(Circulation. 1997;95:1360-1362.)
© 1997 American Heart Association, Inc.
Articles |
Catheter-Based Ultrasound Thrombolysis
Shake, Rattle, and Reperfuse
the Division of Cardiovascular Medicine, Stanford (Calif) University Medical School.
Correspondence to Paul G. Yock, MD, Acting Chief, Division of Cardiovascular Medicine, H3554, Stanford University Medical Center, 300 Pasteur Ave, Stanford, CA 94305.
Key Words: Editorials • thrombolysis • ultrasonics • catheters
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Introduction |
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 Top Introduction References |
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Therapeutic ultrasound—the use of high-intensity, low- frequency ultrasound to ablate pathological tissues—has found a role in several different specialties during the past 10 years. By far the most common application is the noninvasive disintegration of kidney and gallstones (lithotripsy). An ultrasound scalpel has been developed and is primarily used for extraction of intracranial and hepatic tumors. In cardiology, we have been introduced to therapeutic ultrasound for aortic valve decalcification.
These applications are all based on the fact that ultrasound, at the right combination of frequency and amplitude, will vigorously disrupt abnormal, inelastic tissue while healthy tissue in the same region simply shakes off the injection of energy. This principle of differential destruction is familiar from low-amplitude cutters such as the cast saw or the rotational atherectomy device. These devices work because compliant tissue is able to move out of the way of the short, quick displacements of the cutting element.
The potential for using therapeutic ultrasound to treat atherosclerosis and thrombosis has been appreciated for decades, but actual development efforts were slow to get under way. Catheter-based delivery systems for therapeutic ultrasound were first conceived and patented in the 1960s.1 2 Dedicated in vivo experimental work began in the early 1970s with the demonstration by Sobbe and colleagues3 that ultrasound delivered through a wire probe could be used to disrupt blood clots in animals. As with many other technologies in cardiology, however, it was the explosive growth of angioplasty in the 1980s that brought attention, funding, and real momentum to the development of therapeutic catheter ultrasound.
Significant technical issues had to be resolved in the design of the catheters. The most straightforward approach was to base the system around an external ultrasound source (a piezoelectric transducer attached to the proximal end of the catheter). The real challenge was to develop a catheter that would provide efficient transmission of the ultrasound energy to the lesion. Unfortunately, the best wave guides for ultrasound are made of solid metal-not a welcome design constraint when the target is within a tortuous coronary artery. In fact, significant curves in the wave guide tend to spin off ultrasound energy, further reducing the efficiency of energy transfer to the tip. To make matters worse for miniaturization, early studies also suggested that the probe diameters needed to be large to maximize delivery of energy from the probe tip to the target.
In the late 1980s, two groups, headed by Siegel and Rosenschein, began serious development efforts to address these issues.4 5 The resulting catheter designs have converged on some basic features. The current catheters from both groups are built around a solid-metal wave guide made of titanium or aluminum alloy. In the distal segment, which must be relatively flexible, the wire is either tapered or replaced by several thinner wire components. At the tip of the probe, there is a ball of larger diameter (1.2 to 1.7 mm), designed to increase energy delivery to the target. Proximal to this ball tip, the wire guide is ensheathed in plastic catheter. The catheters accept a standard guidewire in some version of a "rail" design and can be delivered through conventional guiding catheters. The proximal end of the ultrasound catheter is attached to an ultrasound transducer with a frequency of 
20 kHz (compared with 20 to 30 MHz for intravascular ultrasound imaging transducers). The power at the transducer is 16 to 20 W, but because of loss of energy in the wave guide, the power actually delivered to the lesion is reduced by 50% or more.
Initial in vitro work with these systems concentrated on the mechanisms of ablation and the effects of ultrasound on normal tissues. It was observed that part of the destructive effect of the catheters was due to direct percussion of the ball tip moving back and forth at 20 000 cycles per second. The amplitude of motion of the tip is very small (10 to 30 mm), so tissues with a compliant matrix of collagen and elastin are not affected. A second and more powerful disruptive force is cavitation around the tip.6 During the negative part of the acoustic cycle, a dramatic pressure drop occurs in the region the ball has just vacated. In this tiny region, the pressure falls below the vapor pressure of the tissue, causing the formation of microbubbles. As the pressure returns toward normal, these bubbles implode violently, resulting in an intense shear force (equivalent to an instantaneous local pressure gradient of up to 3 atm). In vitro studies have shown that ultrasound ablation is only evident at energy levels above the cavitation threshold and that the rate of tissue disintegration correlates with the amount of power delivered above this threshold.
