most widely studied in the cardiovascular sys- From the Departments of Surgery and Pathology, University of Utah School of Medicine, and the Veterans Administration Hospital, Salt Lake City, Utah. Presented at the Thirty-eighth Annual Meeting of the Society for Vascular Surgery, Atlanta, Ga., June 7-8, Supported by the Veterans Administration. Reprint requests: Peter F. Lawrence, M.D., 50 North Medical Drive, Salt Lake City, UT tern 6 because the beam can be delivered through a flexible catheter and causes an intermediate depth of tissue injury. This study was conducted to answer four questions: (1) Can an argon laser resect t'~ range of atherosclerotic plaque seen in the human aorta? (2) What is the risk of perforation while resecting the plaque? (3) What are the acute effects of the argon laser on surrounding normal artery? (4) Does the transmission medium (air, saline solution, or blood) have a signifcant influence on the resectability of plaque? METHODS Seventy-five adult human cadaveric aortas were harvested within 24 hours of death and placed in chilled Collins or saline solution. Sections of the infrarenal aorta and iliac arteries were initially graded by gross inspection for the extent of atherosclerosis (1 = normal artery, 2 = fatty streaks, 3 =~ raised, 6brous, noncalcified plaques, 4 = simple

2 Volume 1 Number 6 November 1984 Acute effects of argon laser on atherosclerotic plaque 853 Fig. 1. Area of grade II atherosclerotic artery subjected to 300 to 400 J/cm 2 of argon laser. Thickened intima is blistered and injury extends to media. calcified plaques, and 5 = complex calcified plaques with ulceration and subintirnal hemorrhage). To simplify the reporting of results, categories were modified to 1 = normal artery, 2 = atherosclerotic plaque without calcification, and 3 = atherosclerotic plaque with calcification. Application of the laser to the artery was performed with an argon laser (8- or 20-watt capacity). The power (measured in watts) was selected and then confirmed with a meter prior to application of the laser to the artery. The laser tip was placed between 0.1 and 0.7 cm from the intimal surface of the artery and the distance recorded. The duration of application of the laser energy was selected from 0.1 to 5 seconds and delivered with a timer. The total,energy delivered/unit area was calculated and exi~ _essed as energy density (J/cm2). Effect of argon laser on normal and atherosclerotic plaque. Artery specimens were placed on a 'mounting board and either submerged in saline solution or blood or left in an air medium. The laser beam was applied to the intimal surface of the artery, with an ink mark placed on the adventitial side of the artery to identify the site of application. The laser was then moved at least 1 cm from the edges of Msible injury and applied again. This technique was used repeatedly along the specimen with 5 to 15 laser applications per vessel. Following laser exposure the vessel was inspected and an estimate made of the extent of gross injury. The artery was placed in formalin, fixed in paraffin, and 4 to 6 mm thick "sections were stained with hematoxylin and eosin, Verhoeff's elastin, and/or trichrome. The tissue sections were examined with light microscopy. The depth and width of injury was then graded by a pathologist using morphologic criteria and an estimate made of the extent of injury to the intima and media. Particular attention was directed to the extent of injury to elastin and collagen. Sections demonstrating the maximal laser injury for each energy density were photographed at 10x magnification and the width and depth of injury measured with the use of a template. Perforation of vessels. Arteries were subjected to the argon laser with energies varying from 500 to >20,000 J/cm 2. The laser was placed at a 90-degree angle to the intimal surface of the artery and continuous energy applied until the light visibly perforated the adventitia of the artery. This procedure was repeated at least two subsequent times within an area of similar plaque composition and grading. Perforation time was recorded, and the grade of atherosclerosis noted at the site of perforation. To determine the effect of the transmission medium on the delivery of laser energy to the artery, perforation times for different media were compared with the laser in an air medium, then in saline solution, and finally in blood with a hematocrit of 35%. Perforation times for comparable grades of atherosclerosis were recorded for each transmission medium. RESULTS Effects on normal and atherosclerotic arteries. When normal aorta is exposed to an energy density of 300 J/cm 2, a raised, blistered intima develops

