- Email: [email protected]
Late Vascular Healing Response to Stents
Journal of the American College of Cardiology © 2010 by the American College of Cardiology Foundation Published by Elsevier Inc.
EDITORIAL COMMENT
Late Vascular Healing Response to Stents New Insights From Optical Coherence Tomography* Brigitta C. Brott, MD Birmingham, Alabama
As clinicians, we presume the vascular response to stent placement is complete and quiescent at 1 year after implant. By using optical coherence tomography (OCT) to examine bare-metal stents, in this issue of the Journal, Takano et al. (1) demonstrate that late restenosis and unstable plaque progression may develop within the stent more than 5 years after implantation. Although neointimal tissue reaction has been hypothesized to be relatively static, the use of OCT permits a new more detailed understanding of the vascular response to stenting. See page 26
Takano et al. (1) examined patients at 6 months and more than 5 years after stent implantation. In many of the late follow-up patients, OCT surprisingly demonstrated the late development of in-stent tissue morphologies associated with unstable lesions. Rather than smooth passivated fibrous neointima, late in-stent examination found significantly more microvessels distributed throughout the neointima, intimal disruption, thrombus, and lipid-laden intima. Many of these patients had been clinically stable and asymptomatic until their late follow-up presentations at 5 years. Although the incidence of these responses remains undefined, these new in vivo OCT data challenge our current paradigm of vascular healing response to stenting. Our previous understanding of the vascular response to stents has been developed from post-mortem, atherectomy, and animal studies, as well as sparse long-term angiographic follow-up studies. Stents initially are covered by albumin, fibrinogen, and complement factors. Platelet-rich thrombi and inflammatory cells then seed stents (2). Subsequently medial smooth muscle cells migrate and proliferate and
*Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology. From Interventional Cardiology, University of Alabama at Birmingham, Birmingham, Alabama.
Vol. 55, No. 1, 2010 ISSN 0735-1097/10/$36.00 doi:10.1016/j.jacc.2009.08.033
synthesize the extracellular matrix (3). Thrombi resolve over the course of approximately 30 days, although an inflammatory response may persist (3). Over time, the neointima matures, becoming predominantly an extracellular matrix with few cells (4). During the initial years, the characteristics of in-stent restenosis lesions are quite distinct from the adjacent atherosclerosis. Matrix remodeling continues to 18 months after stent deployment (5). Atherectomy specimens retrieved from bare-metal stent late restenosis demonstrate extracellular matrix accumulation and depletion of cells (4,5). Severe in-stent restenosis lesions have extensive neovascularization (6). In de novo atherosclerosis, intimal vascularization correlates with extent of disease, including intimal thickness. Intimal neovascularization likely plays a role in vascular remodeling, inflammation (7), intraplaque hemorrhage, and plaque rupture (8). More controversial is the role of neointimal vessels in restenosis. Neovessels and increased vascular endothelial growth factor expression have been identified around stent struts along with increased inflammatory cells, suggesting a role in the response to injury (6,9). Angiographic follow-up of stents demonstrates several phases. During the first 6 months, neointima develops with luminal narrowing. Between 6 months and 1 year, there is minimal progression. By 3 years there may be improvement in lumen diameter, suggesting fibrotic maturation and regression (10,11). In general, there is minimal progression between 2 and 4 years (12). Beyond 4 years, however, a late restenosis phenomenon has been described in some patients. Although its incidence is unknown, late restenosis is associated with significant rates of mortality (13,14). For instance, Kimura et al. (15) describe a triphasic response, with early restenosis, plaque stabilization, and regression, followed by late renarrowing beyond 4 years. At autopsy, late restenosis has been associated with focal inflammation adjacent to struts along with metalloproteinase activity, suggesting a long-term inflammatory response (16). With an imaging resolution 10 to 30 times greater than intravascular ultrasound, OCT now permits more precise in vivo morphological assessment (17). The use of OCT has undergone extensive validation compared with histology (18). It has added to the understanding of vulnerable plaque, plaque