The effects of the ultrasound energy on normal arterial wall are now known to be to be relatively innocent under conditions simulating clinical use. Initial in vitro and animal studies raised concern about thermal effects, recording temperatures as high as 50°C at the probe tip during continuous administration of ultrasound energy.7 This led to a number of strategies for temperature reduction, including saline flushing, use of pulsed instead of continuous ultrasound, and limited periods of sonication in a given treatment cycle (typically 30 or 60 seconds). With these modifications, the degree of heating has been reduced to <5°C, and histology studies have shown minimal evidence for thermal damage. It is worth keeping in mind, however, that in a worst-case experimental situation (prolonged delivery of ultrasound energy perpendicular to the arterial wall), thermal damage can be severe enough to perforate a vessel.
One unanticipated and fascinating beneficial effect of catheter ultrasound is its ability to induce local vasodilation in the region of the probe tip. The in vitro studies of Fischell et al8 demonstrated ultrasound dose–dependent, endothelium-independent smooth muscle cell relaxation. These investigators suggested that ultrasound may promote a reversible disruption of the actin filament interaction in the contractile apparatus, leading to muscle cell relaxation.
Another important area of preclinical investigation was characterization of the particulate material generated by the ultrasound probe. In an intraoperative study on surgically isolated peripheral arterial segments by Rosenschein et al,9 the mean diameter of particles collected within the treated segment was 18.9 µm. Just over half of the particulate was subcapillary in size (<10 µm). This is comparable to results from studies on the characteristics of atherosclerotic debris generated by rotational atherectomy.10 Ultrasound lysis of thrombus may produce smaller particles than ablation of plaque. In an in vitro study by Steffen et al,11 the average particle size was 5.3 mm, with all particulate smaller than 10 mm.
Initial studies of catheter-based ultrasound were performed in peripheral vessels in the late 1980s by both groups. In the first 45 patients reported by Siegel et al,12 86% of completely occluded segments were recanalized using ultrasound. The ability of the ultrasound probe to induce local vasodilation (and to overcome spasm) was clearly demonstrated. There was no angiographic or clinical evidence of distal embolization. Restenosis, judged by ankle-brachial index, was 20%.
The first clinical application of therapeutic ultrasound in coronary arteries was reported by Siegel et al13 in 1994. A summary of 44 cases from this group's continuing series has become available recently,14 including patients with stable and unstable angina as well as myocardial infarction. All 44 procedures were clinically successful, with all but 1 using balloon angioplasty after the ultrasound treatment. In 7 of 44 cases, the ultrasound probe was not successful in crossing the lesion; however, in 9 other cases of complete occlusion, the probe was successful where conventional techniques had failed. The average residual stenosis after ultrasound treatment alone was 71%; after balloon dilation, this was further reduced to 34%. Although only 14 of the patients had completed a 6-month follow-up at the time of the report, the rate of revascularization was high enough (3 among these 14) to lead the authors to suggest that there may be "no major effect on restenosis" compared with standard catheter techniques. In the 7 patients with acute myocardial infarction, ultrasound treatment appeared to be successful in reducing thrombus burden. After ultrasound angioplasty alone, the TIMI (Thrombolysis In Myocardial Infarction) flow ranking was generally 1, increasing to 3 after angioplasty. One patient had evidence of distal embolization that was not clinically significant.
In this issue of Circulation, Rosenschein et al15 extend this experience with coronary ultrasound thrombolysis in their report on the first 15 patients in the feasibility phase of the ACUTE trial (Analysis of Coronary Ultrasound Thrombolysis Endpoints). Patients were treated in two stages: first with the ultrasound catheter and then with balloon angioplasty if required. The cases were carefully selected: patients were primarily in Killip class 1 and, for reasons that are not explained in the article, only patients with left anterior descending artery lesions were included (possibly reflecting the delivery characteristics of this prototype catheter). The authors report that after they stabilized their technique in the first case, the remaining 14 applications of ultrasound were successful. What is particularly encouraging from their report is that in 13 of 14 cases, the ultrasound treatment alone established TIMI grade 3 flow with a relatively low residual stenosis (48%). There was no angiographic, electrocardiographic, or clinical evidence for distal embolization or no reflow. Taken together, these findings suggest that the ultrasound catheter was effective in substantially reducing thrombus burden and, to an intermediate degree, relieving stenoses.
