Noninvasive in vivo measurement of vascular inflammation with F-18 fluorodeoxyglucose positron emission tomography

BACKGROUND: Fluorine 18 fluorodeoxyglucose (FDG) has been shown to accumulate in inflamed tissues. However, it is not known whether vascular inflammation can be measured noninvasively. The aim of this study was to test the hypothesis that vascular inflammation can be measured noninvasively by use of positron emission tomography (PET) with FDG. METHODS AND RESULTS: Inflamed atherosclerotic lesions were induced in 9 male New Zealand white rabbits via balloon injury of the aortoiliac arterial segment and exposure to a high cholesterol diet. Ten rabbits fed standard chow served as controls. Three to six months after balloon injury, the rabbits were injected with FDG (1 mCi/kg), after which aortic uptake of FDG was assessed (3 hours after injection). Biodistribution of FDG activity within aortic segments was obtained by use of standard well gamma counting. FDG uptake was also determined noninvasively in a subset of 6 live atherosclerotic rabbits and 5 normal rabbits, via PET imaging and measurement of standardized uptake values over the abdominal aorta. Plaque macrophage density and smooth muscle cell density were determined by planimetric analysis of RAM-11 and smooth muscle actin staining, respectively. Biodistribution of FDG within nontarget organs was similar between atherosclerotic and control rabbits. However, well counter measurements of FDG uptake were significantly higher within atherosclerotic aortas compared with control aortas (P < .001). Within the upper abdominal aorta of the atherosclerotic group (area of greatest plaque formation), there was an approximately 19-fold increase in FDG uptake compared with controls (108.9 +/- 55.6 percent injected dose [%ID]/g x 10(3) vs 5.7 +/- 1.2 %ID/g x 10(3) [mean +/- SEM], P < .001). In parallel with these findings, FDG uptake, as determined by PET, was higher in atherosclerotic aortas (standardized uptake value for atherosclerotic aortas vs control aortas, 0.68 +/- 0.06 vs 0.13 +/- 0.01; P < .001). Moreover, macrophage density, assessed histologically, correlated with noninvasive (PET) measurements of FDG uptake (r = 0.93, P < .0001). In contrast to this finding, FDG uptake did not correlate with either aortic wall thickness or smooth muscle cell staining of the specimens. CONCLUSION: These data show that FDG accumulates in macrophage-rich atherosclerotic plaques and demonstrate that vascular macrophage activity can be quantified noninvasively with FDG-PET. As such, measurement of vascular FDG uptake with PET holds promise for the noninvasive characterization of vascular inflammation.     

Superparamagnetic iron oxide-enhanced MRI of atherosclerotic plaques in Watanabe hereditable hyperlipidemic rabbits

RATIONALE AND OBJECTIVES: Inflammatory atherosclerotic plaques are characterized by increased endothelial permeability and multiple macrophages. Blood-pool MRI contrast agents like superparamagnetic iron oxide (SPIO) have an affinity for the monocyte-macrophage system and thus, may label inflammatory plaques. The objective was to demonstrate SPIO uptake in plaques of atherosclerotic rabbits by MRI and histology. METHODS: Aortas of anesthetized Watanabe hereditable hyperlipidemic rabbits were studied with a moderately T2*-weighted gradient-echo sequence at 1.5 T. Four groups of five animals each were studied: (1) without ultrasmall SPIO (carboxydextran coating; particle size, 25 nm; estimated plasma half-life, 6 hours) or with imaging after intravenous injection of SPIO at a dose (micromol Fe/kg) and postcontrast time delay (hours) of 50/8 (2), 50/24 (3), or 200/48 (4). In vivo MRI was compared with corresponding ex vivo histological iron stains. RESULTS: Animals receiving 200 micromol Fe/kg demonstrated areas of focal signal loss clearly confined to the aortic wall on a mean of 24 +/- 9 (31% +/- 11%) of 76 +/- 5 images compared with 0 +/- 0 of 76 +/- 5 images in controls (P = 0.009). The number of images with this finding in groups 2 and 3 was not significantly different compared with controls. By microscopy, SPIO-iron was seen in the endothelial cells and subendothelial intimal macrophages of atherosclerosis-prone aortic wall segments. Atherosclerotic lesions demonstrating iron uptake also showed a high macrophage content. CONCLUSIONS: SPIO accumulates in aortic plaques of atherosclerotic rabbits, producing a characteristic MRI finding. As SPIO accumulates in plaques with increased endothelial permeability and a high macrophage content, two established features of plaque inflammation, it may have a potential for noninvasive assessment of inflammatory atherosclerotic plaques.     