3 854 Lawrence et al. Journal of VASCULAR SURGERY Fig, 2. Area of vaporization extending into plaque and media is caused by 500 to 600 J/cm 2 injury with argon laser. with little other gross evidence of media or adventitial injury. Histologically, there is edema of the intima and sometimes separation of the intima from the media lateral to the site of injury for 3 to 4 mm. At times there is intimal vaporization and subintimal edema with necrosis and fracture of the superficial layers of elastin. The histologic injury is limited to the upper one third of the artery in all sections. When the energy density is increased to 500 J/cm 2, the intima and upper layers of media are vaporized in a wedge-shaped incision. On histologic examination the tissue around the area of vaporization shows morphologic changes indicative of thermal injury, and the effect on the media extends to greater than one half of the arterial wall. Elastin and collagen are fractured or disordered. With an increase in energy to 800 J/cm 2 the injury becomes deeper and sometimes extends to the adventitia. There is no histologic evidence of increased lateral injury as the energy density is increased; therefore the depth of penetration is the major variable once the initial lateral injury has occurred. When the same three energy densities are applied to a grade II artery with noncalcified atherosclerosis (Figs, 1 and 2), the artery has a similar gross and histologic appearance as that of an injury to a normal artery. We see no evidence of an increase in the vaporization depth or extent of thermal injury to the plaque compared with normal artery, either grossly or microscopically. In grade III atherosclerosis with areas of cal- cification and subintimal hemorrhage, the depth of vaporization am thermal injury is dependent on the area of plaque studied. The argon laser beam penetrates hemorrhagic areas more deeply than normal artery or noncalcified fatty streaks or plaque, whereas grossly calcified areas are not penetrated by the laser (Fig. 3). Areas of plaque with microcalcification may be vaporized, although the calcium remains in the base of the vaporized vessel. The inability to penetrate or resect extensively calcified plaque is seen at 300, 500, and 800 J/cm 2 of energy. Perforation of arteries. The perforation time for each grade ofatherosclerosis was determined at a power density of 500 to 600 watts/cm 2. Normal arteries (grade I) and arteries with noncalcified at~ erosclerosis (grade II) were perforated in a mean time of 4.2 and 3.8 seconds, respectively (Fig. 4). The range of perforation times was small and wa~ the same for normal and noncalcified atherosclerotic arteries. Grade III atherosclerosis has double the mean perforation time of grade I and II vessels, and the range of times is much greater. Individual perforation times from grade III atherosclerosis (Fig. 5) dramatically demonstrate that some portions of grade III plaque take <2 seconds to perforate, while others take >45 seconds or never perforate. Consequently, vessel perforation times are not only longer but less predictable for complex plaques with areas of hemorrhage, necrosis, and calcification. To determine the effect of the medium through ~ which the laser beam passes on the ability to resect

4 Volume 1 Number 6 November 1984 Acute effects of argon laser on atherosclerotic plaque 855 Fig. 3. Gross appearance of extensively calcified aortic plaque with hemorrhagic areas of arterial wall vaporized and adjacent areas of calcification unaffected. A towel is seen behind wall perforation. q n-- 36 I n:21 n~ j i i i I II II! Grade of Atherosclerosis Fig. 4. Comparison of perforation times for normal (grade I), noncalcified atherosclerofic (grade II) and calcified atherosclerofic (grade III) aortas when exposed to 500 to 600 watts/cm 2 of argon energy. and perforate the artery, we compared perforation times for all three grades of plaque in air, saline solution, and blood (Fig. 6). In grade I and II disease, saline solution slightly increases perforation times, whereas blood markedly delays perforation of the artery. In addition, blood absorbs the laser en-, ergy, causing burning of the plastic sheath on the laser. When extensively calcified areas of grade III atherosclerosis are studied, the argon laser does not penetrate the artery in any medium. DISCUSSION As the incidence of clinically significant atherosclerosis increases because of our aging population, the need for simplified procedures to remove atherosclerotic plaque will increase. Although surgical end-

5 856 Lawrence et al. Journal of VASCULAR SURGERY ~" a5 m N 2o 5 o Fig. 5. Perforation times for 36 aortic specimens with calcified (grade III) atherosclerosis demonstrate variable response of heterogeneous plaques to argon laser re.a O0 0 ne "'2 b_ 0 "'3 C3 ne AIR SALINE BLOOD (= 5) 50 +_ sz >30 52o + _ 5B (n:5) >30 >30 (n =5) >50 >30 (n:5) (.9 p< 02 Power Density = J/era 2 Fig. 6. Comparison of perforation times demonstrates that more extensive atherosclerosis increases time for perforation. In addition, medium through which laser energy is delivered determines perforation time, with blood markedly reducing delivery of energy to artery and subsequent perforation of artery. arterectomy or bypass remains the standard against which all other therapy is compared, 7 the marked increase in use of transluminal angioplasty over the past 5 to 6 years indicates that there are frequent situations in which less invasive procedures are preferred by clinicians. 