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FIGURE 20.1 Microscopy of liquefied thrombi after in vitro ultrasound thrombolysis. Note the fibrin fragments and the intact red blood cells.
bypass surgery and compared with control of mechanical penetration with the system’s catheter. The activated ultrasound
device catheter recanalized the surgically exposed segment of the obstructed artery within an average of 78 s, documented
by histology or angiography, without perforations.
The peripheral angiograms revealed an average lumen patency of 82.5%. No acute thrombosis, dissection embolization,
or spasm was observed [4].
Both the area of and the flow through treated recanalized arterial segments were significantly greater than those of
mechanically crossed control segments.
Histological examination revealed similar arterial wall injury indices in both groups. Furthermore, the sonicated test
arteries did not exhibit evidence of thermal injury, blast damage, or perforation.
In the arteries occluded by atherosclerotic plaques only, a channel in the diameter of the catheter was observed, whereas
in thrombotically occluded grafts a very large area of recanalization was observed. This observation was consistent
with our previous observatio ns in vitro and in vivo that thrombi and atherosclerotic plaques are disrupted at different rates.
Also in this study, thrombi appear to liquefy more rapidly and effectively than atherosclerotic plaques. Complicated
plaques, particularly in the presence of fibrous tissue, appear to undergo ultrasonic disruption more slowly and only in the
immediate vicinity of the ultrasound wire.
These observations in human atherothrombotic pathology suggest that thrombi may be disrupted primarily by the effect
of the cavitation field, whereas the disruption of fibrous plaques probably involves a great component of mecha nical
fragmentation by the vibrating wire [4]. Furthermore, in this mode, LFHP ultrasound did not seem to damage the human
arterial wall at the energy levels used for recanalization of human peripheral arteries.
Thus, at that point we believed that the experimental and clinical experiences with LFHP ultrasound suggested that the
thrombus-rich lesion may be the ideal target lesion for ablation with ultrasound. The data suggested that thrombi and
arterial walls have the difference in sensitivity to LFHP ultrasound ablation needed for successful transluminal ultrasound
thrombolysis.
SECOND-GENERATION DEVICE
The first-generation device answered partially the developmental challenges for a catheter-based therapeutic ultrasound
device an d was not practical for clinical use; it was too short, too stiff, and incompatible with guidewires. As a result we
dedicated considerable efforts to developing a clinically capable system.
The coronary ultrasound thrombolysis system consisted of three basic elements: the external power generator, the
external piezoelectric transducer (which converts electrical to ultrasonic energy), and the ultrasound catheter. The coronary
system developed by our group (Acolysis System) utilized a 125-cm-long probe connected at its proximal end to the
piezoelectric transducer. To maximize the transmission of ultrasound and to minimize its dissipation, we developed the
ultrasound wire from high-mechanical-Q aluminum. The mechanical Q of a material is proportional to the ratio of energy
stored to energy dissipated per unit of material volume per cycle of vibration. Thus, the higher the mechanical Q, the
smaller the quantity of ultrasound energy that is dissipated as heat, and the lower the attenuation of ultrasound per unit
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length of ultrasound wire. Aluminum has a higher mechanical Q than does titanium (50,000 vs. 24,000), which is
traditionally used for the construction of ultrasound probes. We found minimal conversion of high-energy ultrasound to
heat in the aluminum wires. The ultrasound generator was operated in the pulsed mode with a 50% duty cycle to ensure
resonance capture. The duration of the pulse was 0.5 s with an interval of 0.5 s. The distal part (18 cm) of the probe was a
three-wire flexible segment with a 1.6-mm tip, designed to achieve maximal cavitation effect and to optimize the
thrombolytic effects. The special design of the distal segment enables the use of a solid metal probe for optimal ultrasound
transmission while still maintaining flexibility. The three-wire design of the distal segment permits the use of solid metal
for optimal ultrasound transmission while still achieving the desired flexibility. This is similar to the way in which optic
fibers enable effective transmission of light waves through glass while maintaining flexibility. Ultrasonic energy (41.9 kHz,
18 W) generated at the transducer was transmitted as longitudinal vibrations of the probe and directed the energy into the
arterial system. The device was compatible with a standard 6-Fr angioplasty guiding catheter and accepted a 0.014-inch
guidewire through a coaxial central lumen in a rapid exchange fashion. A technique we thought was optimal was
recommended: prior to sonication, the lesion is to be crossed with a 0.014-inch guidewire. The ultrasound probe is then
introduced over the guidewire and positioned at a depth of w2 mm into the thrombotic lesion. Sonication is done at 60-s
intervals for a cumulative time not exceeding 3 min per probe. During sonication, the probe is either left stationary or
moved slowly back and forth with an excursion of w3 mm. To minimize the risk of distal embolization, the lesion is
mechanically crossed only after effective thrombolysis achieves angiographic reperfusion.