response to drug-eluting stents, and acute myocardial infarction, with descriptions of thin-cap fibroatheroma, fibrous cap erosion, neointimal coverage, and thrombus (18 –20). Now with OCT evaluation at 5 years after stent implantation, Takano et al. (15) add to the limited available long-term angiographic follow-up studies, demonstrating late intimal progression. With a new window into the in vivo characteristics of neointima, OCT confirms limited autopsy and atherectomy data. The authors found that early after stent implantation, neointima is composed of fibrotic tissue with neovessels primarily located in the peri-stent region (21). However, late in-stent restenosis is characterized by diffuse neovascularization, intimal disruption, lipid-
34
Brott Late Vascular Healing Response to Stents
rich regions, and thrombus formation within the stented segment. Like the previous post-mortem and atherectomy studies, this OCT study has the intrinsic limitation of a convenience sample rather than a specific protocol. In patients with both early and late OCT examinations, an angiographic assessment also was obtained. In those patients who underwent OCT at 5 years, serial quantitative coronary angiography also demonstrated late angiographic renarrowing. Although selection bias likely occurred, the clinical and angiographic characteristics of the patients at early and late time points were similar. Importantly, patients examined beyond 5 years included both those with and without clinical evidence of restenosis. What causes late in-stent restenosis? Inoue et al. (16) have suggested a chronic inflammatory response to the presence of metallic stents. Or, it may be disease progression with de novo atherosclerosis formation within the stented segment. Future analyses should include evaluation of longterm changes of the stent itself as well as the stent-vessel interaction that may induce chronic inflammation, such as stent corrosion and associated metallic ion release into surrounding tissues (22–24). This detailed OCT analysis challenges the current assumption that stent deployment induces chronic fibrotic changes and plaque stabilization. If the long-term vascular response to stenting were better understood and manipulated to be predictably quiescent, perhaps emerging plaque stability imaging technologies could be coupled with stent placement as a rational treatment for vulnerable plaque. Reprint requests and correspondence: Dr. Brigitta C. Brott, Interventional Cardiology, FOT 907, 510 20th Street South, University of Alabama at Birmingham, Birmingham, Alabama 35294. E-mail: [email protected].
JACC Vol. 55, No. 1, 2010 December 29, 2009/January 5, 2010:33–4
7.
8. 9.
10. 11. 12.
13. 14.
15. 16. 17. 18. 19.
20. REFERENCES
1. Takano M, Yamamoto M, Inami S, et al. Appearance of lipid-laden intima and neovascularization after implantation of bare-metal stents: extended late-phase observation by intracoronary optical coherence tomography. J Am Coll Cardiol 2010;55:26 –32. 2. Virmani R, Farb A. Pathology of in-stent restenosis. Curr Opin Lipidol 1999;10:499 –506. 3. Grewe PH, Deneke T, Machraoui A, Barmeyer J, Muller KM. Acute and chronic tissue response to coronary stent implantation: pathologic findings in human specimen. J Am Coll Cardiol 2000;35:157– 63. 4. Chung IM, Gold HK, Schwartz SM, Ikari Y, Reidy MA, Wight TN. Enhanced extracellular matrix accumulation in restenosis of coronary arteries after stent deployment. J Am Coll Cardiol 2002;40:2072– 81. 5. Farb A, Kolodgie FD, Hwang JY, et al. Extracellular matrix changes in stented human coronary arteries. Circulation 2004;110:940 –7. 6. Brasen JH, Kivela A, Roser K, et al. Angiogenesis, vascular endothelial growth factor and platelet-derived growth factor-BB expression, iron
21.
22.
23. 24.
deposition, and oxidation-specific epitopes in stented human coronary arteries. Arterioscler Thromb Vasc Biol 2001;21:1720 – 6. Kockx MM, Cromheeke KM, Knaapen MW, et al. Phagocytosis and macrophage activation associated with hemorrhagic microvessels in human atherosclerosis. Arterioscler Thromb Vasc Biol 2003;23: 440 – 6. Moreno PR, Purushothaman KR, Sirol M, Levy AP, Fuster V. Neovascularization in human atherosclerosis. Circulation 2006;113: 2245–52. Shibata M, Suzuki H, Nakatani M, et al. The involvement of vascular endothelial growth factor and flt-1 in the process of neointimal proliferation in pig coronary arteries following stent implantation. Histochem Cell Biol 2001;116:471– 81. Kimura T, Yokoi H, Nakagawa Y, et al. Three-year follow-up after implantation of metallic coronary-artery stents. N Engl J Med 1996; 334:561– 6. Asakura M, Ueda Y, Nanto S, et al. Remodeling