8 However, one major disadvantage of balloon angioplasty is the inability to dilate certain ather0sclerotic plaques that are nondistendable, often because of calcification. 9 In addition, it is frequently difficult for a balloon catheter to penetrate an occluded vessel. The laser offers significant theoretic appeal as an instrument to resect atherosclerotic plaque. Of the three lasers in common clinical use (Nd: YAG, argon, and CO2), the argon and Nd: YAG laser beam can be directed through a small flexible quartz fiber. This allows delivery of the laser energy at distances of greater than 6 feet from the source of the light. The ability to deliver the energy at a distance from the operator potentially allows percutaneous procedures on all of the major arteries in the body. In addition to the ability to deliver laser energy at a distance from its source, the other major theoretic advantage of lasers is the ability to resect atherosclerotic tissue, leaving normal tissue behind; Lasers deliver a single wavelength of coherent morn,: chromatic light, whose absorption is determined by the composition of the tissue it contacts. Each laser is selectively absorbed by tissue, dependent on the color of the tissue, water content, and density. Of the three lasers in common clinical use, the COs laser is absorbed by water and creates a superficial injury, the argon causes vaporization with an intermediate-depth thermal injury and is absorbed by red chromogens such as blood, and the Nd : YAG laser causes vaporization with a more extensive and deeper thermal injury and is absorbed by black chromogens. The argon laser was selected for this study because it can be delivered through a flexible quartz fiber and it rapidly vaporizes tissue with an intermediate depth of injury to surrounding tissue. Pre-

6 Volttme 1 Number 6 November 1984 Ac,~te effects of argon laser on atherosclerotic plaque 857 liminary studies in our laboratory also indicated that atherosclerotic plaque might selectively absorb the argon light, so that selective resection of athcrosclerotic plaque with minimal damage to normal artery was potentially possible. In addition, other investigators who are working on laser angioplasty have used the argon laser for coronary artew plaques, s so that considerable information is currently available about the response of coronary vessels to the argon laser. These studies have indicated that the argon laser can resect simple atherosclerotic plaques in coronary arteries, n and the investigators also state that calcified plaques are resected as easily as noncalcified plaques. 12 However, these encouraging results have been obtained in a small number of atherosclerotic vessels and therefore may not apply to the range of ~therosclerotic plaques seen in large peripheral vessels such as the aorta. Consequently, we believe that studies of the effects of the argon laser should use the range of atherosclerosis found in peripheral vessels before this procedure is applied clinically in the aorta and peripheral arterial tree. In this study we have found that the effects of the argon laser on normal and atherosclerotic arteries without calcification are predictable, particularly when the laser is held at a 90-degree angle to the intima and the distance between the tip of the laser and the intimal surface of the artery is accurately measured. Since the energy delivered to an artery is related to the square of the distance, minor adjustments in distance result in major differences in energy density. Under controlled conditions, the vaporization of noncalcified plaque, thermal injury to surrounding artery, and perforation times are quite predictable. As the atherosclerotic plaque becomes more heterogeneous with areas of hemorrhage and calcification, the ability to resect plaque and the time for perforation become much less predictable. Areas of hemorrhage are rapidly vaporized since the red chromogen absorbs the blue-green argon light. In areas where there is extensive calcification, we either had difficulty or were unable to resect plaque. In the complex plaque the location of the beam is critical, since plaque without calcification may be quickly penetrated, leaving the calcified portion of the plaque behind. Therefore we would predict that when the argon laser is used clinically in advanced atherosclerotic lesions, there will either be a low rate of resection or a high risk of perforation, depending on the aggressiveness of the laser operator, The effect of the transmission medium on the ability to resect plaque was the other factor investigated in this study. Although studies in an air medium may be impressive, la the laser is unlikely to be used frequently in air, since surgical exposure of a vessel defeats one of the laser's major advantages. With an argon laser it is quite apparent that saline solution has major advantages over blood as a transmission medium. Since argon energy is absorbed by red chromogens, the blood absorbs much of the argon energy, leaving less energy to