In Vivo Characterization of Carotid Neointimal Hyperplasia by use of Optical Coherence Tomography: Before and After Cutting Balloon Angioplasty Kristine A. Blackham, Benny S. Kim, Richard S. Jung, Chaitra Badve, Sunil Manjila, Cathy A. Sila, Nicholas C. Bambakidis From the Department of Radiology, University Hospitals of Cleveland, Case Western Reserve University, Cleveland, OH (KAB, CB); Interventional Neuroradiology, Lahey Clinic Medical Center, Burlington, MA (BSK); Interventional Neurology, CoxHealth, Springfield, MO (RSJ); Neurosurgery, University Hospitals of Cleveland, Case Western Reserve University, Cleveland, OH (SM, NCB); and Neurology, University Hospitals of Cleveland, Case Western Reserve University, Cleveland, OH (CAS).
ABSTRACT Optical coherence tomography (OCT) is a modern intravascular imaging modality that has the capability to provide detailed, in vivo characterization of the arterial wall and atherosclerotic plaque. The current understanding of the appearance of atherosclerotic plaque via OCT is largely based on coronary arterial studies where OCT information has been employed to guide therapeutic management and permits the immediate evaluation of percutaneous intervention. The clinical success of OCT in the coronary arteries has laid the foundation for investigation of the carotid artery and thus, stroke risk assessment. We report the novel use of OCT for tissue characterization of severe stenosis subsequent to carotid artery stenting (CAS), both before and after treatment with cutting balloon angioplasty. Keywords: Carotid stenosis, optical coherence tomography, angiography. Acceptance: Received October 6, 2014. Accepted for publication November 27, 2014. Correspondence: Address correspondence to Kristine A. Blackham, MD, Radiology Department, University Hospitals of Cleveland, Case Western Reserve University, Cleveland, OH 44106. E-mail: [email protected]. J Neuroimaging 2015;25:1044-1046. DOI: 10.1111/jon.12223
Introduction
Case Report
Optical Coherence Tomography (OCT) is an imaging modality which provides micron level tomographic images of human tissue based on the coherence of light. A near-infrared light is produced by a fiber optic system which is absorbed by red blood cells, water, lipids, and protein. OCT produces cross-sectional endoluminal images of a vessel with a 10 times greater detail than other similar imaging modalities such as intravascular ultrasound (IVUS) and utilization of both modalities has been demonstrated in coronary vessels and more recently the cervical carotid arteries.1–3 There have been increasing case reports and small series over the last few years describing the neurointerventional application of OCT imaging in the cervicocerebral vessels.4–7 The high resolution of OCT allows it to characterize native tissue, differentiate plaque composition (such as fibrous, calcified, or lipid-rich), and assess stent implantation, including intraluminal thrombus, in-stent restenosis, and plaque protrusion.7 It is a promising tool for in vivo detection of unstable thin-cap fibroatheroma, which may be a significant source for thromboembolic strokes. In this case report, we demonstrate the use of OCT in evaluating carotid stent restenosis and to characterize the tissue response to cutting balloon angioplasty. The cutting balloon is a noncompliant angioplasty balloon with longitudinally mounted blades which produce controlled microdissections in atherosclerotic plaque, thereby reducing vessel stretch, injury and risk of a neoproliferative response which otherwise could result in restenosis. This balloon has been shown to be safe, effective, and durable for carotid artery stenting.8
A 74-year-old Caucasian male with hypertension, diabetes mellitus, hyperlipidemia, coronary artery disease presented with recurrent in-stent stenosis in his left internal carotid artery (ICA) following carotid artery stenting (CAS) with a 4 × 24 mm balloon-mounted Medtronic (Minneapolis, Minnesota, USA) Driver stent. The initial CAS was performed acutely, for a symptomatic 90% stenosis, as determined by criteria used in the North American Symptomatic Carotid Endarterectomy Trial (NASCET). The postprocedure medication regimen included oral statin and dual antiplatelet therapy with 81 mg aspirin and 75 mg clopidogrel daily. Over the course of the following 17 months after CAS, the patient underwent four separate intraluminal balloon angioplasties for asymptomatic, recurrent, severe, in-stent stenosis, as detected by ultrasound. Follow-up ultrasonographic monitoring 3 months after his last treatment again demonstrated luminal narrowing >70%. An 85% luminal narrowing and flow limitation was demonstrated by catheter angiography, and an alternative evaluation and treatment method were deemed appropriate by the treating vascular neurologist and neurointerventional surgeon.