We initiated our coronary ultrasound thrombolysis investigations in vivo in intact canine coronary arteries to gain
experience with coronary artery sonication. The study enabled us to compare the effects of coronar y sonication at energy
levels known to induce thrombus ablation with those of balloon dilation, the “gold standard” of coronary intervention [7].
We monitored for hemodynamic, electrocardiographic, laboratory, echocardiographic, histopathologic, and angiographic
end points. No adverse side effects were observed of flowing sonication in the coronary tree when a delivery system and
energies known to induce effective thrombus ablation were used. Histopathology analysis revealed no significant damage
to the endothelium, internal elastic lamina, media, and adventitia. The observed resistance of the coronary arterial wall to
acoustic energy was consistent with earlier studies.
In the next step, because of the exceptionally high efficacy of LFHP ultrasound in thrombolysis, we decided to
investigate the feasibility of coronary ultrasound thrombolysis in patients with ST-segment elevation myocardial infarction
(STEMI), the archetypal clinical manifestation of thrombus-rich lesion. In the single-center first-in-human trial [8],
consecutive patients with electrocardiographic evidence of anterior STEMI occluded in the left anterior descending artery
and no prior history of STEMI underwent coronary ultrasound thrombolysis. Forty consecutive patients were clinically
eligible. Twenty-five patients underwent cardiac catheterization and 15 were angiographically eligible and treated with
coronary ultrasound thrombolysis. Device success (TIMI [thrombolysis in myocardial infarction] grade 3 flow) was
obtained in 87% of the patients and clinical success in 80% (Fig. 20.2). No adverse clinical side effects were observed
during sonication in the coronary tree.
Adjunct percutaneous transluminal coronary angioplasty (PTCA) after ultrasound thrombolysis produced a final
residual stenosis of 20 12%. There was no change in the degree of flow in any of the patients at the 12- to 24-h
angiograms. Furthermore, there was no angiographic electrocardiographic or clinical evidence for distal embolization or
no-reflow phenomenon. Adverse clinical events during hospitalization were limited to reocclusion of the infarct-related
artery in only one patient (7%). At 6-month follow-up, there was one death and one reinfection and no urgent targetvessel revascularization. A significant improvement of left-ventricular ejection function was observed (47 10% to
60 15%, P ¼ .003) (Fig. 20.3). Analysis of the full cohort of 39 patients enrolled in the ACUTE trial showed results
similar to those observed in the feasibility phase, both acute in-hospital and at 6 months postprocedure [9].
The successful preliminary clinical experience with coronary ultrasound thrombolysis in STEMI patients set the basis
for the Acolysis Registry study and the SVG (saphenous vein graft) Registry. The Acolysis Registry was a multicenter
effort to investigate the efficacy and safety of coronary ultrasound thrombolysis in various clinical settings of acute
coronary syndrome (ACS) with angiographic suggestion of recent intracoronary thrombosis [10]. Eligible patients had to
have ACS and angiographic suggestion of thrombus in a “culprit” lesion. The remainder of the decisions was left to the
discretion of the operators, who were informed of the available data and suggested technique. Data on 126 patients showed
that 29% of the recruited patients were treated for STEMI and the remainder for unstable angina and non-STEMI
(NSTEMI). Angiographic analysis revealed that the majority of the target vessels (84%) were occluded at baseline. The
median age of clot was 3 days with a range between several hours and several weeks. Sonication led to device success
(TIMI 2e3 fl
were used in 2% and 16% of the patients, respectively. Adjunct PTCA or stenting was used in 97% of the patients.
