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Intraplaque therapies for facilitating percutaneous recanalization of chronic total occlusions
ADVANCES IN VASCULAR BIOLOGY
Intraplaque therapies for facilitating percutaneous recanalization of chronic total occlusions Paul Fefer MD1, Mauro Carlino MD2, Bradley H Strauss MD PhD1
P Fefer, M Carlino, BH Strauss. Intraplaque therapies for facilitating percutaneous recanalization of chronic total occlusions. Can J Cardiol 2010;26(Suppl A):32A-36A. Chronic total occlusions (CTOs) are found in up to 30% of angiograms performed on patients with coronary disease. The technical difficulty of performing percutaneous coronary interventions (PCIs) in CTOs, primarily because of the inability to cross CTOs with a guide wire, is reflected in low rates of PCI for CTO (approximately 9% of PCI procedures). The main barrier to successful CTO crossing is the dense collagenous extracellular matrix, particularly at the entrance, known as the ‘proximal fibrous cap’. Current interventional strategies to overcome this barrier are based primarily on forceful penetration of the CTO plaque by the use of dedicated CTO guide wires. These extra-stiff wires are designed to transfer maximal force to the tip to create a path within the plaque. However, these wires can also cause vascular complications such as dissections; overall procedural success rates remain modest. Several groups are working on new approaches to actually alter the biology and structural characteristics of the CTO plaque to facilitate guide wire crossing. Preliminary data suggest that plaque-directed therapies aimed at ‘priming’ it for wire crossing may increase PCI success in these challenging cases. New techniques for plaque modification, either by ‘softening’ the collagenous matrix (collagenase) or by exposing and enlarging existing microvessels (intravascular thrombolysis, contrast injection) or by inducing new microvessels (angiogenic growth factor[s]) are described in the present review. Key Words: Angioplasty; CTO; Plaque; Therapy
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oronary artery disease remains the leading cause of mortality in the western world. Chronic total occlusions (CTOs), defined as occlusions of six or more weeks in duration (1), are found in up to 30% of angiograms performed on patients with coronary artery disease (2). Contemporary data from the Canadian Multicentre CTO Registry on 1553 patients with CTOs indicate that these patients are often symptomatic (Canadian Cardiovascular Society class III to IV in 53%), have no history of previous myocardial infarction in 52%, and have normal left ventricular function in 53% (P Fefer, unpublished data). Successful revascularization of CTOs significantly improves angina in symptomatic patients (3,4), and there are some data that indicate improvement in left ventricular function (5,6) and even mortality (7). Successful angioplasty requires that the operator place a guide wire through the tissue obstructing the lumen in a CTO to reach the distal arterial lumen. The technical difficulty of performing percutaneous coronary intervention (PCI) in CTOs, primarily because of inability to cross the obstruction with a guide wire, is reflected in the low rates of PCI for CTOs (accounting for approximately 9% of all PCIs), despite the benefits of a positive outcome (8). CTOs are one of the most common reasons for referral for coronary artery bypass surgery and many are left untreated because of uncertainty regarding procedural success and long-term benefit (9). Successful treatment of CTOs with bare metal stents
Les thérapies intraplaques pour faciliter la recanalisation percutanée des occlusions totales chroniques On observe des occlusions totales chroniques (OTC) dans jusqu’à 30 % des angiogrammes effectués sur des patients ayant une maladie coronarienne. La difficulté technique des interventions coronaires percutanées (ICP) en cas d’OTC, surtout en raison de l’incapacité de les traverser à l’aide d’un guide métallique, se reflète par le faible taux d’ICP dans le traitement des OTC (environ 9 % des ICP). Le principal obstacle au passage à travers les OTC est la dense matrice collagène extracellulaire, notamment à l’entrée, où on l’appelle « chape fibreuse proximale ». Les stratégies d’intervention actuelles pour vaincre cet obstacle se fondent surtout sur la pénétration forcée de la plaque d’OTC par des guides métalliques prévus à cet effet. Ces guides ultra-rigides sont conçus pour transférer une force maximale à leur extrémité, afin de créer une voie dans la plaque. Cependant, ils peuvent également provoquer des complications vasculaires telles que des dissections. Le taux de succès global des interventions demeure modeste. Plusieurs groupes se penchent sur de nouvelles approches pour altérer les caractéristiques biologiques et structurelles de la plaque d’OTC pour faciliter le passage des guides métalliques. D’après les données provisoires, les thérapies axées sur la plaque visant à les « préparer » pour y passer le guide métalliques pourraient accroître la réussite des ICP dans ces cas difficiles. De nouvelles techniques visant à modifier la plaque, que ce soit en « ramollissant » la matrice collagène (collagénase), en exposant et en élargissant les microvaisseaux existants (thrombolyse intravasculaire, injection d’un produit de contraste) ou en induisant la formation de nouveaux microvaisseaux (facteur[s] de croissance angiogène[s]), sont décrites dans la présente analyse.
has been limited by high restenosis rates (4,10), but the dramatic improvements in restenosis rates observed with the use of drugeluting stents in CTOs (11,12) has increased enthusiasm for percutaneous treatment. This, in turn, has stimulated the development of specialized equipment that include designated guide wires such as Miracle Bros (Asahi Intecc, Japan) and Conquest (Asahi Intecc). These guide wires are specifically designed to cross CTOs and differ in their tip stiffness, tip shape and tapering, and coating. Extreme care must be taken when using these stiff guide wires to cross CTOs because they are more likely to create false channels, dissections and perforation. Other specialty devices have been developed to enable safe crossing of CTOs, including the Frontrunner (Cordis, Johnson & Johnson, USA), which performs blunt microdissection (13); Safecross (Intraluminal Therapeutics Inc, USA), which uses optical coherence reflectometry for traversing the CTO (14) and the Rapid Exchange CROSSER (FlowCardia, USA), which uses highfrequency vibration to facilitate guide wire crossing. To date, none of these devices have shown superior results compared with new guide wire technology. Recanalization of a CTO remains technically challenging, with overall success rates between 50% and 80% (1,15,16). An important limitation to developing more effective therapeutic strategies is the lack of understanding of CTO plaque morphology and pathogenesis.