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Copyright
Methods The percutaneous intervention was performed according to standard practice using an .014" (.36 mm) exchange length guidewire through a 6-French shuttle sheath under systemic heparinization. Digital subtraction angiography (DSA) revealed an 85% in-stent restenosis of the proximal cervical left ICA as calculated per NASCET criteria.
◦ 2015 by the American Society of Neuroimaging C
Fig 1. (A) Preangioplasty angiogram shows 85% restenosis of left ICA stent (arrow). (B) Postcutting balloon angioplasty angiogram with residual 40% stenosis (arrow). (C) Preangioplasty axial OCT image at the site of maximal stenosis reveals severe neointimal hyperplasia. Multiple shadows can be seen arising from the intramural stent which appears as a circumferential speckled bright outline. The large shadow at 7 o’clock is from the microguidewire upon which the OCT catheter is loaded. (D) The postcutting balloon angioplasty axial OCT image demonstrates improved vessel caliber. The white arrows denote the intimal microdissections from the cutting balloon blades.
Fig 2. (A) Longitudinal OCT image through the left ICA stent reveals diffuse neointimal hyperplasia (arrows). (B) Postcutting balloon angioplasty OCT demonstrates improvement in vessel caliber. Note the unopposed portion of the stent in the carotid bulb (star).
A St. Jude Medical C7 Dragonfly intravascular OCT imaging catheter (St. Paul, Minnesota, USA) was advanced over the exchange length .014" guidewire and positioned across the stenosis. With the shuttle sheath primed with contrast, an injection through the sheath at rate of 5 mL/second for a total volume of 25 mL, was performed simultaneously with OCT imaging and biplane digital subtraction angiography over the neck (Figs 1 and 2). OCT imaging was acquired via a motorized pullback
in a retrograde fashion in order to image the artery from the distal end of the stenosis to the bifurcation. The OCT catheter was removed and a 4 mm × 1.5 cm Boston Scientific Peripheral Cutting Balloon (Natick, Massachusetts, USA) was advanced over the exchange length .014" guidewire and positioned across the area of maximal stenosis and inflated supranominally to 10 atmospheres and subsequently deflated. Improvement of the vessel caliber and distal flow was seen with a residual 40% stenosis.
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Repeat OCT imaging was obtained. The patient tolerated the procedure well without any neurological complications. The patient was asymptomatic and well at 3-month follow-up.
Discussion OCT is an endovascular imaging device with tremendous potential to contribute to the knowledge of carotid plaque morphology. Similar to IVUS, OCT provides in situ images of the vascular wall with a field of view of 10 mm; allowing its use in the larger lumen of the cervical carotid artery. In contrast to a 100 µm resolution for IVUS, the resolution of OCT is 10-15 µm. This substantial difference in resolution is relevant to the detection of a thin-cap fibroatheroma, in which a thin fibrous plaque is defined as less than 65 µm. Significant microstructural details of a vessel can be visualized, such as the internal and external elastic laminae, intima, media, and adventitia. The high resolution allows for the composition of the tissue of interest to be characterized into its fibrous, collagen, lipid, and calcium components.9,10 Highrisk unstable plaques have been identified by presence of intraplaque hemorrhage, inflammatory cell infiltration, plaque ulceration, or a lipid rich core with a thin fibrous cap by histology.11,12 These plaque characteristics are associated with increased risk of clinical embolic events even in the setting of hemodyamically insignificant luminal stenosis;13 therefore, an accurate, reproducible imaging correlation of these histologic characteristics is highly sought after. In the cardiology literature, experience with OCT in the coronaries arteries has provided a wealth of knowledge regarding normal and diseased vascular wall morphology, stent placement and apposition, and in-stent tissue characteristics such as neointimal growth.14 In our case report, OCT was utilized to detail the endovascular microstructure of delayed recurrent in-stent stenosis before and after cutting balloon angioplasty. The preangioplasty angiogram demonstrates extrinsic mass effect on the lumen within the stent (Fig 1A) corresponding to homogenous soft tissue thickening on axial