The large majority of the patients in the study underwent balloon angioplasty to optimize the residual stenosis (final result, 20%). One patient had an asymptomatic reocclusion in the laboratory that was redilated; another patient had reocclusion at day 5; and a third was redilated for diffuse disease on follow-up angiography in the hospital.
Given the small numbers involved, it is difficult to put these results into a meaningful context with respect to current interventional approaches to acute infarction. Certainly the recent studies with "plain old balloon angioplasty" (POBA) in myocardial infarction have set a high standard. Primary angioplasty is associated with excellent initial success rates (90% to 97%) and recurrent ischemia or infarction in the range of 5% to 15%. Given these relatively favorable statistics, it will be difficult for investigators to show a generalized advantage for ultrasound over POBA. The significant further reduction in thrombotic events resulting from the use of antiplatelet agents such as ReoPro and the potential for increased benefit from plain or coated stents make the competitive landscape formidable for any new technology in the area of acute infarction.
This is not to say that the future for therapeutic coronary ultrasound is necessarily shaky. It is still fairly common to encounter patients in the catheterization laboratory with large and refractory clot burdens that do not respond to advanced catheter strategies and pharmacotherapy. In a review of their extensive infarct angioplasty experience, Bedotto and colleagues16 found that half of their failures were cases in which a large clot burden could not be overcome, resulting in persistent occlusion or no reflow. These patients have dramatically worse prognoses than those with otherwise comparable infarcts and successful reperfusion. Interestingly, patients with large clot burdens have typically been excluded from randomization in the primary angioplasty trials. It remains unproved that ultrasound will in fact benefit these cases, but this is certainly a strategic and important area of focus for future trials.
Other catheters with different mechanisms for disrupting clots are being developed. The most extensively tested technique at this point is the "hydrolysis" approach, in which water jets break up thrombus and, in one design, create suction through a Venturi effect to help remove the particulate.17 It is too early to make a meaningful comparison between this approach and the ultrasound catheters. Both catheters appear to be effective in reducing clot burden promptly. Neither system is particularly difficult to use; both require an external "box," but the expense of this equipment should not be formidable. The ultrasound catheters do have two potential advantages of uncertain importance: (1) they tend to prevent and even overcome spasm, and (2) ultrasound can be effective in ablating plaque as well as thrombus.
This latter characteristic, plaque ablation, will continue to be studied in parallel to the clinical trials on thrombolysis. Initial experience suggests that there are at least some cases in which ultrasound may be more effective than conventional techniques for crossing complete occlusions. Ultrasound does have the ability to ablate fibrocalcific tissue, which is the major source of difficulty for the interventionist in dealing with old occlusions. Another fascinating potential application for ultrasound stems from its ability to enhance the compliance of a lesion. The in vitro studies of Demer et al18 indicate that ultrasound treatment produces a large increase in lesion distensibility, presumably by disrupting fibrous elements and calcium within the plaque. It follows that there may be a role for ultrasound in heavily fibrocalcific lesions, particularly in the context of stenting. Pretreatment of these segments with ultrasound might allow for full expansion of stents at relatively low pressures, potentially reducing trauma to the vessel wall.
We now enter a familiar waiting period as these devices move from demonstration of clinical feasibility to comparative clinical trials. The investigators are to be commended for their thorough background work in defining the performance characteristics and biological effects of their catheters. It will be a year or two, however, before we will begin to understand the scope of practical applications for this technology.
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Acknowledgments |
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We appreciate the editorial assistance of Cynthia Yock and the background information provided by Robert Siegel.
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Footnotes |
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The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
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References |
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TopIntroductionReferences |
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1. Delaney LJ. Method for clot lysis. US Patent 3,352,303, July 28, 1965.
2. Kuris A. Ultrasonic method and apparatus for removing cholesterol and other deposits from blood vessels and the like. US Patent 3,565,062, June 3, 1968.