1Schulich
Heart Centre, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario; 2Interventional Cardiology Unit, San Raffaele Scientific Institute, Milan, Italy Correspondence: Dr Bradley H Strauss, Reichmann Chair in Cardiovascular Medicine, Sunnybrook Health Sciences Centre, 2075 Bayview Avenue, Room A-253, Toronto, Ontario M4N 3M5. Telephone 416-480-6066, fax 416-480-4745, e-mail [email protected] Received for publication September 14, 2009. Accepted December 8, 2009
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Intraplaque therapies for percutaneous recanalization of CTOs
Figure 2) Summary of intraplaque therapies. FIM First in Man study Figure 1) Movat’s stain of histopathology specimen showing the proximal cap and microvessels in a porcine model of a six-week-old chronic total occlusion. Note the fibrous proximal cap with cellular and matrix components. Microvessels are evident approximately 0.5 mm distal to the cap. IEL Internal elastic lamina
PATHOLOGY OF CTO PLAQUE: MATRIX AND MICROVESSELS Extracellular matrix In the majority of cases, the initial acute event leading to the development of a CTO is likely a ruptured atherosclerotic plaque with bidirectional thrombus formation. The thrombus and lipid-rich cholesterol esters are gradually replaced by extracellular matrix composed of proteoglycans and collagen. Over time, proteoglycan is gradually replaced by collagen formation and calcium deposition (17). This fibrous tissue is particularly dense at the proximal and distal ends of the lesion (so-called proximal and distal caps), which are conventionally regarded to be the most resistant areas of the CTO for guide wire crossing (Figure 1). Microvessels Despite the absence of flow within a CTO in angiographic studies, a limited number of pathology studies have reported the presence of microvessels to be quite common in human coronary CTOs (greater than 75%) (17,18). Microvessels can form in the vasa vasorum of the artery (19), within atherosclerotic intimal plaques (20), and within and parallel to the parent vessel. These latter ‘recanalization’ channels occur as part of the organization phase in CTO in which thrombus is replaced by fibrous tissue. These microvessels generally range in size from 100 μm to 200 μm but can sometimes be as large as 500 μm (17). We have recently described the natural history of CTOs in an animal model (21). Intraluminal recanalization channels with a ‘corkscrew’ appearance were present at the proximal part of the occlusion at six weeks. The endoluminal channels within the proximal portion were on the order of 50 μm in diameter. The midsection typically illustrated little contrast perfusion, with channels appearing discontinuous. At 12 weeks and beyond, there was progressive regression of the proximal recanalization channels and the entrance appeared blunt. In addition, there were several small, highly fragmented channels within the lumen, suggesting an apparent loss of microvessel continuity.
INTRAPLAQUE THERAPY: THE CONCEPT The main physical barrier to successful CTO crossing is the dense collagenous extracellular matrix. Current interventional strategies to overcome this barrier are based on forceful penetration of the CTO plaque by the use of dedicated CTO guide wires. These extra stiff wires
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are designed to transfer maximal force to the tip to create a path within the plaque. Tapered tip guide wires (such as the cross-IT XT [Abbott Vascular, USA], Fielder XT and Conquest [Asahi Intecc]) containing smaller diameter distal tips of 0.09 in to 0.010 in (compared with conventional 0.014 in) are also used to traverse small microchannels within the CTO. Several groups, including our own, are working on new approaches to actually alter the biology and structural characteristics of the CTO plaque to facilitate guide wire crossing. Data from both animal studies and preliminary human studies suggest that plaque-directed therapies aimed at ‘priming’ it for wire crossing may increase PCI success in these challenging cases. Historically, the first attempt to modify the CTO plaque was intracoronary injection of thrombolytic agents, with some success (Figure 2). With this approach, the drug was administered through the guiding catheter into the coronary artery in the presence of antegrade blood flow. Recently, we have modified this approach by injecting directly into the plaque or by creating a reservoir immediately proximal to the plaque while blocking antegrade coronary blood flow. In the present review, we describe the various techniques for plaque modification (Figure 2), either by ‘softening’ the collagenous matrix (collagenase), by exposing and enlarging existing microvessels (intravascular thrombolysis, contrast injection) or by inducing new microvessels (vascular endothelial growth factor [VEGF]).
MICROVESSEL MANIPULATION Mechanical: The microchannel technique Working on the premise that intraocclusion microvessels provide a pathway for guide wire crossing of a CTO (22), Carlino et al (23) postulated that injection of contrast immediately distal to the proximal cap of the CTO could enable both identification and enlargement of these pre-existing microvessels, creating a larger passage for crossing the CTO with a guide wire. A detailed description of the technique is provided in the original publication. Briefly, the technique requires advancement of a 1.5 mm over-the-wire balloon to the CTO and penetration of the proximal cap with a dedicated CTO guidewire to 1 mm to 3 mm. The balloon is then advanced into the CTO while the guide wire is removed. Subsequently, nitroglycerine is injected through the balloon lumen to dilate the microchannels. Finally, 1 mL of undiluted contrast is injected via the wire port of the angioplasty balloon catheter directly into the CTO (Figure 3). This technique was evaluated by a single operator in 32 patients (22). Median age of the CTO was nine years and the median occlusion length was approximately 24 mm. Overall technical success of microchannel injection was obtained in 20 patients (63%), with angiographic success in 19 (95%). In the remaining 12 patients, despite technical failure of this particular
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Figure 3) This series of images demonstrates how intraocclusion injection of contrast using the microchannel technique can identify and enlarge microvessels in the chronic total occlusion (CTO) that were not visible on standard angiography. A A blunt occlusion at the ostium of the second obtuse marginal branch is evident (arrow); distal opacification (arrows) of the occluded vessel by retrograde flow from ipsilateral collaterals is seen. Although there appears to be no evidence of anterograde flow through the CTO and no microchannels present, when contrast was injected into the proximal cap using the microchannel technique, a microvessel (B, arrows) became apparent, which allowed opacification of the distal vessel. C The final result after successfully recanalizing the CTO by manipulating the intraplaque microvessels