Procedural success was obtained in 98% of the patients, with a residual stenosis of 6 10%. There was a low rate (3%) of
angiographic evidence of distal embolization, and no device-related major adverse coronary events were noted.
ow) in 89% of the patients, with a residual stenosis of 69 20%. Adjunct thrombolytic drugs and abciximab
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FIGURE 20.2 (A) Baseline coronary angiography of anterior ST-segment elevation myocardial infarction in the first patient in the ATLAS study. Note
the large clot in the left anterior descending artery and TIMI 1 flow. (B) After ultrasound thrombolysis for 2 min the flow has improved to TIMI 3 and the
lumen diameter increased, with only 50% residual stenosis. (C) After final stenting, there is no residual stenosis, no reduction of flow, nor distal
embolization. TIMI, Thtombolysis in myocardial infarction.
FIGURE 20.3 Left ventriculography of the patient in Fig. 20.2 (A) at the primary percutaneous coronary intervention reveals akinesis of the left anterior
descending artery territory and (B) no segmental wall motion abnormalities at the 6-month follow-up catheterization.
In the SVG Registry, data were collected in a prospective multicenter registry. Eligible patients had to have a history of
SVG bypass surgery, ACS, and angiographic suggestion of thrombus in SVG [11]. In cases of total occlusion, the clinical
symptoms had to suggest recent clot in the target SVG.
The patients (n ¼ 20) presented with STEMI in two (10%) and unstable angina in the remainder. The median age of
clot was 6 days (range 0e100 days). Angiographic analysis revealed that 75% of the SVGs were occluded before the
procedure. Sonication leading to procedural success (defined as TIMI 2e3 flow without device-related adverse events) was
obtained in 65% of the patients and to a residual stenosis of 65 28%. Similar to the experience in STEMI, ultrasound
thrombolysis was followed by PTCA or stenting in all cases with a final residual stenosis of 5 8%. There was a low rate
(10%) of device-related adverse events, without any serious adverse events during hospitalization.
The data suggested that the strategy of clot burden reduction by LFHP ultrasound followed by correction of the
underlying pathology in the vessel wall by balloon angioplasty and stenting yielded high procedural success and a low rate
of per-procedural complications.
The dilemma we faced was in what clinical scenario to use coronary ultrasound thrombolysis in the pivotal clinical trial.
At that time the CADILLAC trial [12] results were published and the scientific advisory board (SAB) was under the
impression that there were no needs in the STEMI space not met by dual antiplatelet therapy and stenting. The SAB
recommended that we should address the ACS in SVG space.
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As a result, the ATLAS trial (Acolysis During Treatment of Lesions Affecting Saphenous Vein Bypass Grafts) was
initiated. The aim of this study was to establish the safety and efficacy of coronary ultrasound thrombolysis in highly
thrombotic SVGs prior to definitive treatment with PTCA or stenting [13].
The ATLAS Trial was a multicenter randomized controlled trial of ACS patients undergoing vein graft intervention in
the presence of large clot burden, comparing pretreatment with Acolysis followed by balloon angioplasty or stenting with
standard therapy (administration of abciximab and balloon angioplasty of stenting). Inclusion criteria were patients with
unstable angina and recent myocardial infarction (within 24 h ). Enrollment in the study began April 22, 1998, and ended
November 2, 2000, by which time 181 patients had been enrolled, 92 in the ultrasound study group and 89 in standard
therapy group (Fig. 20.4). The trial was stopped prematurely when the Data and Safety Monitoring Committee (DSMB)
found a significantly higher incidence of adverse clinical outcomes in the ultrasound arm. Although there was a chance of
error in the small sample, it could not be determined whether the worse outcome in the ultrasound arm would be
maintained. Further, the DSMB felt there was no suggestion of benefit from the active arm of the trial. The ultrasound
group had a higher rate of composite end point of any major adverse cardiovascular or cerebrovascular event (25% vs.