heat the wall and vaporize plaque. With saline solution the effect of the medium is not so pronounced, although some energy appears to be absorbed by the solution, causing a slight increase in vessel perforation time. Consequently, when the argon laser is used clinically, blood will need to be removed from the space between the tip of the laser and the artery, or it will be difficult to deliver enough energy to vaporize plaque. This may be accomplished by replacing the blood with saline solution through a flush system, eliminating the blood with a balloon, or placing the tip of the argon laser close enough to the artery so that there is minimal blood in the space. We also investigated the short-term effect of the argon laser on the remaining arterial wall. Although initial reports indicated that laser vaporization does not cause arterial wall weakening and subsequent aneurysms, a4 more recent studies have indicated that disruption of the media may result in microaneurysms. 15 From our light microscopic studies of the acute laser injury, we believe that injury to elastin and collagen occurs frequently, with the width and depth of injury dependent on the energy density, and that this medial injury may lead to arterial wall weakening and subsequent aneurysm formation. Long-term studies are not yet available in either animals or humans to know the consequences of this medial injury and whether enough repair will take place to preclude aneurysm formation when large segments of the arterial wall are resected, as will frequently be necessary to resect a hemodynamically significant plaque. Laser injury to the intima and media will also result in increased thrombogenicity of the arterial wall and possibly accelerated atherosclerosis. Although a recent study by Gerrity et al. 16 has not shown thrombus extending into the lumen after an arterial injury, the size of the laser injury was much smaller than the injury necessary to resect plaque, so thrombosis may still be a problem cfinically. We have not addressed the issue of thrombogenicity of the arterial wall in this study. In a previous study accelerated atherosclerosis was not seen following

7 858 Lawrence et al. Journal of VASCULAR SURGERY laser injury in pigs on an atherogenic diet, although the laser has been used by other investigators to cause a reproducible model of intimal injury and accelerated atherosclerosis, tz Therefore acute and long-term studies need to be conducted to determine whether laser injuries of the size necessary to resect plaque will resuk in clinically significant arterial wall thrombosis and accelerated atherosclerosis. From this study and the work of other investigators, we believe that the laser has great potential as a device to percutaneously resect atherosclerotic aortic plaque. Most of the problems we have encountered in this study are solvable, although modifications may be necessary in the type of laser used, medium through which the laser is delivered, and normal response of arteries to injury before the laser can achieve the results currently obtained by surgical intervention. In addition, the variable response of the heterogeneous aortic and peripheral arterial plaque may result in the need to visualize the plaque and artery during resection. As smaller endoscopes are developed with better optical resolution, the ability to simultaneously visualize and resect atherosclerotic plaques may result in a procedure with a lower morbidity and comparable results to surgical resection or bypass. REFERENCES 1. Lee G, Ikeda RM, Dwyer RM, Hussein M, Dietrich P, Mason DT. Feasibility of intravascular laser irradiation for in vivo visualization mad therapy of cardiocirculatory diseases. Am Heart J 1982; 103: Choy DSJ, Stertzer S, Rotterdam HZ, Sharrock N, Kaminow LP. Transltuninal laser catheter angioplasty. Am J Cardiol 1982; 50: Ginsberg R, Kim DS, Guthaner D, Toth 1, and Mitchell RS. Salvage of an ischemic limb by laser angioplasty: Description of a new technique. Clin Cardiol 1984; 7: Abela GS, Normann S, Cohen D, et al. Effects of carbon dioxide, Nd-Yag, and argon laser radiation on coronary atheromatous plaques. Am J Cardiol 1982; 50: Lee G, Ikeda RM, Kozina BS, Mason DT. Laser-dissolution of coronary atherosclerotic obstruction. Am Heart J 1981; 102: Choy DSJ, Stertzer SH, Rotterdam HZ, Bruno MS. Laser coronary angioplasty: Experience with 9 cadaver hearts. Am J Cardio! 