technique, successful recanalization of the artery was still obtained in seven of these 12 cases using another technique. Severe calcifications, side branch at the occlusion site and occlusion length were associated with failure. There were no cases of coronary perforation or rupture. All patients were free of major adverse cardiac events at 30 days follow-up. Based on this initial experience, the microchannel technique appears to be safe, with a low risk of complications. Pharmacological: Thrombolytic infusion Two studies (24,25) have reported the use of intracoronary thrombolytic infusion before PCI of CTOs. Based on the histological finding of multiple layers of clot that occur on top of episodes of plaque fissuring (24), Abbas et al (25) proposed administering intracoronary lytic therapy, hypothesizing that this may lyse the most recent clot component of a CTO to enable passage of the guide wire and facilitate recanalization. These histological features have not been confirmed in old CTOs. This hypothesis was tested in 85 patients with previous unsuccessful PCI procedures of CTO. PCI was repeated after intracoronary administration of preprocedural weight-adjusted alteplase (2 mg/h to 5 mg/h) or tenectaplase (0.5 mg/h) for a total of 8 h, requiring infusion through either a guiding catheter or an intracoronary infusion catheter for several hours in a coronary care unit setting. Not surprising due to the prolonged infusion with a potent thrombolytic agent, there were bleeding complications. Incidence of groin hematomas was 8% and 3.5% had bleeding that required transfusion. Nevertheless, the procedure was successful in 46 of 85 cases (54%). Four of 85 (5%) contained dissections that did not result in perforations, tamponade or major adverse cardiac events. Given that all these patients had already undergone one unsuccessful attempt at recanalizing the CTO and the CTO lesions had unfavourable morphology, a success rate of greater than 50% was considered promising. An earlier study by Zidar et al (26) used a similar protocol involving three doses of urokinase in patients with previously failed PCI of CTO. In this study, successful PCI of CTO following urokinase infusion was achieved in 55% of cases. Major complications including bleeding requiring transfusion were uncommon. The most common minor complication was transient ischemic attack in 3% of the patients. Microvessel induction: VEGF Based on our published observations of marked reductions in both CTO blood volume and intraluminal microvessels in CTOs after six weeks’ duration, we have been investigating approaches to induce intraluminal microvessel formation in older CTOs. These studies involve injecting angiogenic growth factors directly into the CTO through the wire port of an over-the-wire balloon that has been
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Figure 4) Histological specimen showing collagenase-treated artery with successful guide wire crossing (indicated by red arrows) (Movat’s stain, original magnification ×10). EEL External elastic lamina; IEL Internal elastic lamina positioned immediately adjacent to the proximal cap of the CTO. The balloon is inflated to prevent backflow of the solution containing the angiogenic growth factor. The solution is not injected directly into the CTO but, instead, deposited in the intraluminal space immediately proximal to the CTO and then expected to enter into the proximal part of the occlusion over a 45 min period while the balloon is inflated. Our initial studies have used VEGF-164 protein that has been packaged into biodegradable polylactic coglycolic acid microspheres with a mean size of 20 μm to prolong residency time and duration of effect (three to four days) within the CTO. These CTOs are re-evaluated three weeks later for CTO blood volume and microvessel formation, as well as tests of mechanical properties and guide wire crossing. Initial results with this approach have been promising (27).
MATRIX MODIFICATION: COLLAGENASE PLAQUE DIGESTION Collagen is the major extracellular matrix component of an established CTO plaque. Low success rates in guide wire crossing of CTOs are related in large part to the occlusive fibrotic nature of these plaques (17). Collagenase, a matrix metalloproteinase inhibitor, is the initial mediator of interstitial collagen degradation (28). The premise of this approach is that ‘softening’ the CTO plaque by digestion of plaque collagen enables easier guide wire crossing and enhanced procedural success. To test this hypothesis, Strauss et al (29) administered type IA bacterial collagenase or placebo locally to 45 CTOs in a rabbit femoral artery model. The technique of local delivery was similar to the VEGF therapy described above. The collagenase solution was injected through the wireport of an over-the-wire balloon that was positioned immediately proximal to the CTO. The balloon was inflated for 45 min to ensure isolation of the arterial segment containing the collagenase from the anterograde blood flow. Mean CTO occlusion duration was 16 weeks. Attempts to cross the CTO (mean length 28 mm) with conventional guide wires were assessed 72 h after treatment. Successful guide wire crossings were significantly higher in collagen-treated arteries (13 of 21, 62%) than in placebo treated arteries (seven of 24, 29%) (Figure 4). No adverse effects on arterial structure were observed in collagenase-treated arteries. At 24 h after treatment, collagenasetreated arteries demonstrated increased collagenase protein, gelatinous activity and collagen degradation fragments. In an additional study, a second collagenase formulation was tested in a rabbit model of femoral artery CTO (30). Local administration to 10 rabbit CTOs resulted in successful guide wire crossing in all CTOs after 24 h. A dose-response
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Figure 6) Movat’s stain of histopathology specimen showing persistence of microspheres within the lumen and the media of a chronically occluded plaque up to three weeks after injection. EEL External elastic lamina; IEL Internal elastic lamina
2.
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Figure 5) A Magnetic resonance image obtained before (Pre), immediately after (Post), 24 h and 72 h after injection of iron-oxide laden microspheres (red arrows). Note persistence of microspheres in the perivascular space at 72 h after the injection. B Left panel Trichrome stain (original magnification ×2.5) showing extravascular collection (EV) of microspheres with a tear in the wall of the occluded artery, with lumen (L). B Right panel Close-up of box from left panel, tear in wall of artery (indicated by arrow) (Trichrome stain, original magnification ×10). This chronic total occlusion (CTO) was treated with 1 mL of phosphate-buffered saline containing 16 mg of microspheres, containing 2 mg iron oxide
study was also performed in 17 rabbits to assess local effects of collagenase, with local subcutaneous bruising noted at the higher doses. Histological analysis showed no damage to the arterial wall structure. These preclinical studies indicated that local delivery of collagenase degrades collagen in CTO plaques and facilitates guide wire crossing in experimental CTO. A first in man study of collagenase in 20 human CTO patients is now underway.