12.4%, P ¼ .036). The ultrasound-treated patients had more STEMI and NSTEMI but less distal embolization. Of note, in
the ultrasound group there was device failure or malfunction in 15% of the patients.
What have I learned from the ultrasound odyssey? There have b een several major problems in the progre ss of the
project from good clinical concept to practical clinical reality.
1. The environment: by the late 1990s the anti-glycoprotein IIb/IIIa agents were introduced in a massive marketing effort
by the pharma industry as the solution for the problem of thrombus-rich lesions. To many physicians there was no need
for a device solution.
FIGURE 20.4 Baseline coronary angiography of the first patient in the ATLAS trial reveals a totally occluded saphenous vein graft (SVG) in the clinical
context of ST-segment elevation myocardial infarction (top). After 2 min of ultrasound thrombolysis complete recanalization of the SVG was achieved
with TIMI 3 flow and no embolization (bottom). TIMI, thrombolysis in myocardial infarction.
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2. The clinical application: addressing large clot burden in SVG was a mistake. Acute lesions in diseased vein grafts are
composed of a mixture of athermanous material and thrombus layers. The mechanical introduction of a relatively stiff
ultrasound probe can cause substantial embolization of the loose athermanous material. We should have stayed with the
STEMI space, using our clinical trial design on a larger group of patients.
3. The technology: 15% device malfunction suggests that the technology was not mature enough to go into pivotal clinical
trial and routine clinical use.
FUTURE DIRECTIONS: NONINVASIVE ULTRASOUND THROMBOLYSIS
From the beginning of our work with ultrasound I was intrigued by the potential to focus acoustic-energy-generated
cavitations and harness their effect for a noninvasive ultrasound thrombolysis. T hus, we hypothesized tha t highpowered acoustic energy from an external acoustic generator can be foc used and converged into the body to
induce selective ablation of a target thrombus. We initiated the fi rst study during my fellowship at the University of
Michigan using the shock-wave generator at the Department of Urology as a sou rce of acoustic energy. The goal of the
first study was to test the feasibility of noninvasive acoustic thrombolysis in a thrombotic artery model in vitro.
Thrombi were generated in vitro and placed in human femoral arteries filled with saline. When the thrombotic human
arterial segments were placed in the cavitation field at the focal point of focused shock waves, significant thrombolysis
was achieved with no damage to the arterial wall. The data documenting effective and selective noninvasive
thrombolysis by high-powered, acoustic-energy-ge nerated cavitations were consistent with our studies with ultrasonic
catheter, suggesting t hat the level of acoustic energy necessary to liquefy a thrombus has a minimal effect on the
arterial wall [14].
However, with further work we have realized that shock waves are difficult to control, whereas monochromatic
ultrasound produced by a piezoelectric element allows for better control of the operating parameters.
As a result we developed a prototype device for noninvasive ultrasound thrombolysis. We studied the safety and
efficacy of high-intensity focused ultrasound thrombolysis guided by ultrasound imaging in experimental settings. Our
device comprised a therapeutic transducer designed as a spherical ring. The acoustic lens had a focal point 45 mm from
the transd uce r surface. The frequency of 500 kHz was used to accommodate the predeter mine d dimensions of the foc al
point.
The device’s thrombolysis efficacy was tested in vitro using the thrombotic femoral arteries model. External highintensity focused ultrasound was found in vitro to be very efficient in inducing rapid thrombolysis with no damage to
the arteries or intervening tissue. Thrombolysis efficacy correlated with observed cavitation density and total sonication
time. The use of the correct pulse-wave parameters was critical to the success of the system’s operation. Empirical
FIGURE 20.5 Representative drawing of the coronary ultrasound device (Acolysis) components and function. The ultrasound probe is compatible with
a 0.014-inch guidewire and 6-Fr guide catheter.