of in-stent neointima, which became thinner and transparent over 3 years: serial angiographic and angioscopic follow-up. Circulation 1998;97:2003– 6. Laham RJ, Carrozza JP, Berger C, Cohen DJ, Kuntz RE, Baim DS. Long-term (4- to 6-year) outcome of Palmaz-Schatz stenting: paucity of late clinical stent-related problems. J Am Coll Cardiol 1996;28: 820 – 6. Doyle B, Rihal CS, O’Sullivan CJ, et al. Outcomes of stent thrombosis and restenosis during extended follow-up of patients treated with bare-metal coronary stents. Circulation 2007;116:2391– 8. Jorgensen E, Helqvist S, Klovgaard L, et al. Restenosis in coronary bare metal stents. Importance of time to follow-up: a comparison of coronary angiograms 6 months and 4 years after implantation. Scand Cardiovasc J 2009;43:87–93. Kimura T, Abe K, Shizuta S, et al. Long-term clinical and angiographic follow-up after coronary stent placement in native coronary arteries. Circulation 2002;105:2986 –91. Inoue K, Abe K, Ando K, et al. Pathological analyses of long-term intracoronary Palmaz-Schatz stenting; is its efficacy permanent? Cardiovasc Pathol 2004;13:109 –15. Guagliumi G, Sirbu V. Optical coherence tomography: high resolution intravascular imaging to evaluate vascular healing after coronary stenting. Catheter Cardiovasc Interv 2008;72:237– 47. Kume T, Akasaka T, Kawamoto T, et al. Assessment of coronary arterial plaque by optical coherence tomography. Am J Cardiol 2006;97:1172–5. Kubo T, Imanishi T, Takarada S, et al. Assessment of culprit lesion morphology in acute myocardial infarction: ability of optical coherence tomography compared with intravascular ultrasound and coronary angioscopy. J Am Coll Cardiol 2007;50:933–9. Jang IK, Tearney GJ, MacNeill B, et al. In vivo characterization of coronary atherosclerotic plaque by use of optical coherence tomography. Circulation 2005;111:1551–5. Komatsu R, Ueda M, Naruko T, Kojima A, Becker AE. Neointimal tissue response at sites of coronary stenting in humans: macroscopic, histological, and immunohistochemical analyses. Circulation 1998;98: 224 –33. Brott BC, Halwani D, Anderson PG, Anayiotos AS, Lemons JE. Scanning electron microscopy analysis of corrosion of stainless steel and nitinol stents from autopsy retrievals (abstr). J Am Coll Cardiol 2008;51 Suppl 2:B92. Halwani D, Brott BC, Anderson PG, Anayiotos AS, Lemons JE. Local release of metallic ions from stents into vascular tissue (abstr). J Am Coll Cardiol 2008;51 Suppl 2:B93. Shih CC, Shih CM, Chen YL, et al. Growth inhibition of cultured smooth muscle cells by corrosion products of 316 L stainless steel wire. J Biomed Mater Res 2001;57:200 –7.
Key Words: neointima y stents y thrombus.
EDITORIAL COMMENT
Late Vascular Healing Response to Stents New Insights From Optical Coherence Tomography* Brigitta C. Brott, MD Birmingham, Alabama
As clinicians, we presume the vascular response to stent placement is complete and quiescent at 1 year after implant. By using optical coherence tomography (OCT) to examine bare-metal stents, in this issue of the Journal, Takano et al. (1) demonstrate that late restenosis and unstable plaque progression may develop within the stent more than 5 years after implantation. Although neointimal tissue reaction has been hypothesized to be relatively static, the use of OCT permits a new more detailed understanding of the vascular response to stenting. See page 26
Takano et al. (1) examined patients at 6 months and more than 5 years after stent implantation. In many of the late follow-up patients, OCT surprisingly demonstrated the late development of in-stent tissue morphologies associated with unstable lesions. Rather than smooth passivated fibrous neointima, late in-stent examination found significantly more microvessels distributed throughout the neointima, intimal disruption, thrombus, and lipid-laden intima. Many of these patients had been clinically stable and asymptomatic until their late follow-up presentations at 5 years. Although the incidence of these responses remains undefined, these new in vivo OCT data challenge our current paradigm of vascular healing response to stenting. Our previous understanding of the vascular response to stents has been developed from post-mortem, atherectomy, and animal studies, as well as sparse long-term angiographic follow-up studies. Stents initially are covered by albumin, fibrinogen, and complement factors. Platelet-rich thrombi and inflammatory cells then seed stents (2). Subsequently medial smooth muscle cells migrate and proliferate and
*Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology. From Interventional Cardiology, University of Alabama at Birmingham, Birmingham, Alabama.