OUTSTANDING ISSUES Local therapy for CTO seems to hold promise as a novel approach to improve percutaneous revascularization. However, there are many aspects of this therapeutic approach that need further investigation. A major area that requires further study is understanding the kinetics of drug delivery with various injection sites and at different CTO durations. Current therapies have been injected at varying distance from the CTO (thrombolytics at the origin of the coronary artery, VEGF microspheres and collagenase in the space adjacent to the CTO, and contrast directly into the CTO). Each of these approaches have limitations that include the following: 1. Intracoronary injection will cause loss of much of the solution into small vessels before the occlusion and have required prolonged
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injection periods up to 8 h, necessitating coronary care unit observation with intracoronary catheters. Injection of drug or agents into the space immediately proximal to the CTO must be relatively small to prevent flow into adjacent side branches. Direct injection into the plaque can result in opening of microchannels but can also result in perivascular staining, resulting from dissection of contrast in the extravascular/perivascular space. While preliminary studies (22) and clinical experience in more than 60 cases (M Carlino and B Strauss, personal communication) indicate that this technique is indeed safe, larger multicentre studies are needed. Diffusion characteristics into the CTO, particularly given the variable composition of the proximal fibrous cap and microvessel network at different ages of the CTO, need to be addressed for individual agents and microspheres. Injection of microspheres into a CTO raises many technical questions with regard to the localization of the microspheres within or outside the plaque. In one experiment using iron oxide-laden microspheres that were delivered adjacent to the CTO, we observed that the microspheres may exit the vessel wall and accumulate in the perivascular tissue, even 72 h after injections (BH Strauss, unpublished data) (Figure 5). Residency time of microspheres in the tissue is unclear. Preliminary experiments have shown evidence of microsphere persistence in the CTO for up to three weeks postinjection (BH Strauss, unpublished data) (Figure 6). Possibly, microsphere size has an effect on residency time in the tissue. The clinical implications of these observations are not known. Dose and time effects: While direct contrast injection has an immediate and direct mechanical effect, collagenase injection and VEGF administration rely on activation of biological processes for effect, which is expected to be both dose and time related. Too small a dose may have no effect, while too high a dose may be associated with side effects. Likewise, the maximal biological effect is likely to range from hours to weeks to reach maximal effect and may wane thereafter. Further studies are needed to elucidate the optimal dose- and time-related effects of these therapies.
SUMMARY Despite significant improvement in operator skill and availability of dedicated equipment, the percutaneous treatment of CTOs remains challenging, with both lower procedural success and higher periprocedural risk than conventional angioplasty. Intraplaque therapy is a new
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way of approaching an old problem. While much previous research and development has been focused on stiffer wires that can penetrate and traverse the fibrous CTO plaque, the concept behind intraplaque therapy is based on modifying the plaque itself to enable easier and, possibly, safer guide wire crossing. A wide variety of therapeutic agents could have important and novel effects on the CTO to facilitate guide wire crossing and percutaneous interventions. Additional research to
optimize delivery strategies and the timing of the effects are needed, particularly with respect to the composition and age of the CTO. DISCLOSURE: Dr Strauss holds or has applied for patents on collagenase and angiogenic growth factors for treatment of chronic total occlusions.
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16. Prasad A, Rihal CS, Lennon RJ, Wiste HJ, Singh M, Holmes DR Jr. Trends in outcomes after percutaneous coronary intervention for chronic total occlusions: A 25-year experience from the Mayo Clinic. J Am Coll Cardiol 2007;49:1611-8. 17. Srivatsa SS, Edwards WD, Boos CM, et al. Histologic correlates of angiographic chronic total coronary artery occlusions: Influence of occlusion duration on neovascular channel patterns and intimal plaque composition. J Am Coll Cardiol 1997;29:955-63. 18. Katsuragawa M, Fujiwara H, Miyamae M, Sasayama S. Histologic studies in percutaneous transluminal coronary angioplasty for chronic total occlusion: Comparison of tapering and abrupt types of occlusion and short and long occluded segments. J Am Coll Cardiol 1993;21:604-11. 19. Kwon HM, Sangiorgi G, Ritman EL, et al. Enhanced coronary vasa vasorum neovascularization in experimental hypercholesterolemia. J Clin Invest 1998;101:1551-6. 20. Celetti FL, Waugh JM, Amabile PG, et al. Vascular endothelial growth factor enhances atherosclerotic plaque progression. Nat Med 2001;37:7:2126-30. 21. Jaffe R, Leung G, Munce,NR, et al. Natural history of experimental arterial chronic total occlusions. J Am Coll Cardiol 2009;53:1148-58. 22. Strauss BH, Segev A, Wright GA, et al. Microvessels in chronic total occlusions: Pathways for successful guidewire crossing? J Interv Cardiol 2005;18:425-36. 23. Carlino M, Latib A, Godino C, Cosgrove J, Colombo A. CTO recanalization by intraocclusion injection of contrast: The microchannel technique. Catheter Cardiovasc Interv 2008;71:20-6. 24. Meier B. Chronic total occlusions. In: Topol EJ, ed. Textbook of Interventional Cardiology, 4th edn. Philadelphia, PA: Saunders, 2003:303-16. 25. Abbas AE, Brewington SD, Dixon SR, Boura JA, Grines CL, O’Neill WW. Intracoronary fibrin-specific thrombolytic infusion facilitates percutaneous recanalization of chronic total occlusion. J Am Coll Cardiol 2005;46:793-8. 26. Zidar FJ, Kaplan BM, O’Neill WW, et al. Prospective randomized trial of prolonged intracoronary urokinase infusion for chronic total occlusions in native arteries. J Am Coll Cardiol 1996;27:1406-12. 27. Teitelbaum A, Qi X, Anderson K, et al. Quantitative magnetic resonance angiographic analysis of CTO perfusion in response to VEGF treatment. Can J Cardiol 2008;24(Suppl E):215E. (Abst) 28. Dollery CM, McEwan JR, Henney AM. Matrix metalloproteinases and cardiovascular disease. Circ Res 1995;77:863-8. 29. Strauss BH, Goldman L, Qiang B, et al. Collagenase plaque digestion for facilitating guide wire crossing in chronic total occlusions. Circulation 2003;108:1259-62. 30. Segev A, Nili N, Qiang B, Charron T, Butany J, Strauss BH. Human-grade purified collagenase for the treatment of experimental arterial chronic total occlusion. Cardiovasc Revasc Med 2005;6:65-9.