动脉粥样硬化斑块MRI和近红外分子影像的实验研究

目的 探讨7.0 T MRI和近红外荧光成像(NIRF)检测动脉粥样硬化(AS)斑块的可行性.方法 对14周龄ApoE-/-小鼠按高脂饮食喂养20周,建立AS模型,以正常C57BL/6小鼠作为对照.MRI实验中,5只ApoE-/-小鼠及5只C57小鼠经尾静脉注入超微超顺磁性氧化铁颗粒(USPIO)前及36 h后分别行7.0 T MRI.NIRF实验中,10只ApoE-/-小鼠和4只C57小鼠经尾静脉注入抗氧化修饰的低密度脂蛋白(oxLDL)抗体-NIR 797(抗-oxLDL-抗体-NIR 797)近红外探针,4只ApoE-/-小鼠经尾静脉注入非特异性IgG-NIR 797,另4只ApoE-/-小鼠注入PBS,24h后分别行NIRF.用SPSS17.0软件对计量数据行独立样本t检验和单因素方差分析.结果 ApoE-/-小鼠注入USPIO 36 h后,在T2WI上腹主动脉斑块信号较注射前减低,相对信号强度分别为0.70±0.04和1.28±0.06,差异有统计学意义(t =3.376,P＜O.05),信号改变率达(-56.58±4.25)％;普鲁士蓝染色证实斑块内有铁沉积.注入抗-oxLDL-抗体-NIR 797 24 h后,ApoE-/-小鼠主动脉离体NIRF示强荧光信号(SNR为42.51 ±5.24)聚集于主动脉根、主动脉弓及降主动脉起始段,而非特异性IgG-NIR 797组(19.58±3.06)、PBS组(4.19±0.82)及对照C57小鼠(2.29±1.11)仅见较弱荧光信号,与靶向探针组比较差异有统计学意义(F =25.104,P＜0.05).斑块油红O染色与NIRF阳性面积分别为(41.69 ±5.29)％和(39.45±5.35)％,两者呈线性相关(r=0.738,P＜0.05,n=8),免疫荧光证实斑块内oxLDL的表达与巨噬细胞共区域.结论 应用新型分子影像探针在7.0 T MRI和NIRF上可有效检测AS斑块,有助于鉴别高危斑块,可为AS多模式成像提供依据.     

Evaluation of neovessels in atherosclerotic plaques of rabbits using an albumin-binding intravascular contrast agent and MRI

Purpose

To test whether B‐22956/1, a novel intravascular contrast agent with a high affinity to serum albumin (Bracco Imaging SpA.), allowed quantifying neovessel and macrophage density in atherosclerotic plaques of rabbits using MRI.

Materials and Methods

A T1‐weighted MRI of the aorta was acquired in 10 rabbits (7 atherosclerotic and 3 control rabbits) before and up to 2 h after intravenous injection of 100 μmol/kg of Gd‐DTPA or 75 μmol/kg of B‐22956/1. Plaque enhancement was measured at different time points. Immunohistochemistry was performed using anti‐CD 31 antibodies and anti‐RAM 11 antibodies to correlate to neovessel and macrophage density, respectively.

Results

MRI showed a significant plaque enhancement 2 h after B‐22956/1 versus Gd‐DTPA in the atherosclerotic group (39.75% versus 9.5%; P < 0.0001. Early atherosclerotic plaques (n = 146) enhancement positively correlates with neovessel density on corresponding histological sections (r = 0.42; P < 0.01). Enhancement of atherosclerotic plaques 2 h after injection of B‐22956/1 correlated with macrophage density (r = 0.71; P < 0.01).

Conclusion

Enhancement of atherosclerotic plaques with MRI correlated with neovessel density at early time points after the injection of B‐22956/1 and with macrophage density, at later time points. Hence, B‐22956/1‐enhanced MRI represents a promising imaging technique for the identification of “high‐risk” plaques. J. Magn. Reson. Imaging 2008;27:1406–1411. © 2008 Wiley‐Liss, Inc.     

Uptake of inflammatory cell marker [<Superscript>11</Superscript>C]PK11195 into mouse atherosclerotic plaques

