Noninvasive Detection of Plaque Instability with Use of Radiolabeled Annexin A5 in Patients with Carotid-Artery Atherosclerosis
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《新英格兰医药杂志》
To the Editor: Although progressive stenosis of the arterial lumen constitutes the basis for ischemic symptoms in atherosclerotic vascular disease, acute vascular events are for the most part associated with instability of the plaque and formation of an occlusive thrombus.1 Apoptosis of smooth-muscle cells and of macrophages in the plaque has been causally linked to plaque rupture.2 Therefore, we reasoned that noninvasive detection of apoptosis could be used to identify instability of atherosclerotic plaques. We have recently demonstrated the feasibility of the noninvasive detection of apoptosis, using technetium-99m–labeled annexin A5 (previously referred to as annexin V), in experimental atherosclerotic lesions.3 Annexin A5 is a plasma protein with a strong affinity for phosphatidylserine expressed by apoptotic cells.4,5
In a pilot clinical study, we evaluated four patients with a recent or remote history of transient ischemic attack, using technetium-99m–labeled annexin A5, one to three days before carotid endarterectomy. Six hours after the infusion of 600 to 800 MBq of radiolabeled annexin A5, gamma images were obtained with a single-photon-emission computed tomographic camera (MultiSPECT, Siemens). In two patients who had had transient ischemic attacks three and four days before imaging, uptake of annexin A5 (Figure 1A) was evident in the area of the ultrasonically verified carotid-artery lesion. Annexin A5 uptake was observed in the left carotid artery in Patient 1 and in the right carotid artery in Patient 2. No evidence of uptake of radiolabeled annexin A5 was observed on the contralateral side in either patient; however, Doppler ultrasonography had previously demonstrated severe stenosis of the right carotid artery in Patient 1. Histopathological characterization of the endarterectomy specimens revealed morphologic features characteristic of unstable plaque, including substantial macrophage infiltration and intraplaque hemorrhage. Immunohistochemical analysis demonstrated specific binding of annexin A5 to macrophage cell membranes (in 15.7 percent of cells within the lesion) (Figure 1B).
Figure 1. Images of Unstable Atherosclerotic Carotid-Artery Lesions Obtained with Radiolabeled Annexin A5.
Panel A shows transverse and coronal views obtained by single-photon-emission computed tomography (SPECT) in Patient 1, who had a left-sided transient ischemic attack (TIA) three days before imaging. Although this patient had clinically significant stenosis of both carotid arteries, uptake of radiolabeled annexin A5 is evident only in the culprit lesion (arrows). Histopathological analysis of an endarterectomy specimen from Patient 1 (Panel B; polyclonal rabbit anti–annexin A5 antibody, x400) shows substantial infiltration of macrophages into the neointima, with extensive binding of annexin A5 (brown). In contrast, SPECT images of Patient 3 (Panel C), who had had a right-sided TIA three months before imaging, do not show evidence of annexin A5 uptake in the carotid-artery region on either side. Doppler ultrasonography revealed a clinically significant obstructive lesion on the affected side. Histopathological analysis of an endarterectomy specimen from Patient 3 (Panel D; polyclonal rabbit anti–annexin A5 antibody, x400) shows a lesion rich in smooth-muscle cells, with negligible binding of annexin A5. ANT denotes anterior, and L left.
The other two patients, who had had transient ischemic attacks three months before imaging, did not have evidence of annexin A5 uptake in the carotid artery (Figure 1C). Both patients had severe carotid lesions and had been treated with statins and antiplatelet agents since the acute event. Examination of endarterectomy specimens from these patients showed stable plaque characteristics, with minimal macrophage infiltration and no intraplaque hemorrhage; negligible annexin binding was evident on immunohistochemical analysis (in 1.7 percent of cells within the lesion) (Figure 1D).
These data indicate that molecular imaging with the use of technetium-99m–labeled annexin A5 may be a new method for assessing plaque instability and identifying patients at risk for acute vascular events. Prospective outcome studies in a larger group of patients are needed to establish the value of this imaging method, and sequential studies may be needed to test the efficacy of interventions to stabilize plaques, as with statin drugs.
Bas L.J.H. Kietselaer, M.D.
Chris P.M. Reutelingsperger, Ph.D.
Guido A.K. Heidendal, M.D., Ph.D.
Mat J.A.P. Daemen, M.D., Ph.D.
Werner H. Mess, Ph.D.
Leonard Hofstra, M.D., Ph.D.
University Hospital of Maastricht
6202 AZ, Maastricht, the Netherlands
l.hofstra@cardio.azm.nl
Jagat Narula, M.D., Ph.D.
University of California–Irvine Medical Center
Orange, CA 92868-4080
References
Burke AP, Farb A, Malcom GT, Liang YH, Smialek J, Virmani R. Coronary risk factors and plaque morphology in men with coronary disease who died suddenly. N Engl J Med 1997;336:1276-1282.
Kolodgie FD, Narula J, Burke AP, et al. Localization of apoptotic macrophages at the site of plaque rupture in sudden coronary death. Am J Pathol 2000;157:1259-1268.