Can J Cardiol Vol 26 Suppl A March 2010
Intraplaque therapies for facilitating percutaneous recanalization of chronic total occlusions Paul Fefer MD1, Mauro Carlino MD2, Bradley H Strauss MD PhD1
P Fefer, M Carlino, BH Strauss. Intraplaque therapies for facilitating percutaneous recanalization of chronic total occlusions. Can J Cardiol 2010;26(Suppl A):32A-36A. Chronic total occlusions (CTOs) are found in up to 30% of angiograms performed on patients with coronary disease. The technical difficulty of performing percutaneous coronary interventions (PCIs) in CTOs, primarily because of the inability to cross CTOs with a guide wire, is reflected in low rates of PCI for CTO (approximately 9% of PCI procedures). The main barrier to successful CTO crossing is the dense collagenous extracellular matrix, particularly at the entrance, known as the ‘proximal fibrous cap’. Current interventional strategies to overcome this barrier are based primarily on forceful penetration of the CTO plaque by the use of dedicated CTO guide wires. These extra-stiff wires are designed to transfer maximal force to the tip to create a path within the plaque. However, these wires can also cause vascular complications such as dissections; overall procedural success rates remain modest. Several groups are working on new approaches to actually alter the biology and structural characteristics of the CTO plaque to facilitate guide wire crossing. Preliminary data suggest that plaque-directed therapies aimed at ‘priming’ it for wire crossing may increase PCI success in these challenging cases. New techniques for plaque modification, either by ‘softening’ the collagenous matrix (collagenase) or by exposing and enlarging existing microvessels (intravascular thrombolysis, contrast injection) or by inducing new microvessels (angiogenic growth factor[s]) are described in the present review. Key Words: Angioplasty; CTO; Plaque; Therapy
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oronary artery disease remains the leading cause of mortality in the western world. Chronic total occlusions (CTOs), defined as occlusions of six or more weeks in duration (1), are found in up to 30% of angiograms performed on patients with coronary artery disease (2). Contemporary data from the Canadian Multicentre CTO Registry on 1553 patients with CTOs indicate that these patients are often symptomatic (Canadian Cardiovascular Society class III to IV in 53%), have no history of previous myocardial infarction in 52%, and have normal left ventricular function in 53% (P Fefer, unpublished data). Successful revascularization of CTOs significantly improves angina in symptomatic patients (3,4), and there are some data that indicate improvement in left ventricular function (5,6) and even mortality (7). Successful angioplasty requires that the operator place a guide wire through the tissue obstructing the lumen in a CTO to reach the distal arterial lumen. The technical difficulty of performing percutaneous coronary intervention (PCI) in CTOs, primarily because of inability to cross the obstruction with a guide wire, is reflected in the low rates of PCI for CTOs (accounting for approximately 9% of all PCIs), despite the benefits of a positive outcome (8). CTOs are one of the most common reasons for referral for coronary artery bypass surgery and many are left untreated because of uncertainty regarding procedural success and long-term benefit (9). Successful treatment of CTOs with bare metal stents
Les thérapies intraplaques pour faciliter la recanalisation percutanée des occlusions totales chroniques On observe des occlusions totales chroniques (OTC) dans jusqu’à 30 % des angiogrammes effectués sur des patients ayant une maladie coronarienne. La difficulté technique des interventions coronaires percutanées (ICP) en cas d’OTC, surtout en raison de l’incapacité de les traverser à l’aide d’un guide métallique, se reflète par le faible taux d’ICP dans le traitement des OTC (environ 9 % des ICP). Le principal obstacle au passage à travers les OTC est la dense matrice collagène extracellulaire, notamment à l’entrée, où on l’appelle « chape fibreuse proximale ». Les stratégies d’intervention actuelles pour vaincre cet obstacle se fondent surtout sur la pénétration forcée de la plaque d’OTC par des guides métalliques prévus à cet effet. Ces guides ultra-rigides sont conçus pour transférer une force maximale à leur extrémité, afin de créer une voie dans la plaque. Cependant, ils peuvent également provoquer des complications vasculaires telles que des dissections. Le taux de succès global des interventions demeure modeste. Plusieurs groupes se penchent sur de nouvelles approches pour altérer les caractéristiques biologiques et structurelles de la plaque d’OTC pour faciliter le passage des guides métalliques. D’après les données provisoires, les thérapies axées sur la plaque visant à les « préparer » pour y passer le guide métalliques pourraient accroître la réussite des ICP dans ces cas difficiles. De nouvelles techniques visant à modifier la plaque, que ce soit en « ramollissant » la matrice collagène (collagénase), en exposant et en élargissant les microvaisseaux existants (thrombolyse intravasculaire, injection d’un produit de contraste) ou en induisant la formation de nouveaux microvaisseaux (facteur[s] de croissance angiogène[s]), sont décrites dans la présente analyse.
has been limited by high restenosis rates (4,10), but the dramatic improvements in restenosis rates observed with the use of drugeluting stents in CTOs (11,12) has increased enthusiasm for percutaneous treatment. This, in turn, has stimulated the development of specialized equipment that include designated guide wires such as Miracle Bros (Asahi Intecc, Japan) and Conquest (Asahi Intecc). These guide wires are specifically designed to cross CTOs and differ in their tip stiffness, tip shape and tapering, and coating. Extreme care must be taken when using these stiff guide wires to cross CTOs because they are more likely to create false channels, dissections and perforation. Other specialty devices have been developed to enable safe crossing of CTOs, including the Frontrunner (Cordis, Johnson & Johnson, USA), which performs blunt microdissection (13); Safecross (Intraluminal Therapeutics Inc, USA), which uses optical coherence reflectometry for traversing the CTO (14) and the Rapid Exchange CROSSER (FlowCardia, USA), which uses highfrequency vibration to facilitate guide wire crossing. To date, none of these devices have shown superior results compared with new guide wire technology. Recanalization of a CTO remains technically challenging, with overall success rates between 50% and 80% (1,15,16). An important limitation to developing more effective therapeutic strategies is the lack of understanding of CTO plaque morphology and pathogenesis.