Vol. 55, No. 1, 2010 ISSN 0735-1097/10/$36.00 doi:10.1016/j.jacc.2009.08.033
synthesize the extracellular matrix (3). Thrombi resolve over the course of approximately 30 days, although an inflammatory response may persist (3). Over time, the neointima matures, becoming predominantly an extracellular matrix with few cells (4). During the initial years, the characteristics of in-stent restenosis lesions are quite distinct from the adjacent atherosclerosis. Matrix remodeling continues to 18 months after stent deployment (5). Atherectomy specimens retrieved from bare-metal stent late restenosis demonstrate extracellular matrix accumulation and depletion of cells (4,5). Severe in-stent restenosis lesions have extensive neovascularization (6). In de novo atherosclerosis, intimal vascularization correlates with extent of disease, including intimal thickness. Intimal neovascularization likely plays a role in vascular remodeling, inflammation (7), intraplaque hemorrhage, and plaque rupture (8). More controversial is the role of neointimal vessels in restenosis. Neovessels and increased vascular endothelial growth factor expression have been identified around stent struts along with increased inflammatory cells, suggesting a role in the response to injury (6,9). Angiographic follow-up of stents demonstrates several phases. During the first 6 months, neointima develops with luminal narrowing. Between 6 months and 1 year, there is minimal progression. By 3 years there may be improvement in lumen diameter, suggesting fibrotic maturation and regression (10,11). In general, there is minimal progression between 2 and 4 years (12). Beyond 4 years, however, a late restenosis phenomenon has been described in some patients. Although its incidence is unknown, late restenosis is associated with significant rates of mortality (13,14). For instance, Kimura et al. (15) describe a triphasic response, with early restenosis, plaque stabilization, and regression, followed by late renarrowing beyond 4 years. At autopsy, late restenosis has been associated with focal inflammation adjacent to struts along with metalloproteinase activity, suggesting a long-term inflammatory response (16). With an imaging resolution 10 to 30 times greater than intravascular ultrasound, OCT now permits more precise in vivo morphological assessment (17). The use of OCT has undergone extensive validation compared with histology (18). It has added to the understanding of vulnerable plaque, plaque response to drug-eluting stents, and acute myocardial infarction, with descriptions of thin-cap fibroatheroma, fibrous cap erosion, neointimal coverage, and thrombus (18 –20). Now with OCT evaluation at 5 years after stent implantation, Takano et al. (15) add to the limited available long-term angiographic follow-up studies, demonstrating late intimal progression. With a new window into the in vivo characteristics of neointima, OCT confirms limited autopsy and atherectomy data. The authors found that early after stent implantation, neointima is composed of fibrotic tissue with neovessels primarily located in the peri-stent region (21). However, late in-stent restenosis is characterized by diffuse neovascularization, intimal disruption, lipid-
34
Brott Late Vascular Healing Response to Stents
rich regions, and thrombus formation within the stented segment. Like the previous post-mortem and atherectomy studies, this OCT study has the intrinsic limitation of a convenience sample rather than a specific protocol. In patients with both early and late OCT examinations, an angiographic assessment also was obtained. In those patients who underwent OCT at 5 years, serial quantitative coronary angiography also demonstrated late angiographic renarrowing. Although selection bias likely occurred, the clinical and angiographic characteristics of the patients at early and late time points were similar. Importantly, patients examined beyond 5 years included both those with and without clinical evidence of restenosis. What causes late in-stent restenosis? Inoue et al. (16) have suggested a chronic inflammatory response to the presence of metallic stents. Or, it may be disease progression with de novo atherosclerosis formation within the stented segment. Future analyses should include evaluation of longterm changes of the stent itself as well as the stent-vessel interaction that may induce chronic inflammation, such as stent corrosion and associated metallic ion release into surrounding tissues (22–24). This detailed OCT analysis challenges the current assumption that stent deployment induces chronic fibrotic changes and plaque stabilization. If the long-term vascular response to stenting were better understood and manipulated to be predictably quiescent, perhaps emerging plaque stability imaging technologies could be coupled with stent placement as a rational treatment for vulnerable plaque. Reprint requests and correspondence: Dr. Brigitta C. Brott, Interventional Cardiology, FOT 907, 510 20th Street South, University of Alabama at Birmingham, Birmingham, Alabama 35294. E-mail: [email protected].
JACC Vol. 55, No. 1, 2010 December 29, 2009/January 5, 2010:33–4
7.
8. 9.
10. 11. 12.
13. 14.
15. 16. 17. 18. 19.
20. REFERENCES
1. Takano M, Yamamoto M, Inami S, et al. Appearance of lipid-laden intima and neovascularization after implantation of bare-metal stents: extended late-phase observation by intracoronary optical coherence tomography. J Am Coll Cardiol 2010;55:26 –32. 2. Virmani R, Farb A. Pathology of in-stent restenosis. Curr Opin Lipidol 1999;10:499 –506. 3. Grewe PH, Deneke T, Machraoui A, Barmeyer J, Muller KM. Acute and chronic tissue response to coronary stent implantation: pathologic findings in human specimen. J Am Coll Cardiol 2000;35:157– 63. 4. Chung IM, Gold HK, Schwartz SM, Ikari Y, Reidy MA, Wight TN. Enhanced extracellular matrix accumulation in restenosis of coronary arteries after stent deployment. J Am Coll Cardiol 2002;40:2072– 81. 5. Farb A, Kolodgie FD, Hwang JY, et al. Extracellular matrix changes in stented human coronary arteries. Circulation 2004;110:940 –7. 6. Brasen JH, Kivela A, Roser K, et al. Angiogenesis, vascular endothelial growth factor and platelet-derived growth factor-BB expression, iron
21.