OCT images, consistent with neointimal hyperplasia (Fig 1C). There is resultant severe endoluminal stenosis most prominently in the mid-stent region seen best on longitudinal OCT images (Fig 2A), which also shows the proximal and distal stent tines to be incompletely apposed to the carotid wall from incorrect sizing of the stent, which is not evident on digital subtraction angiography. The posttreatment angiogram and OCT images show significant improvement in endoluminal caliber (Figs 1B, D, and 2B). Also seen are the circumferential micro dissections within the neointimal tissue corresponding to the longitudinally mounted cutting blades of the balloon (Fig 1D). Current limitations of OCT include lower tissue penetration than IVUS, which may limit complete plaque characterization especially with a large lipid rich core. OCT has a tissue penetration of 3 mm whereas IVUS has a tissue penetration of 4 to 8 mm. Other limitations include those common to any intravascular device: risk of emboli and difficulty navigating within tortuous anatomy and the associated risk-benefit ratio, which must be carefully considered with use in the cervicocerebral circulation.15
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Conclusion This case report demonstrates the application of OCT in the evaluation and treatment of in-stent restenosis. OCT is a promising imaging modality which may become beneficial in guiding therapeutic neurointerventional management due to its potential ability to safely characterize and classify carotid atherosclerotic plaques in vivo as well as to evaluate adequacy and outcome of treatment.
References 1. Yoshimura S, Kawasaki M, Yamada K, et al. Visualization of internal carotid artery atherosclerotic plaques in symptomatic and asymptomatic patients: a comparison of optical coherence tomography and intravascular ultrasound. Am J Neuroradiol 2012;33(2):308-13. 2. Matsumoto D, Shite J, Shinke T, et al. Neointimal coverage of sirolimus-eluting stents at 6-month follow-up: evaluated by optical coherence tomography. Eur Heart J 2007;28(8):961-7. 3. 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(10): 933-9. 4. de Donato G, Setacci F, Sirignano P, et al. Optical coherence tomography after carotid stenting: rate of stent malapposition, plaque prolapse and fibrous cap rupture according to stent design. Eur J Vasc Endovasc Surg 2013;45(6):579-87. 5. Jones MR, Attizzani GF, Given CA 2nd, et al. Intravascular frequency-domain optical coherence tomography assessment of atherosclerosis and stent-vessel interactions in human carotid arteries. Am J Neuroradiol 2012;33(8):1494-1501. 6. Lopes DK, Johnson AK. Evaluation of cerebral artery perforators and the pipeline embolization device using optical coherence tomography. J NeuroInterv Surg 2012;4(4):291-4. 7. Yoshimura S, Kawasaki M, Yamada K, et al. OCT of human carotid arterial plaques. JACC Cardiovasc Imaging 2011;4(4):432-6. 8. Heck D. Results of cutting balloon angioplasty for carotid artery in-stent restenosis in six patients: description of the technique, longterm outcomes, and review of the literature. J NeuroInterv Surg 2009;1(1):48-50. 9. Mathews MS, Su J, Heidari E, et al. Neuroendovascular optical coherence tomography imaging and histological analysis. Neurosurgery 2011;69(2):430-9. 10. Prati F, Regar E, Mintz GS, et al. Expert review document on methodology, terminology, and clinical applications of optical coherence tomography: physical principles, methodology of image acquisition, and clinical application for assessment of coronary arteries and atherosclerosis. Eur Heart J 2010;31(4): 401-15. 11. Virmani R, Burke AP, Farb A, et al. Pathology of the unstable plaque. Prog Cardiovasc Dis 2002;44(5):349-56. 12. Hellings WE, Peeters W, Moll FL, et al. Composition of carotid atherosclerotic plaque is associated with cardiovascular outcome: a prognostic study. Circulation 2010;121(17):1941-50. 13. Ahmed RM, Harris JP, Anderson CS, et al. Carotid endarterectomy for symptomatic, but “haemodynamically insignificant” carotid stenosis. Eur J Vasc Endovasc Surg 2010;40(4):475-82. 14. Chen BX, Ma FY, Luo W, et al. Neointimal coverage of baremetal and sirolimus-eluting stents evaluated with optical coherence tomography. Heart 2008;94(5):566-70. 15. Standish BA, Spears J, Marotta TR, et al. Vascular wall imaging of vulnerable atherosclerotic carotid plaques: current state of the art and potential future of endovascular optical coherence tomography. Am J Neuroradiol 2012;33(9):1642-50.