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experiments yielded the superiority of pulse-wave mode over continuous-wave mode. At optimal operating parameters an
almost complete thrombolysis was achieved within 2 min: 93% of the clot weight was lysed to subcapillary-size particles
(<8 pm) [15].
We have learned that when the optimal operating parameters are used, external ultrasound can generate and sustain a
stable field of cavitation. The ability to better control the cavitation effect by monochromatic ultrasound technique yields a
very effective thrombolysis compared with the effect of shock waves (Fig. 20.5).
REFLECTIONS
The use of ultrasound for thrombolysis delivered either via a catheter or externally has been studied since 2008 by several
groups. We used the cavitation effect produced by LFHP ultrasound to induce effective and safe ultrasound thrombolysis
in both catheter-based and externally focused ultrasound. After 3 decades of work by our group and other investigators
the use of the catheter-based approach has failed and will probably not be resurrected. I strongly believe that the future is in
the application of the externally focused ultrasound thrombolysis method for stroke patients. In this patient population the
value of rapid thrombolysis has been proven, yet the cost of infrastructure and trained labor for the catheter-based
thrombectomy solution will limit the availability of timely therapy for a huge proportion of acute stroke patients.
Externally focused ultrasound systems can potentially offer a relatively inexpensive semiautonomous system free of
thrombolytic agent therapeuti c modality and limit the need for highly trained personnel on a 24/7 basis and expensive
capital equipment.
REFERENCES
[1] Det Wiler P, Watkins JF, Rose EA, Ratner A, Rosenschein U. Mechanical and acoustic analysis in ultrasonic angioplasty. In: Abela GS, editor.
Diagnostic and therapeutic cardiovascular interventions. Proc. SPIE, vol. 1425; 1991. p. 149e55.
[2] Rosenschein U, Frimerman A, Laniado S, Miller HI. Study of the mechanism of ultrasound angioplasty from human thrombi and bovine aorta. Am J
Cardiol 1994;74:1263e6.
[3] Rosenschein U, Bernstein J, DiSegni E, Kaplinsky E, Bernheim J, Rozenszajn LA. Experimental ultrasonic angioplasty: disruption of atherosclerotic
plaques and thrombi in vitro and arterial recanalization in vivo. J Am Coll Cardiol 1990;15:711e7.
[4] Rosenschein U, Rozenszajn LA, Kraus L, Marboe CC, Watkins JF, Rose EA, David D, Cannon JP, Weinstein JS. Ultrasonic angioplasty in totally
occluded peripheral arteries: initial clinical, histologic and angiographic results. Circulation 1991;83:1976e86.
[5] Hartnell GG, Saxton JM, Friedl SE, Abela GS, Rosenschein U. Ultrasonic thrombus ablation: in vitro assessment of a novel device for intracoronary
use. J Interv Cardiol 1993;6:69e76.
[6] Muller DWM, Moncur J, Rosenschein U, Nickla J. Ultrasound thrombolysis: ablated thrombus does not impede microcirculatory flow or impair
regional left ventricular wall motion. Aust N Z J Med 1998;28:128 [abstract].
[7] Rosenschein U, Rozenszajn LA, Bernheim J, Keren G, Alter A, Frimerman A, Laniado S, Roth A, Miller H. Safety of coronary ultrasound
angioplasty: effects of sonication on intact canine coronary arteries. Cathet Cardiovasc Diagn 1995;35:64e71.
[8] Rosenschein U, Roth A, Rassin T, Bassan S, Laniado S, Miller HI. Analysis of coronary ultrasound thrombolysis endpoints in acute myocardial
infarction (ACUTE trial): results of the feasibility phase. Circulation 1997;95:1411e6.
[9] Rosenschein U. Transcatheter ultrasound thrombolysis: from AMI to saphenous vein grafts and beyond. Jpn J Interv Cardiol 1999;14:106 [abstract].