1Schulich
Heart Centre, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario; 2Interventional Cardiology Unit, San Raffaele Scientific Institute, Milan, Italy Correspondence: Dr Bradley H Strauss, Reichmann Chair in Cardiovascular Medicine, Sunnybrook Health Sciences Centre, 2075 Bayview Avenue, Room A-253, Toronto, Ontario M4N 3M5. Telephone 416-480-6066, fax 416-480-4745, e-mail [email protected] Received for publication September 14, 2009. Accepted December 8, 2009
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©2010 Pulsus Group Inc. All rights reserved
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Figure 2) Summary of intraplaque therapies. FIM First in Man study Figure 1) Movat’s stain of histopathology specimen showing the proximal cap and microvessels in a porcine model of a six-week-old chronic total occlusion. Note the fibrous proximal cap with cellular and matrix components. Microvessels are evident approximately 0.5 mm distal to the cap. IEL Internal elastic lamina
PATHOLOGY OF CTO PLAQUE: MATRIX AND MICROVESSELS Extracellular matrix In the majority of cases, the initial acute event leading to the development of a CTO is likely a ruptured atherosclerotic plaque with bidirectional thrombus formation. The thrombus and lipid-rich cholesterol esters are gradually replaced by extracellular matrix composed of proteoglycans and collagen. Over time, proteoglycan is gradually replaced by collagen formation and calcium deposition (17). This fibrous tissue is particularly dense at the proximal and distal ends of the lesion (so-called proximal and distal caps), which are conventionally regarded to be the most resistant areas of the CTO for guide wire crossing (Figure 1). Microvessels Despite the absence of flow within a CTO in angiographic studies, a limited number of pathology studies have reported the presence of microvessels to be quite common in human coronary CTOs (greater than 75%) (17,18). Microvessels can form in the vasa vasorum of the artery (19), within atherosclerotic intimal plaques (20), and within and parallel to the parent vessel. These latter ‘recanalization’ channels occur as part of the organization phase in CTO in which thrombus is replaced by fibrous tissue. These microvessels generally range in size from 100 μm to 200 μm but can sometimes be as large as 500 μm (17). We have recently described the natural history of CTOs in an animal model (21). Intraluminal recanalization channels with a ‘corkscrew’ appearance were present at the proximal part of the occlusion at six weeks. The endoluminal channels within the proximal portion were on the order of 50 μm in diameter. The midsection typically illustrated little contrast perfusion, with channels appearing discontinuous. At 12 weeks and beyond, there was progressive regression of the proximal recanalization channels and the entrance appeared blunt. In addition, there were several small, highly fragmented channels within the lumen, suggesting an apparent loss of microvessel continuity.
INTRAPLAQUE THERAPY: THE CONCEPT The main physical barrier to successful CTO crossing is the dense collagenous extracellular matrix. Current interventional strategies to overcome this barrier are based on forceful penetration of the CTO plaque by the use of dedicated CTO guide wires. These extra stiff wires
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are designed to transfer maximal force to the tip to create a path within the plaque. Tapered tip guide wires (such as the cross-IT XT [Abbott Vascular, USA], Fielder XT and Conquest [Asahi Intecc]) containing smaller diameter distal tips of 0.09 in to 0.010 in (compared with conventional 0.014 in) are also used to traverse small microchannels within the CTO. Several groups, including our own, are working on new approaches to actually alter the biology and structural characteristics of the CTO plaque to facilitate guide wire crossing. Data from both animal studies and preliminary human studies suggest that plaque-directed therapies aimed at ‘priming’ it for wire crossing may increase PCI success in these challenging cases. Historically, the first attempt to modify the CTO plaque was intracoronary injection of thrombolytic agents, with some success (Figure 2). With this approach, the drug was administered through the guiding catheter into the coronary artery in the presence of antegrade blood flow. Recently, we have modified this approach by injecting directly into the plaque or by creating a reservoir immediately proximal to the plaque while blocking antegrade coronary blood flow. In the present review, we describe the various techniques for plaque modification (Figure 2), either by ‘softening’ the collagenous matrix (collagenase), by exposing and enlarging existing microvessels (intravascular thrombolysis, contrast injection) or by inducing new microvessels (vascular endothelial growth factor [VEGF]).
MICROVESSEL MANIPULATION Mechanical: The microchannel technique Working on the premise that intraocclusion microvessels provide a pathway for guide wire crossing of a CTO (22), Carlino et al (23) postulated that injection of contrast immediately distal to the proximal cap of the CTO could enable both identification and enlargement of these pre-existing microvessels, creating a larger passage for crossing the CTO with a guide wire. A detailed description of the technique is provided in the original publication. Briefly, the technique requires advancement of a 1.5 mm over-the-wire balloon to the CTO and penetration of the proximal cap with a dedicated CTO guidewire to 1 mm to 3 mm. The balloon is then advanced into the CTO while the guide wire is removed. Subsequently, nitroglycerine is injected through the balloon lumen to dilate the microchannels. Finally, 1 mL of undiluted contrast is injected via the wire port of the angioplasty balloon catheter directly into the CTO (Figure 3). This technique was evaluated by a single operator in 32 patients (22). Median age of the CTO was nine years and the median occlusion length was approximately 24 mm. Overall technical success of microchannel injection was obtained in 20 patients (63%), with angiographic success in 19 (95%). In the remaining 12 patients, despite technical failure of this particular
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Figure 3) This series of images demonstrates how intraocclusion injection of contrast using the microchannel technique can identify and enlarge microvessels in the chronic total occlusion (CTO) that were not visible on standard angiography. A A blunt occlusion at the ostium of the second obtuse marginal branch is evident (arrow); distal opacification (arrows) of the occluded vessel by retrograde flow from ipsilateral collaterals is seen. Although there appears to be no evidence of anterograde flow through the CTO and no microchannels present, when contrast was injected into the proximal cap using the microchannel technique, a microvessel (B, arrows) became apparent, which allowed opacification of the distal vessel. C The final result after successfully recanalizing the CTO by manipulating the intraplaque microvessels