Journal of Neuroimaging Vol 25 No 6 November/December 2015
ABSTRACT Optical coherence tomography (OCT) is a modern intravascular imaging modality that has the capability to provide detailed, in vivo characterization of the arterial wall and atherosclerotic plaque. The current understanding of the appearance of atherosclerotic plaque via OCT is largely based on coronary arterial studies where OCT information has been employed to guide therapeutic management and permits the immediate evaluation of percutaneous intervention. The clinical success of OCT in the coronary arteries has laid the foundation for investigation of the carotid artery and thus, stroke risk assessment. We report the novel use of OCT for tissue characterization of severe stenosis subsequent to carotid artery stenting (CAS), both before and after treatment with cutting balloon angioplasty. Keywords: Carotid stenosis, optical coherence tomography, angiography. Acceptance: Received October 6, 2014. Accepted for publication November 27, 2014. Correspondence: Address correspondence to Kristine A. Blackham, MD, Radiology Department, University Hospitals of Cleveland, Case Western Reserve University, Cleveland, OH 44106. E-mail: [email protected]. J Neuroimaging 2015;25:1044-1046. DOI: 10.1111/jon.12223
Introduction
Case Report
Optical Coherence Tomography (OCT) is an imaging modality which provides micron level tomographic images of human tissue based on the coherence of light. A near-infrared light is produced by a fiber optic system which is absorbed by red blood cells, water, lipids, and protein. OCT produces cross-sectional endoluminal images of a vessel with a 10 times greater detail than other similar imaging modalities such as intravascular ultrasound (IVUS) and utilization of both modalities has been demonstrated in coronary vessels and more recently the cervical carotid arteries.1–3 There have been increasing case reports and small series over the last few years describing the neurointerventional application of OCT imaging in the cervicocerebral vessels.4–7 The high resolution of OCT allows it to characterize native tissue, differentiate plaque composition (such as fibrous, calcified, or lipid-rich), and assess stent implantation, including intraluminal thrombus, in-stent restenosis, and plaque protrusion.7 It is a promising tool for in vivo detection of unstable thin-cap fibroatheroma, which may be a significant source for thromboembolic strokes. In this case report, we demonstrate the use of OCT in evaluating carotid stent restenosis and to characterize the tissue response to cutting balloon angioplasty. The cutting balloon is a noncompliant angioplasty balloon with longitudinally mounted blades which produce controlled microdissections in atherosclerotic plaque, thereby reducing vessel stretch, injury and risk of a neoproliferative response which otherwise could result in restenosis. This balloon has been shown to be safe, effective, and durable for carotid artery stenting.8
A 74-year-old Caucasian male with hypertension, diabetes mellitus, hyperlipidemia, coronary artery disease presented with recurrent in-stent stenosis in his left internal carotid artery (ICA) following carotid artery stenting (CAS) with a 4 × 24 mm balloon-mounted Medtronic (Minneapolis, Minnesota, USA) Driver stent. The initial CAS was performed acutely, for a symptomatic 90% stenosis, as determined by criteria used in the North American Symptomatic Carotid Endarterectomy Trial (NASCET). The postprocedure medication regimen included oral statin and dual antiplatelet therapy with 81 mg aspirin and 75 mg clopidogrel daily. Over the course of the following 17 months after CAS, the patient underwent four separate intraluminal balloon angioplasties for asymptomatic, recurrent, severe, in-stent stenosis, as detected by ultrasound. Follow-up ultrasonographic monitoring 3 months after his last treatment again demonstrated luminal narrowing >70%. An 85% luminal narrowing and flow limitation was demonstrated by catheter angiography, and an alternative evaluation and treatment method were deemed appropriate by the treating vascular neurologist and neurointerventional surgeon.
1044
Copyright
Methods The percutaneous intervention was performed according to standard practice using an .014" (.36 mm) exchange length guidewire through a 6-French shuttle sheath under systemic heparinization. Digital subtraction angiography (DSA) revealed an 85% in-stent restenosis of the proximal cervical left ICA as calculated per NASCET criteria.