1982; 50: de Wolfe VG. Arteriosclerosis obliterans: Clinical diagnosis and treatment. Geriatrics 1973; 28: Kumpe DA, Kempczinski RF. Percutaneous transluminal angioplasty in the selected management of proximal arterial occlusive disease of the lower extremities: A preliminary report. Surgery 1979; 87: Connolly JE, Kwaan )'HM, McCart PM. Complications after percutaneous transluminal angioplasty. Am J Surg 1981; 142: Abela GS, Feldman RL, Normann S, et al. Use of laser radiation to recanalize totally obstructed coronary arteries. J Am Coil Cardiol 1983; 1: Gessman LJ, Reno CW, Hastie R. Model for testing coro. nary angioplasty by laser catheter. J Am Coil Cardiol 1983; 1: Abeta GS, Normann S, Cohen D, et al. Effects of carbon dioxide, Nd-Yag, and argon laser radiation on coronary atheromatous plaques. Am J Cardiol 1982; 50: Lee G, Ikeda RM, Kozina BS, Mason DT. Laser-dissolution of coronary atherosclerofic obstruction. Am Heart J 1981; 102: Abela GS, Staples ED, Conti CR. Immediate and long-term effects of laser radiation on the arterial wall: Light and electron microscopic observation. Surg Forum 1983; 34: Van Stiegmarm G, Kalm D, Rose AG, Boruman PC, Terblanche L Endoscopic laser endarterectomy. Surg Gynecol Obstet 1984; 158: Gerrity RG, Loop FD, Golding LAR, Ehrhart LA, Argenyi ZB. Arterial response to laser operation for removal of atherosclerotic plaques. J Thorac Cardiovasc Surg 1983; 85: Wiedeman MP: Vascular reactions to laser in vivo. Microvasc Res 1974; 8: DISCUSSION Dr. James J. Livesay (Houston, Tex.). I commend Dr. Lawrence and his colleagues on a well-prepared study investigating laser effects on human atherosclerotic plaques. We at the Texas Heart Institute also believe that laser technology has great promise for future surgical use in vascular disease. Based on our studies in this field, I would like to make several comments and ask two questions. The biologic effects of laser radiation are demonstrated in this photomicrograph of a 2 mm left anterior descending coronary artery. To vaporize this plaque, 2.5 J of CO2 laser energy was needed, thus relieving the critical coronary stenosis, and doubling the cross-sectional area of the vessel lumen. We have been successful in relieving stenosis in 22 of 24 human cadaveric coronary arteries. In two severely calcified arteries the laser was ineffective. With the CO2 laser there is remarkably little thermal injury to the vessel wall adjacent to the atheroma. Only a thin rim of charring lines the wall of the crater. This unique property of CO~ lasers is due to the rapid tissue absorption of this wavelength of light energy. In con-, strast, unless hemoglobin is present, the argon laser requires five times the amount of radiant energy to vaporize the same amount of plaque. This additional energy has been shown to produce undesirable thermal injury to the ~ vessel wall and result in aneurysm formation.

8 Volume 1 Number 6 November 1984 Acute effects of argon laser on atherosclerotic plaque 859 To minimize the risk of injury to the vessel wall and to allow precise control of laser energy, we have found the pulsed CO2 laser to be the optimal method of laser endarterectomy. Once the laser is adjacent to the plaque and aligned for coaxial passage, each pulse of laser radiation cuts a conical crater in the plaque. We and others have found that the optimal pulse duration for the CO2 laser to be 30 msec or less. The CO~ laser provides a unique surgical tool with enormous potential for use by the vascular surgeon as an intraoperative adjunct to bypass surgery. I would like to close by asking two questions of Dr. Lawrence: (1) Since the CO2 laser has been demonstrated to have better absorption characteristics than the argon or Nd: YAG lasers, with less risk of thermal damage to the artery wall, do you not agree that this is the preferred wavelength for endarterectomy purposes? (2) Has your group examined the taser effects on arteries using shorter pulse durations, for example, less than 100 msec? Dr. John T. Bergan (Chicago, Ill.). Dr. Lawrence, I wonder if you would tell us what happens to the tissue that is destroyed. Will that be a problem washing downstream? In addition, will you comment on the natural history of healing? Will atherosclerosis be produced by the laser beam? Dr. Lawrence (closing). Dr. Bergan, CO2, nitrogen, and water are produced as by-products of laser vaporiza- tion. From studies by other investigators, including Choy, it does not appear that there is much particulate matter left when the plaque is vaporized. I would predict that laser angioplasty is a superb model for accelerated atherosclerosis, similar to balloon catheter angioplasty, and I would anticipate that there would be little difference between the argon laser injury and other techniques of injuring the intima. Dr. Livesay, we chose the argon laser because it can be delivered with a flexible catheter. The CO2 laser at the current time does not have a flexible catheter; consequently the vessel has to be exposed directly. However, I would agree with Dr. Livesay that the ideal wavelength for the resection of a plaque is not necessarily in the range of the argon laser; it may be in the CO2 wavelength or it may be at some other wavelength that we might ultimately achieve with tunable lasers. Considering the length of duration of pulses, we have compared power and time; and at least in the range of energy that we have used, which is from 0. i second up to greater than 5 seconds, it appears to us that the total energy delivered (that is why I used Joules per square centimeter) is the critical factor. We have not looked at the shorter pulse durations repeatedly, but other investigators have reported that this is associated with less thermal injury.