technique, successful recanalization of the artery was still obtained in seven of these 12 cases using another technique. Severe calcifications, side branch at the occlusion site and occlusion length were associated with failure. There were no cases of coronary perforation or rupture. All patients were free of major adverse cardiac events at 30 days follow-up. Based on this initial experience, the microchannel technique appears to be safe, with a low risk of complications. Pharmacological: Thrombolytic infusion Two studies (24,25) have reported the use of intracoronary thrombolytic infusion before PCI of CTOs. Based on the histological finding of multiple layers of clot that occur on top of episodes of plaque fissuring (24), Abbas et al (25) proposed administering intracoronary lytic therapy, hypothesizing that this may lyse the most recent clot component of a CTO to enable passage of the guide wire and facilitate recanalization. These histological features have not been confirmed in old CTOs. This hypothesis was tested in 85 patients with previous unsuccessful PCI procedures of CTO. PCI was repeated after intracoronary administration of preprocedural weight-adjusted alteplase (2 mg/h to 5 mg/h) or tenectaplase (0.5 mg/h) for a total of 8 h, requiring infusion through either a guiding catheter or an intracoronary infusion catheter for several hours in a coronary care unit setting. Not surprising due to the prolonged infusion with a potent thrombolytic agent, there were bleeding complications. Incidence of groin hematomas was 8% and 3.5% had bleeding that required transfusion. Nevertheless, the procedure was successful in 46 of 85 cases (54%). Four of 85 (5%) contained dissections that did not result in perforations, tamponade or major adverse cardiac events. Given that all these patients had already undergone one unsuccessful attempt at recanalizing the CTO and the CTO lesions had unfavourable morphology, a success rate of greater than 50% was considered promising. An earlier study by Zidar et al (26) used a similar protocol involving three doses of urokinase in patients with previously failed PCI of CTO. In this study, successful PCI of CTO following urokinase infusion was achieved in 55% of cases. Major complications including bleeding requiring transfusion were uncommon. The most common minor complication was transient ischemic attack in 3% of the patients. Microvessel induction: VEGF Based on our published observations of marked reductions in both CTO blood volume and intraluminal microvessels in CTOs after six weeks’ duration, we have been investigating approaches to induce intraluminal microvessel formation in older CTOs. These studies involve injecting angiogenic growth factors directly into the CTO through the wire port of an over-the-wire balloon that has been
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Figure 4) Histological specimen showing collagenase-treated artery with successful guide wire crossing (indicated by red arrows) (Movat’s stain, original magnification ×10). EEL External elastic lamina; IEL Internal elastic lamina positioned immediately adjacent to the proximal cap of the CTO. The balloon is inflated to prevent backflow of the solution containing the angiogenic growth factor. The solution is not injected directly into the CTO but, instead, deposited in the intraluminal space immediately proximal to the CTO and then expected to enter into the proximal part of the occlusion over a 45 min period while the balloon is inflated. Our initial studies have used VEGF-164 protein that has been packaged into biodegradable polylactic coglycolic acid microspheres with a mean size of 20 μm to prolong residency time and duration of effect (three to four days) within the CTO. These CTOs are re-evaluated three weeks later for CTO blood volume and microvessel formation, as well as tests of mechanical properties and guide wire crossing. Initial results with this approach have been promising (27).
MATRIX MODIFICATION: COLLAGENASE PLAQUE DIGESTION Collagen is the major extracellular matrix component of an established CTO plaque. Low success rates in guide wire crossing of CTOs are related in large part to the occlusive fibrotic nature of these plaques (17). Collagenase, a matrix metalloproteinase inhibitor, is the initial mediator of interstitial collagen degradation (28). The premise of this approach is that ‘softening’ the CTO plaque by digestion of plaque collagen enables easier guide wire crossing and enhanced procedural success. To test this hypothesis, Strauss et al (29) administered type IA bacterial collagenase or placebo locally to 45 CTOs in a rabbit femoral artery model. The technique of local delivery was similar to the VEGF therapy described above. The collagenase solution was injected through the wireport of an over-the-wire balloon that was positioned immediately proximal to the CTO. The balloon was inflated for 45 min to ensure isolation of the arterial segment containing the collagenase from the anterograde blood flow. Mean CTO occlusion duration was 16 weeks. Attempts to cross the CTO (mean length 28 mm) with conventional guide wires were assessed 72 h after treatment. Successful guide wire crossings were significantly higher in collagen-treated arteries (13 of 21, 62%) than in placebo treated arteries (seven of 24, 29%) (Figure 4). No adverse effects on arterial structure were observed in collagenase-treated arteries. At 24 h after treatment, collagenasetreated arteries demonstrated increased collagenase protein, gelatinous activity and collagen degradation fragments. In an additional study, a second collagenase formulation was tested in a rabbit model of femoral artery CTO (30). Local administration to 10 rabbit CTOs resulted in successful guide wire crossing in all CTOs after 24 h. A dose-response
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Figure 6) Movat’s stain of histopathology specimen showing persistence of microspheres within the lumen and the media of a chronically occluded plaque up to three weeks after injection. EEL External elastic lamina; IEL Internal elastic lamina
2.
3.
Figure 5) A Magnetic resonance image obtained before (Pre), immediately after (Post), 24 h and 72 h after injection of iron-oxide laden microspheres (red arrows). Note persistence of microspheres in the perivascular space at 72 h after the injection. B Left panel Trichrome stain (original magnification ×2.5) showing extravascular collection (EV) of microspheres with a tear in the wall of the occluded artery, with lumen (L). B Right panel Close-up of box from left panel, tear in wall of artery (indicated by arrow) (Trichrome stain, original magnification ×10). This chronic total occlusion (CTO) was treated with 1 mL of phosphate-buffered saline containing 16 mg of microspheres, containing 2 mg iron oxide
study was also performed in 17 rabbits to assess local effects of collagenase, with local subcutaneous bruising noted at the higher doses. Histological analysis showed no damage to the arterial wall structure. These preclinical studies indicated that local delivery of collagenase degrades collagen in CTO plaques and facilitates guide wire crossing in experimental CTO. A first in man study of collagenase in 20 human CTO patients is now underway.