Kolodgie FD, Petrov A, Virmani R, et al. Targeting of apoptotic macrophages and experimental atheroma with radiolabeled annexin-V: a technique with potential for noninvasive imaging of vulnerable plaque. Circulation 2003;108:3134-3139.
Hofstra L, Liem IH, Dumont EA, et al. Visualisation of cell death in vivo in patients with acute myocardial infarction. Lancet 2000;356:209-212.
Narula J, Acio ER, Narula N, et al. Annexin-V imaging for noninvasive detection of cardiac allograft rejection. Nat Med 2001;7:1347-1352.
In a pilot clinical study, we evaluated four patients with a recent or remote history of transient ischemic attack, using technetium-99m–labeled annexin A5, one to three days before carotid endarterectomy. Six hours after the infusion of 600 to 800 MBq of radiolabeled annexin A5, gamma images were obtained with a single-photon-emission computed tomographic camera (MultiSPECT, Siemens). In two patients who had had transient ischemic attacks three and four days before imaging, uptake of annexin A5 (Figure 1A) was evident in the area of the ultrasonically verified carotid-artery lesion. Annexin A5 uptake was observed in the left carotid artery in Patient 1 and in the right carotid artery in Patient 2. No evidence of uptake of radiolabeled annexin A5 was observed on the contralateral side in either patient; however, Doppler ultrasonography had previously demonstrated severe stenosis of the right carotid artery in Patient 1. Histopathological characterization of the endarterectomy specimens revealed morphologic features characteristic of unstable plaque, including substantial macrophage infiltration and intraplaque hemorrhage. Immunohistochemical analysis demonstrated specific binding of annexin A5 to macrophage cell membranes (in 15.7 percent of cells within the lesion) (Figure 1B).
Figure 1. Images of Unstable Atherosclerotic Carotid-Artery Lesions Obtained with Radiolabeled Annexin A5.
Panel A shows transverse and coronal views obtained by single-photon-emission computed tomography (SPECT) in Patient 1, who had a left-sided transient ischemic attack (TIA) three days before imaging. Although this patient had clinically significant stenosis of both carotid arteries, uptake of radiolabeled annexin A5 is evident only in the culprit lesion (arrows). Histopathological analysis of an endarterectomy specimen from Patient 1 (Panel B; polyclonal rabbit anti–annexin A5 antibody, x400) shows substantial infiltration of macrophages into the neointima, with extensive binding of annexin A5 (brown). In contrast, SPECT images of Patient 3 (Panel C), who had had a right-sided TIA three months before imaging, do not show evidence of annexin A5 uptake in the carotid-artery region on either side. Doppler ultrasonography revealed a clinically significant obstructive lesion on the affected side. Histopathological analysis of an endarterectomy specimen from Patient 3 (Panel D; polyclonal rabbit anti–annexin A5 antibody, x400) shows a lesion rich in smooth-muscle cells, with negligible binding of annexin A5. ANT denotes anterior, and L left.
The other two patients, who had had transient ischemic attacks three months before imaging, did not have evidence of annexin A5 uptake in the carotid artery (Figure 1C). Both patients had severe carotid lesions and had been treated with statins and antiplatelet agents since the acute event. Examination of endarterectomy specimens from these patients showed stable plaque characteristics, with minimal macrophage infiltration and no intraplaque hemorrhage; negligible annexin binding was evident on immunohistochemical analysis (in 1.7 percent of cells within the lesion) (Figure 1D).
These data indicate that molecular imaging with the use of technetium-99m–labeled annexin A5 may be a new method for assessing plaque instability and identifying patients at risk for acute vascular events. Prospective outcome studies in a larger group of patients are needed to establish the value of this imaging method, and sequential studies may be needed to test the efficacy of interventions to stabilize plaques, as with statin drugs.
Bas L.J.H. Kietselaer, M.D.
Chris P.M. Reutelingsperger, Ph.D.
Guido A.K. Heidendal, M.D., Ph.D.
Mat J.A.P. Daemen, M.D., Ph.D.
Werner H. Mess, Ph.D.
Leonard Hofstra, M.D., Ph.D.
University Hospital of Maastricht
6202 AZ, Maastricht, the Netherlands
l.hofstra@cardio.azm.nl
Jagat Narula, M.D., Ph.D.
University of California–Irvine Medical Center
Orange, CA 92868-4080
References
Burke AP, Farb A, Malcom GT, Liang YH, Smialek J, Virmani R. Coronary risk factors and plaque morphology in men with coronary disease who died suddenly. N Engl J Med 1997;336:1276-1282.
Kolodgie FD, Narula J, Burke AP, et al. Localization of apoptotic macrophages at the site of plaque rupture in sudden coronary death. Am J Pathol 2000;157:1259-1268.
Kolodgie FD, Petrov A, Virmani R, et al. Targeting of apoptotic macrophages and experimental atheroma with radiolabeled annexin-V: a technique with potential for noninvasive imaging of vulnerable plaque. Circulation 2003;108:3134-3139.
Hofstra L, Liem IH, Dumont EA, et al. Visualisation of cell death in vivo in patients with acute myocardial infarction. Lancet 2000;356:209-212.
Narula J, Acio ER, Narula N, et al. Annexin-V imaging for noninvasive detection of cardiac allograft rejection. Nat Med 2001;7:1347-1352.