22.
23. 24.
deposition, and oxidation-specific epitopes in stented human coronary arteries. Arterioscler Thromb Vasc Biol 2001;21:1720 – 6. Kockx MM, Cromheeke KM, Knaapen MW, et al. Phagocytosis and macrophage activation associated with hemorrhagic microvessels in human atherosclerosis. Arterioscler Thromb Vasc Biol 2003;23: 440 – 6. Moreno PR, Purushothaman KR, Sirol M, Levy AP, Fuster V. Neovascularization in human atherosclerosis. Circulation 2006;113: 2245–52. Shibata M, Suzuki H, Nakatani M, et al. The involvement of vascular endothelial growth factor and flt-1 in the process of neointimal proliferation in pig coronary arteries following stent implantation. Histochem Cell Biol 2001;116:471– 81. Kimura T, Yokoi H, Nakagawa Y, et al. Three-year follow-up after implantation of metallic coronary-artery stents. N Engl J Med 1996; 334:561– 6. Asakura M, Ueda Y, Nanto S, et al. Remodeling of in-stent neointima, which became thinner and transparent over 3 years: serial angiographic and angioscopic follow-up. Circulation 1998;97:2003– 6. Laham RJ, Carrozza JP, Berger C, Cohen DJ, Kuntz RE, Baim DS. Long-term (4- to 6-year) outcome of Palmaz-Schatz stenting: paucity of late clinical stent-related problems. J Am Coll Cardiol 1996;28: 820 – 6. Doyle B, Rihal CS, O’Sullivan CJ, et al. Outcomes of stent thrombosis and restenosis during extended follow-up of patients treated with bare-metal coronary stents. Circulation 2007;116:2391– 8. Jorgensen E, Helqvist S, Klovgaard L, et al. Restenosis in coronary bare metal stents. Importance of time to follow-up: a comparison of coronary angiograms 6 months and 4 years after implantation. Scand Cardiovasc J 2009;43:87–93. Kimura T, Abe K, Shizuta S, et al. Long-term clinical and angiographic follow-up after coronary stent placement in native coronary arteries. Circulation 2002;105:2986 –91. Inoue K, Abe K, Ando K, et al. Pathological analyses of long-term intracoronary Palmaz-Schatz stenting; is its efficacy permanent? Cardiovasc Pathol 2004;13:109 –15. Guagliumi G, Sirbu V. Optical coherence tomography: high resolution intravascular imaging to evaluate vascular healing after coronary stenting. Catheter Cardiovasc Interv 2008;72:237– 47. Kume T, Akasaka T, Kawamoto T, et al. Assessment of coronary arterial plaque by optical coherence tomography. Am J Cardiol 2006;97:1172–5. Kubo T, Imanishi T, Takarada S, et al. Assessment of culprit lesion morphology in acute myocardial infarction: ability of optical coherence tomography compared with intravascular ultrasound and coronary angioscopy. J Am Coll Cardiol 2007;50:933–9. Jang IK, Tearney GJ, MacNeill B, et al. In vivo characterization of coronary atherosclerotic plaque by use of optical coherence tomography. Circulation 2005;111:1551–5. Komatsu R, Ueda M, Naruko T, Kojima A, Becker AE. Neointimal tissue response at sites of coronary stenting in humans: macroscopic, histological, and immunohistochemical analyses. Circulation 1998;98: 224 –33. Brott BC, Halwani D, Anderson PG, Anayiotos AS, Lemons JE. Scanning electron microscopy analysis of corrosion of stainless steel and nitinol stents from autopsy retrievals (abstr). J Am Coll Cardiol 2008;51 Suppl 2:B92. Halwani D, Brott BC, Anderson PG, Anayiotos AS, Lemons JE. Local release of metallic ions from stents into vascular tissue (abstr). J Am Coll Cardiol 2008;51 Suppl 2:B93. Shih CC, Shih CM, Chen YL, et al. Growth inhibition of cultured smooth muscle cells by corrosion products of 316 L stainless steel wire. J Biomed Mater Res 2001;57:200 –7.
Key Words: neointima y stents y thrombus.