Purpose  The ligand [¹¹C]PK11195 binds with high affinity and selectivity to peripheral benzodiazepine receptor, expressed in high amounts in macrophages. In humans, [¹¹C]PK11195 has been used successfully for the in vivo imaging of inflammatory processes of brain tissue. The purpose of this study was to explore the feasibility of [¹¹C]PK11195 in imaging inflammation in the atherosclerotic plaques. Methods  The presence of PK11195 binding sites in the atherosclerotic plaques was verified by examining the in vitro binding of [³H]PK11195 onto mouse aortic sections. Uptake of intravenously administered [¹¹C]PK11195 was studied ex vivo in excised tissue samples and aortic sections of a LDLR/ApoB48 atherosclerotic mice. Accumulation of the tracer was compared between the atherosclerotic plaques and non-atherosclerotic arterial sites by autoradiography and histological analyses. Results  The [³H]PK11195 was found to bind to both the atherosclerotic plaques and the healthy wall. The autoradiography analysis revealed that the uptake of [¹¹C]PK11195 to inflamed regions in plaques was more prominent (p = 0.011) than to non-inflamed plaque regions, but overall it was not higher than the uptake to the healthy vessel wall. Also, the accumulation of ¹¹C radioactivity into the aorta of the atherosclerotic mice was not increased compared to the healthy control mice. Conclusions  Our results indicate that the uptake of [¹¹C]PK11195 is higher in inflamed atherosclerotic plaques containing a large number of inflammatory cells than in the non-inflamed plaques. However, the tracer uptake to other structures of the artery wall was also prominent and may limit the use of [¹¹C]PK11195 in clinical imaging of atherosclerotic plaques.     

Fluorescence reflectance imaging of macrophage-rich atherosclerotic plaques using an alphavbeta3 integrin-targeted fluorochrome

Macrophages play an important role during the development and progression of atherosclerotic plaques. alphavbeta3 integrins are highly expressed by macrophages; thus, targeting alphavbeta3 may allow targeting of culprit macrophage-loaded atherosclerotic lesions in vivo. METHODS: An alphavbeta3-targeted Arg-Gly-Asp (RGD) peptide was labeled with the cyanine 5.5 (Cy 5.5) dye and applied to image atherosclerotic plaques in apolipoprotein E-deficient mice. RESULTS: The peptide-dye conjugate binds to alphavbeta3 integrin-positive RAW264.7 macrophages with high affinity. Competition experiments confirmed binding specificity of the probe. A significant fluorochrome accumulation in atherosclerotic plaques was demonstrated 24 h after injection by fluorescence reflectance imaging, which was blocked with high efficiency by competition with the unlabeled peptide. Conversely, the nonconjugated dye revealed only a minor fluorescence signal in the plaques. Fluorescence microscopy revealed colocalization of the probe with macrophages in the plaque of a mouse model for accelerated atherosclerosis, which was corroborated in human carotid artery specimens. In addition to macrophage-associated signals, binding of the probe to the neointima or elastica of the arteries was observed. CONCLUSION: RGD-Cy 5.5, combined with near-infrared optical imaging methods, allows the specific imaging of alphavbeta3-integrin expression on macrophages recruited to vascular lesions and may serve to estimate macrophage-bound inflammatory activity of atherosclerotic lesions.     

18F-FDG PET and intravascular ultrasonography (IVUS) images compared with histology of atherosclerotic plaques: 18F-FDG accumulates in foamy macrophages

Purpose

Intravascular ultrasonography (IVUS) and ¹⁸F-FDG PET have been used to evaluate the efficacy of antiatherosclerosis drugs. These two modalities image different characteristics of atherosclerotic plaques, and a comparison of IVUS and PET images with histology has not been performed. The aim of this study was to align IVUS and PET images using anatomic landmarks in Watanabe heritable hyperlipidaemic (WHHL) rabbits, enabling comparison of their depiction of aortic atherosclerosis. Cellular ¹⁸F-FDG localization was evaluated by ³H-FDG microautoradiography (micro-ARG).

Methods

A total of 19 WHHL rabbits (7 months of age) were divided into three groups: baseline (n?=?6), 3 months (n?=?4), and 6 months (n?=?9). PET, IVUS and histological images of the same aortic segments were analysed. Infiltration by foamy macrophages was scored from 0 to IV using haematoxylin and eosin (H&E) and antimacrophage immunohistochemical staining, and compared with ³H-FDG micro-ARG findings in two additional WHHL rabbits.

Results

IVUS images did not identify foamy macrophage deposition but revealed the area of intimal lesions (r?=?0.87). ¹⁸F-FDG PET revealed foamy macrophage distribution in the plaques. The intensity of ¹⁸F-FDG uptake was correlated positively with the degree of foamy macrophage infiltration. Micro-ARG showed identical ³H-FDG accumulation in the foamy macrophages surrounding the lipid core of the plaques.

Conclusion

F-FDG PET localized and quantified the degree of infiltration of foamy macrophages in atherosclerotic lesions. IVUS defined the size of lesions. ¹⁸F-FDG PET is a promising imaging technique for evaluating atherosclerosis and for monitoring changes in the composition of atherosclerotic plaques affecting their stability.     