◦ 2015 by the American Society of Neuroimaging C
Fig 1. (A) Preangioplasty angiogram shows 85% restenosis of left ICA stent (arrow). (B) Postcutting balloon angioplasty angiogram with residual 40% stenosis (arrow). (C) Preangioplasty axial OCT image at the site of maximal stenosis reveals severe neointimal hyperplasia. Multiple shadows can be seen arising from the intramural stent which appears as a circumferential speckled bright outline. The large shadow at 7 o’clock is from the microguidewire upon which the OCT catheter is loaded. (D) The postcutting balloon angioplasty axial OCT image demonstrates improved vessel caliber. The white arrows denote the intimal microdissections from the cutting balloon blades.
Fig 2. (A) Longitudinal OCT image through the left ICA stent reveals diffuse neointimal hyperplasia (arrows). (B) Postcutting balloon angioplasty OCT demonstrates improvement in vessel caliber. Note the unopposed portion of the stent in the carotid bulb (star).
A St. Jude Medical C7 Dragonfly intravascular OCT imaging catheter (St. Paul, Minnesota, USA) was advanced over the exchange length .014" guidewire and positioned across the stenosis. With the shuttle sheath primed with contrast, an injection through the sheath at rate of 5 mL/second for a total volume of 25 mL, was performed simultaneously with OCT imaging and biplane digital subtraction angiography over the neck (Figs 1 and 2). OCT imaging was acquired via a motorized pullback
in a retrograde fashion in order to image the artery from the distal end of the stenosis to the bifurcation. The OCT catheter was removed and a 4 mm × 1.5 cm Boston Scientific Peripheral Cutting Balloon (Natick, Massachusetts, USA) was advanced over the exchange length .014" guidewire and positioned across the area of maximal stenosis and inflated supranominally to 10 atmospheres and subsequently deflated. Improvement of the vessel caliber and distal flow was seen with a residual 40% stenosis.
Blackham et al: Characterization of Carotid Neointimal Hyperplasia
1045
Repeat OCT imaging was obtained. The patient tolerated the procedure well without any neurological complications. The patient was asymptomatic and well at 3-month follow-up.
Discussion OCT is an endovascular imaging device with tremendous potential to contribute to the knowledge of carotid plaque morphology. Similar to IVUS, OCT provides in situ images of the vascular wall with a field of view of 10 mm; allowing its use in the larger lumen of the cervical carotid artery. In contrast to a 100 µm resolution for IVUS, the resolution of OCT is 10-15 µm. This substantial difference in resolution is relevant to the detection of a thin-cap fibroatheroma, in which a thin fibrous plaque is defined as less than 65 µm. Significant microstructural details of a vessel can be visualized, such as the internal and external elastic laminae, intima, media, and adventitia. The high resolution allows for the composition of the tissue of interest to be characterized into its fibrous, collagen, lipid, and calcium components.9,10 Highrisk unstable plaques have been identified by presence of intraplaque hemorrhage, inflammatory cell infiltration, plaque ulceration, or a lipid rich core with a thin fibrous cap by histology.11,12 These plaque characteristics are associated with increased risk of clinical embolic events even in the setting of hemodyamically insignificant luminal stenosis;13 therefore, an accurate, reproducible imaging correlation of these histologic characteristics is highly sought after. In the cardiology literature, experience with OCT in the coronaries arteries has provided a wealth of knowledge regarding normal and diseased vascular wall morphology, stent placement and apposition, and in-stent tissue characteristics such as neointimal growth.14 In our case report, OCT was utilized to detail the endovascular microstructure of delayed recurrent in-stent stenosis before and after cutting balloon angioplasty. The preangioplasty angiogram demonstrates extrinsic mass effect on the lumen within the stent (Fig 1A) corresponding to homogenous soft tissue thickening on axial OCT images, consistent with neointimal hyperplasia (Fig 1C). There is resultant severe endoluminal stenosis most prominently in the mid-stent region seen best on longitudinal OCT images (Fig 2A), which also shows the proximal and distal stent tines to be incompletely apposed to the carotid wall from incorrect sizing of the stent, which is not evident on digital subtraction angiography. The posttreatment angiogram and OCT images show significant improvement in endoluminal caliber (Figs 1B, D, and 2B). Also seen are the circumferential micro dissections within the neointimal tissue corresponding to the longitudinally mounted cutting blades of the balloon (Fig 1D). Current limitations of OCT include lower tissue penetration than IVUS, which may limit complete plaque characterization especially with a large lipid rich core. OCT has a tissue penetration of 3 mm whereas IVUS has a tissue penetration of 4 to 8 mm. Other limitations include those common to any intravascular device: risk of emboli and difficulty navigating within tortuous anatomy and the associated risk-benefit ratio, which must be carefully considered with use in the cervicocerebral circulation.15
1046
Conclusion This case report demonstrates the application of OCT in the evaluation and treatment of in-stent restenosis. OCT is a promising imaging modality which may become beneficial in guiding therapeutic neurointerventional management due to its potential ability to safely characterize and classify carotid atherosclerotic plaques in vivo as well as to evaluate adequacy and outcome of treatment.