[10] Brosh D, Bartorelli AL, Cribier A, Mesa J, Calderon L, Martyn T, Amann F, Sampaolesi A, Desmet W, Fajadet J, Rosenschein U. Acolysis Registry
Study Group. Percutaneous transluminal therapeutic ultrasound for high-risk thrombus-containing lesions in native coronary arteries. Catheter
Cardiovasc Interv 2002;55(1):43e9.
[11] Rosenschein U, Gaul G, Erbel R, Amann F, Velasguez D, Stoerger H, Simon R, Gomez G, Troster J, Bartorelli A, Pieper M, Kyriakidis Z,
Laniado S, Miller HI, Fajadet J. Percutaneous transluminal therapy of occluded saphenous vein grafts: can the challenge be met with ultrasound
thrombolysis? Circulation 1999;99:26e9.
[12] Stone GW, Grines CL, Cox DA, et al. Comparison of angioplasty with stenting, with or without abciximab, in acute myocardial infarction. N Engl J
Med 2002;346:957e66.
[13] Singh M, Rosenschein U, Kalon KH, Berger PB, Kuntz R, Holmes DR. Treatment of saphenous vein bypass grafts with ultrasound thrombolysis: a
randomized trial (ATLAS). Circulation 2003;107:2331e6.
[14] Rosenschein U, Yakubov SJ, Guberinich D, Bach DS, Sonda PL, Abrams GD, Topol EJ. Shock wave thrombus ablation: a new method for
noninvasive mechanical thrombolysis. Am J Cardiol 1992;70:1358e61.
[15] Rosenschein U, Furman V, Kerner E, Fabian I, Bernheim J, Eshel Y. Ultrasound imaging-guided non-invasive ultrasound thrombolysis: pre-clinical
results. Circulation 2000;102:238e45.
Chapter 21
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The Role and Impact of Thrombus in
Formation and Revascularization of
Chronic Total Occlusions
Allyne Topaz1and On Topaz
1
Brooklyn Medical Center, Brooklyn, NY, United States;2Charles George Veterans Affairs Medical Center, Asheville, NC, United States;3Duke
University School of Medicine, Asheville, NC, United States
2,3
FORMATION OF CHRONIC TOTAL OCCLUSION
The rupture of an atherosclerotic plaque initiates thrombus formation, which slows antegrade blood flow. As the thrombus
grows in size it leads to further flow restriction and, eventually, complete arterial occlusion ensues (Fig. 21.1). The
thrombus contains erythrocytes and platelets embedded within a scaffolding mesh of fibrin fibers. This process is followed
by development of an inflammatory reaction. During the first 2 weeks after the initial pathologic event that created an
unstable, ruptured atherosclerotic plaque, an acute inflammatory response is accompanied by patchy formation of
proteoglycan-enriched extracellular matrix and myofibroblast infiltration onto the thrombotic occlusion [1]. At 6 weeks
following the initial pathologic event there is marked negative arterial remodeling and disruption of the internal elastic
FIGURE 21.1 Cross section of a chronic total occlusion in the right coronary artery. The vessel is occluded by a calcified, complex atherosclerotic
plaque (P) and an organized thrombus (T)(H&E). Courtesy of Shannon Mackey-Bojack MD, Jesse E. Edwards Registry of Cardiovascular Disease
Collection, Nasseff Heart Center, United Hospitals, University of Minnesota School of Medicine, St. Paul, MN. Printed with permission from Topaz O.
The thrombus containing lesion. In: Topol EJ, Teirstein PS, editors. Textbook of interventional cardiology. 6th ed. Philadelphia: Elsevier; 2012 [Chapter
26-Figure 2].
Cardiovascular Thrombus. https://doi.org/10.1016/B978-0-12-812615-8.00021-1
Copyright © 2018 Elsevier Inc. All rights reserved.