3. Sobbe A, Stumpff U, Trübestein G, Figge H, Kozuschek W. Die Ultraschall-Auflösung von Thromben. Klin Wochenschr. 1974;52:1117-1121.[Medline] [Order article via Infotrieve]
4.
Siegel RJ, Fishbein MC, Forrester J, Moore K, DeCastro E, Daykhovsky Z, DonMichael TA. Ultrasonic plaque ablation: a new method for recanalization of partially or totally occluded arteries. Circulation. 1988;78:1443-1448.
5. Rosenschien U, Bernstein J, Di Segni E, Kaplinsky E, Bernheim J, Rozenszain LA. Ultrasonic angioplasty: disruption of atherosclerotic plaques and thrombi in vitro and arterial recanalization in vivo. J Am Coll Cardiol. 1990;15:711-717.[Abstract]
6. Miller DL. A review of the ultrasonic bioeffects of microsonation, gas-body activation and related cavitation-like phenomena. Ultrasound Med Biol. 1987;13:443-470.[Medline] [Order article via Infotrieve]
7. Siegel RJ, DonMichael A, Fishbein M, Bookstein J, Adler L, Reinsvold T, DeCastro E, Forrester JS. In vivo ultrasound recanalization of atherosclerotic total occlusions. J Am Coll Cardiol. 1990;15:345-351.[Abstract]
8.
Fischell TA, Abbas MA, Grant GW, Siegel RJ. Ultrasonic energy: effects on vascular function and integrity. Circulation. 1991;84:1783-1795.
9.
Rosenschein U, Rozenszajn A, Kraus L, Marboe CC, Watkins JF, Rose EA, David D, Cannon PJ, Weinstein JS. Ultrasonic angioplasty in totally occluded peripheral arteries: initial clinical, histological, and angiographic results. Circulation. 1991;83:1976-1986.
10. Hansen DD, Auth DC, Vracko R. Rotational atherectomy in atherosclerotic rabbit iliac arteries. Am Heart J. 1998;115:160-165.
11. Steffen W, Luo H, Nita H, Passafaro J, Fishbein M, Maurer G, Siegel RJ. Catheter delivered therapeutic ultrasound recanalizes thrombotically occluded canine coronary arteries. J Am Coll Cardiol. 1994;24:1571-1579.[Abstract]
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13.
Siegel RJ, Gunn J, Ahsan A, Fishbein MC, Bowes RJ, Oakley D, Wales C, Steffen W, Campbell S, Nita H, Wills T, Silverton P, Myler RH, Cumberland DC. Use of therapeutic ultrasound in percutaneous coronary angioplasty: experimental in vitro studies and initial clinical experience. Circulation. 1994;89:1587-1592.
14. Hamm C, Reimers J, Wolfgang S. Therapeutic coronary ultrasound angioplasty in patients with symptomatic coronary artery disease. In: Siegel RJ, ed. Coronary Ultrasound. Boston, Mass: Kluwer Academic Publishers; 1996:241-254.
15.
Rosenschein U, Roth A, Rassin T, Basan S, Laniado S, Miller HI. Analysis of Coronary Ultrasound Thrombolysis Endpoints in acute myocardial infarction (ACUTE trial): results of the feasibility phase. Circulation. 1997;95:1411-1416.
16. Bedotto JB, Kahn JK, Rutherford BD, McConahay DR, Giorgi LV, Johnson WL, O'Keefe JH, Shimshak TM, Ligon RW, Hartzler GO. Failed direct coronary angioplasty for acute myocardial infarction: in-hospital outcome and predictors of death. J Am Coll Cardiol. 1993;22:690-694.[Abstract]
17. Hamburger JN, de Feyter PJ, de Mario C, Colombo R, Erbel R, Marco J, Bertrand M, Wijns W, Almagor Y, Serruys PW. Preliminary experience with the coronary angiojet rheolytic thrombectomy catheter: a preamble to the Euro-arts study. Eur Heart J. 1996;17(suppl):181. Abstract.
18. Demer LL, Ariani M, Siegel RJ. High intensity ultrasound increases distensibility of calcific atherosclerotic arteries. J Am Coll Cardiol. 1991;18:1259-1262.[Abstract]
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