References 1. Yoshimura S, Kawasaki M, Yamada K, et al. Visualization of internal carotid artery atherosclerotic plaques in symptomatic and asymptomatic patients: a comparison of optical coherence tomography and intravascular ultrasound. Am J Neuroradiol 2012;33(2):308-13. 2. Matsumoto D, Shite J, Shinke T, et al. Neointimal coverage of sirolimus-eluting stents at 6-month follow-up: evaluated by optical coherence tomography. Eur Heart J 2007;28(8):961-7. 3. 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(10): 933-9. 4. de Donato G, Setacci F, Sirignano P, et al. Optical coherence tomography after carotid stenting: rate of stent malapposition, plaque prolapse and fibrous cap rupture according to stent design. Eur J Vasc Endovasc Surg 2013;45(6):579-87. 5. Jones MR, Attizzani GF, Given CA 2nd, et al. Intravascular frequency-domain optical coherence tomography assessment of atherosclerosis and stent-vessel interactions in human carotid arteries. Am J Neuroradiol 2012;33(8):1494-1501. 6. Lopes DK, Johnson AK. Evaluation of cerebral artery perforators and the pipeline embolization device using optical coherence tomography. J NeuroInterv Surg 2012;4(4):291-4. 7. Yoshimura S, Kawasaki M, Yamada K, et al. OCT of human carotid arterial plaques. JACC Cardiovasc Imaging 2011;4(4):432-6. 8. Heck D. Results of cutting balloon angioplasty for carotid artery in-stent restenosis in six patients: description of the technique, longterm outcomes, and review of the literature. J NeuroInterv Surg 2009;1(1):48-50. 9. Mathews MS, Su J, Heidari E, et al. Neuroendovascular optical coherence tomography imaging and histological analysis. Neurosurgery 2011;69(2):430-9. 10. Prati F, Regar E, Mintz GS, et al. Expert review document on methodology, terminology, and clinical applications of optical coherence tomography: physical principles, methodology of image acquisition, and clinical application for assessment of coronary arteries and atherosclerosis. Eur Heart J 2010;31(4): 401-15. 11. Virmani R, Burke AP, Farb A, et al. Pathology of the unstable plaque. Prog Cardiovasc Dis 2002;44(5):349-56. 12. Hellings WE, Peeters W, Moll FL, et al. Composition of carotid atherosclerotic plaque is associated with cardiovascular outcome: a prognostic study. Circulation 2010;121(17):1941-50. 13. Ahmed RM, Harris JP, Anderson CS, et al. Carotid endarterectomy for symptomatic, but “haemodynamically insignificant” carotid stenosis. Eur J Vasc Endovasc Surg 2010;40(4):475-82. 14. Chen BX, Ma FY, Luo W, et al. Neointimal coverage of baremetal and sirolimus-eluting stents evaluated with optical coherence tomography. Heart 2008;94(5):566-70. 15. Standish BA, Spears J, Marotta TR, et al. Vascular wall imaging of vulnerable atherosclerotic carotid plaques: current state of the art and potential future of endovascular optical coherence tomography. Am J Neuroradiol 2012;33(9):1642-50.
Journal of Neuroimaging Vol 25 No 6 November/December 2015