311
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lamina accompanied by intense intraluminal revascularization and perfusion. At 12 weeks decreased microvessel formation
and perfusion occur, and the next stage occurs at 18e24 weeks, with replacement of proteoglycans by collagen in the
extracellular matrix leading to further decrease in the chronic total occlusion (CTO) perfusion. The mature CTO contains
accumulated calcium and collagen in addition to organized thrombus [2]. Angiogenesis within the CTO begins with
recanalization of the thrombus through a mechanism that is dependent on the proteolytic activity of mononuclear cells and
endothelial progenitor cells. Angiogenesis within the arterial thrombus is modulated by the balanced activity of proangiogenic molecules in the extracellular matrix, including perlecan hyaluronan, and the antiangiogenic agents collagen type
I and decorin [3]. Altogether, as the composition of the CTO evolves over time, thrombus becomes an integral constituent
of this type of atherosclerotic lesion. Angiographically, a CTO is de fined as a stenosis at least 1 month old with
accompanying angiographic thrombolysis in myocardial infarction (TIMI) flow grade of 0 (i.e., no flow) or 1 (i.e., minimal
flow) [4]. Then the CTOs are further classified as “early,” i.e., 1e3 months old, or “late,” representing lesions older than
3 months.
STRUCTURAL FEATURES OF CHRONIC TOTAL OCCLUSION
The inner composition of a CTO plaque differs over time along the lesion’s length. Yalonetsky and colleagues from the
University of Toronto elegantly described three distinct anatomic morphologic features characteristic to CTOs: (1) a
thickened proximal-end fibrous cap, (2) the main body of the CTO, and (3) the distal-end fibrous cap [3]. Thrombus mainly
resides in the main body of the CTO. In a majority of CTOs the presence of thrombus in this segment plays a critical
structural role, as the lumen contains organized thrombus with recanalization channels across [4] (Fig. 21.2). Conceivably,
(A) (B)
(C)
(D)
FIGURE 21.2 Histopathology of chronic total occlusion. (A and B) Low-power views (H&E and Lawson’s elastic Van Gieson stain, respectively) of
chronic total occlusion lumen recanalization by large central neovascular channels (NCs) (arrows). Scale bar indicates 385 mm. (C) High-power view
(H&E stain) demonstrating extensive small, medium, and large intimal plaque (IP) NCs (arrows). Scale bar indicates 167 mm. (D) Low-power view
(elastic Van Gieson stain) demonstrating central lumen, IP, and adventitial NC formation (solid, open, and curved open arrows, respectively). Scale bar
indicates 500 mm. With permission from Strivatsa SS, et al. Histologic correlates of angiographic chronic total coronary artery occlusions. J Am Coll
Cardiol 1997;29:955e63.
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the thrombus acts as a better “crossing medium” than the rigid calcium deposits and the resistive fibrotic tissue. The latter,
indeed, frequently constitute formidable obstacles by diverting or deflecting the guidewire tip to buckle away or even
forcing it to penetrate and perforate the lumen of the vessel.
CLINICAL ASPECTS
Patients with ischemic coronary and peripheral arterial syndromes whose diagnostic angiogram demonstrates atherosclerotic CTO frequently require management with percutaneous revascularization (Fig. 21.3AeD). The morphology of
coronary and peripheral arterial CTOs, termed as “one of the last frontiers” in interventional cardiology, constitutes a
complex anatomic structure that imposes considerable technical cha llenges for percutaneous coronary revascularization
(PCI). Clinically, the presence of CTO serves as the most powerful predictor for referral for coronary bypass surgery [5].
The benefits of successful PCI in this complex type of lesion incl ude symptom relief, improved left-ventricular function,
and a potential survival benefit compared with failed attempts of CTO interventions.
(A) (B)
(C) (D)
FIGURE 21.3 Percutaneous coronary intervention in a patient with CTO who presented with exertion-related angina pectoris and shortness of breath.