OUTSTANDING ISSUES Local therapy for CTO seems to hold promise as a novel approach to improve percutaneous revascularization. However, there are many aspects of this therapeutic approach that need further investigation. A major area that requires further study is understanding the kinetics of drug delivery with various injection sites and at different CTO durations. Current therapies have been injected at varying distance from the CTO (thrombolytics at the origin of the coronary artery, VEGF microspheres and collagenase in the space adjacent to the CTO, and contrast directly into the CTO). Each of these approaches have limitations that include the following: 1. Intracoronary injection will cause loss of much of the solution into small vessels before the occlusion and have required prolonged
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4.
5.
injection periods up to 8 h, necessitating coronary care unit observation with intracoronary catheters. Injection of drug or agents into the space immediately proximal to the CTO must be relatively small to prevent flow into adjacent side branches. Direct injection into the plaque can result in opening of microchannels but can also result in perivascular staining, resulting from dissection of contrast in the extravascular/perivascular space. While preliminary studies (22) and clinical experience in more than 60 cases (M Carlino and B Strauss, personal communication) indicate that this technique is indeed safe, larger multicentre studies are needed. Diffusion characteristics into the CTO, particularly given the variable composition of the proximal fibrous cap and microvessel network at different ages of the CTO, need to be addressed for individual agents and microspheres. Injection of microspheres into a CTO raises many technical questions with regard to the localization of the microspheres within or outside the plaque. In one experiment using iron oxide-laden microspheres that were delivered adjacent to the CTO, we observed that the microspheres may exit the vessel wall and accumulate in the perivascular tissue, even 72 h after injections (BH Strauss, unpublished data) (Figure 5). Residency time of microspheres in the tissue is unclear. Preliminary experiments have shown evidence of microsphere persistence in the CTO for up to three weeks postinjection (BH Strauss, unpublished data) (Figure 6). Possibly, microsphere size has an effect on residency time in the tissue. The clinical implications of these observations are not known. Dose and time effects: While direct contrast injection has an immediate and direct mechanical effect, collagenase injection and VEGF administration rely on activation of biological processes for effect, which is expected to be both dose and time related. Too small a dose may have no effect, while too high a dose may be associated with side effects. Likewise, the maximal biological effect is likely to range from hours to weeks to reach maximal effect and may wane thereafter. Further studies are needed to elucidate the optimal dose- and time-related effects of these therapies.
SUMMARY Despite significant improvement in operator skill and availability of dedicated equipment, the percutaneous treatment of CTOs remains challenging, with both lower procedural success and higher periprocedural risk than conventional angioplasty. Intraplaque therapy is a new
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way of approaching an old problem. While much previous research and development has been focused on stiffer wires that can penetrate and traverse the fibrous CTO plaque, the concept behind intraplaque therapy is based on modifying the plaque itself to enable easier and, possibly, safer guide wire crossing. A wide variety of therapeutic agents could have important and novel effects on the CTO to facilitate guide wire crossing and percutaneous interventions. Additional research to
optimize delivery strategies and the timing of the effects are needed, particularly with respect to the composition and age of the CTO. DISCLOSURE: Dr Strauss holds or has applied for patents on collagenase and angiogenic growth factors for treatment of chronic total occlusions.
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16. Prasad A, Rihal CS, Lennon RJ, Wiste HJ, Singh M, Holmes DR Jr. Trends in outcomes after percutaneous coronary intervention for chronic total occlusions: A 25-year experience from the Mayo Clinic. J Am Coll Cardiol 2007;49:1611-8. 17. Srivatsa SS, Edwards WD, Boos CM, et al. Histologic correlates of angiographic chronic total coronary artery occlusions: Influence of occlusion duration on neovascular channel patterns and intimal plaque composition. J Am Coll Cardiol 1997;29:955-63. 18. Katsuragawa M, Fujiwara H, Miyamae M, Sasayama S. Histologic studies in percutaneous transluminal coronary angioplasty for chronic total occlusion: Comparison of tapering and abrupt types of occlusion and short and long occluded segments. J Am Coll Cardiol 1993;21:604-11. 19. Kwon HM, Sangiorgi G, Ritman EL, et al. Enhanced coronary vasa vasorum neovascularization in experimental hypercholesterolemia. J Clin Invest 1998;101:1551-6. 20. Celetti FL, Waugh JM, Amabile PG, et al. Vascular endothelial growth factor enhances atherosclerotic plaque progression. Nat Med 2001;37:7:2126-30. 21. Jaffe R, Leung G, Munce,NR, et al. Natural history of experimental arterial chronic total occlusions. J Am Coll Cardiol 2009;53:1148-58. 22. Strauss BH, Segev A, Wright GA, et al. Microvessels in chronic total occlusions: Pathways for successful guidewire crossing? J Interv Cardiol 2005;18:425-36. 23. Carlino M, Latib A, Godino C, Cosgrove J, Colombo A. CTO recanalization by intraocclusion injection of contrast: The microchannel technique. Catheter Cardiovasc Interv 2008;71:20-6. 24. Meier B. Chronic total occlusions. In: Topol EJ, ed. Textbook of Interventional Cardiology, 4th edn. Philadelphia, PA: Saunders, 2003:303-16. 25. Abbas AE, Brewington SD, Dixon SR, Boura JA, Grines CL, O’Neill WW. Intracoronary fibrin-specific thrombolytic infusion facilitates percutaneous recanalization of chronic total occlusion. J Am Coll Cardiol 2005;46:793-8. 26. Zidar FJ, Kaplan BM, O’Neill WW, et al. Prospective randomized trial of prolonged intracoronary urokinase infusion for chronic total occlusions in native arteries. J Am Coll Cardiol 1996;27:1406-12. 27. Teitelbaum A, Qi X, Anderson K, et al. Quantitative magnetic resonance angiographic analysis of CTO perfusion in response to VEGF treatment. Can J Cardiol 2008;24(Suppl E):215E. (Abst) 28. Dollery CM, McEwan JR, Henney AM. Matrix metalloproteinases and cardiovascular disease. Circ Res 1995;77:863-8. 29. Strauss BH, Goldman L, Qiang B, et al. Collagenase plaque digestion for facilitating guide wire crossing in chronic total occlusions. Circulation 2003;108:1259-62. 30. Segev A, Nili N, Qiang B, Charron T, Butany J, Strauss BH. Human-grade purified collagenase for the treatment of experimental arterial chronic total occlusion. Cardiovasc Revasc Med 2005;6:65-9.
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