(A) Diagnostic angiogram in the lateral view demonstrates a CTO in the middle segment of the right coronary artery. The proximal cap of the CTO is
marked by an arrow. The intraplaque middle segment of the CTO contains a long linear thrombus (marked by red circle). (B) Angiographic results
following successful crossing of the CTO with a guidewire and activation of a 0.9-mm excimer laser catheter along the entire length of the CTO. A
recanalization channel was created with resultant restoration of antegrade flow. (C) Angiographic results following additional removal of thrombus burden
by application of a 2.0-mm X-Sizer catheter. (D) Final angiographic results after adjunct stenting of the CTO site. The target vessel is completely patent
with excellent distal flow. Clinically, the patient improved with no further angina pectoris and shortness of breath. CTO, chronic total occlusion.
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PERCUTANEOUS REVASCULARIZATION
Technically, CTO is considered a highly demanding revascularization target [6] because of the fibrotic tissue, calcifications, and atherosclerotic material. As previously mentioned, these lesions frequently contain layers of organized thrombus
of various ages. Microchannels commonly recanalize the organized thrombus within the CTO, resulting in, albeit limited,
antegrade flow distal to the plaque [7]. Accordingly, while the angiographic hallmark of CTO is a 100% stenosis, the
histopathologic domain and the clinical realm demonstrate that about 50% of these lesions are, in fact, less than 100%
occluded [4]. PCI in such cases could specifically aim at crossing the CTO through the microchannels, followed by
removal of the obstructive plaque [8]. Importantly, this also pertains to CTO within old saphenous bypass vein grafts
(Fig. 21.4). From a technical point, proper selection of guiding catheter and subsequent careful maneuvering of dedicated
guidewires via either the antegrade or the retrograde recanalization approach [9] are prerequisites to ensure successful
revascularization of the CTO. Specifically, based on the aforementioned histopathologic characteristics of CTO, the tip of
the guidewire should enter the intraplaque microchannels. This enables successful crossing and subsequent successful
plaque treatment. Notably, efforts to cross a CTO can be hampered by triggering of uncontrolled thrombosis whereby an
underlying thrombus is provoked, culminating in rapid accumulation of a large thrombus volume. This unwa rranted
phenomenon is termed the “angry” or “hostile” clot. Such unwarranted development can threaten the entire PCI procedure
and its outcome. Thus, to avoid, or if required expeditiously treat, this grave situation operators should consider immediately following guidewire recanalization of the CTO the proper means to decrease the underlying occlusive thrombus
burden. This usually calls for inclusion of a mechanical thrombus removal device. Once most or all the thrombotic
component is extracted, contrast injections can precisely assess the residual plaque. Consequently, balloon dilatations and
accurate stent deployment are facilitated. Evidence from the National Heart, Lung, and Blood Institute registry corroborates the benefit of focusing on the thrombotic component of CTO during targeted PCI. Multivariable regression analysis
demonstrated that the presence of thrombus is a strong predictor of success in CTO revascularization (adjusted odds ratio
0.31, 95% confidence interval 0.15e0.61, P ¼ .0008). This intriguing finding attests to the fact that thrombus removal
clears the way for subsequent successful dilatation and precise stent delivery and deployment [10].
DEDICATED THROMBUS PHARMACOTHERAPY IN CHRONIC TOTAL OCCLUSION
In the peripheral arterial circulation thrombolytic therapy is a mainstay treatment line in acute and subacute arterial
occlusions and in bypass graft thrombosis [11]. Because most CTOs are associated with arterial thrombosis they may be
FIGURE 21.4 Cross-sectional histopathology of a 95%e99% stenosis of a saphenous vein graft. The lumen is mainly narrowed by organized thrombus
(T).The thrombus consists of loose fibrous tissue with small recanalized vascular channels (Elastin Van Gieson, ELVG 4). During percutaneous coronary
intervention such channels enable guidewire crossing, which should be followed by thrombus removal before plaque modification by balloon and stenting.
Courtesy of Shannon Mackey-Bojack MD, Jesse E. Edwards Registry of Cardiovascular Disease Collection, Nasseff Heart Center, United Hospitals,
University of Minnesota School of Medicine, St. Paul, MN.
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