Time-to-time correlation of high-risk atherosclerotic lesions identified with [18F]-FDG-PET/CT

Objective  It has been shown that [¹⁸F]-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) can identify macrophage-rich high-risk atherosclerotic plaques in animal models as well as in patients with atherosclerotic plaques in the carotid arteries. The development of inflamed macrophage-rich plaques over time is not well known. This study was performed to determine the variability of such FDG-accumulating plaques between consecutive PET/CT examinations. Methods  Twenty-eight patients who underwent two whole-body FDG-PET/CT examinations within 7 months for malignant diseases were re-evaluated for atherosclerotic lesions in major arterial segments. The plaques were identified as active, inactive, or mixed depending on their appearance on PET and CT. Every identified plaque was compared with that of the other examination to evaluate the time-to-time correlation. Results  The time-to-time correlation was close to 100% for calcified inactive plaques and about 50% for FDG-accumulating active plaques, with a high consistency between all examined arterial segments in this material. Conclusions  A large proportion of FDG-accumulating plaques can be identified on consecutive FDG-PET/CT examinations within 7 months.     

(18)F-FDG accumulation in atherosclerotic plaques: immunohistochemical and PET imaging study.

The rupture of atherosclerotic plaques and the subsequent formation of thrombi are the main factors responsible for myocardial and cerebral infarctions. Thus, the detection of vulnerable plaques in atherosclerotic lesions is a desirable goal, and attempts to image these plaques with (18)F-FDG have been made. In the present study, the relationship between the accumulation of (18)F-FDG and the biologic characteristics of atherosclerotic lesions was investigated. Furthermore, PET imaging of vulnerable plaques was performed with an animal model of atherosclerosis, Watanabe heritable hyperlipidemic (WHHL) rabbits. METHODS: WHHL (n = 11) and control (n = 3) rabbits were injected intravenously with (18)F-FDG, and the thoracic and abdominal aortas were removed 4 h after injection. The accumulated radioactivity was measured, and the number of macrophages and the intimal area were investigated by examination of stained sections. PET and CT images were also acquired at 210 min after injection of the radiotracer. RESULTS: (18)F-FDG accumulated to a significantly higher level in the aortas of the WHHL rabbits (mean +/- SD differential uptake ratio [DUR], 1.47 +/- 0.90) than in those of the control rabbits (DUR, 0.44 +/- 0.15); DUR was calculated as (tissue activity/tissue weight)/(injected radiotracer activity/animal body weight), with activities given in becquerels and weights given in kilograms. (18)F-FDG uptake and the number of macrophages were strongly correlated in the atherosclerotic lesions of the WHHL rabbits (R = 0.81). In the PET analysis, intense (18)F-FDG radioactivity was detected in the aortas of the WHHL rabbits, whereas little radioactivity was seen in the control rabbits. CONCLUSION: The results suggest that macrophages are responsible for the accumulation of (18)F-FDG in atherosclerotic lesions. Because vulnerable plaques are rich in macrophages, (18)F-FDG imaging should be useful for the selective detection of such plaques.     

Noninvasive localization of human atherosclerotic lesions with indium 111-labeled monoclonal Z2D3 antibody specific for proliferating smooth muscle cells

Background  Targeting exclusive antigens in atherosclerotic plaques with antibodies may provide a noninvasive means to detect rapidly proliferative atherosclerotic lesions. ¹¹¹In-labeled negative charge-modified Z2D3 F(ab′)₂ (Z2D3) specific for an antigen expressed exclusively by proliferating smooth muscle cells has been shown to accumulate in rabbit atherosclerotic plaques. Methods  The safety, biodistribution, accumulation, and elimination of Z2D3 were assessed in 11 patients who were candidates for carotid endarterectomy. The presence of atheromas in these patients was confirmed by angiography and Doppler ultrasound. Z2D3 (250 μg) labeled with 5 mCi of ¹¹¹In was administered by slow intravenous injection. Planar and single photon emission computed tomography (SPECT) images were obtained 4, 24, 48, and 72 hours later. Carotid endarterectomy was performed and the surgical specimens were imaged, weighed, gamma-counted, and analyzed by immunostaining. Results  Uptake of Z2D3 at the site of the carotid plaques was observed in the planar and SPECT views at 4 hours in all subjects. In addition, antibody uptake was noted in the contralateral vessel in 5 subjects. SPECT images identified the atherosclerotic plaques with focal uptake. The antibody uptake corresponded with the angiographic location of the disease. Immunohistochemical studies of the endarterectomy specimens confirmed the localization of Z2D3 into the plaque areas containing smooth muscle cells. Adverse drug reactions were not observed. Conclusion  This study demonstrates the feasibility of targeting atherosclerotic lesions with negative charge-modified antibody. It also proposes the possibility of selective identification of various components of atherosclerotic plaque, which may contribute to determining strategies of intervention in future.     

Radiolabeled Monocyte Chemotactic Protein 1 for the detection of inflammation in experimental atherosclerosis.

Chemotactic peptides, such as Monocyte Chemotactic Protein 1 (MCP-1), play a key role in transendothelial migration of mononuclear cells during the development and progression of atherosclerotic disease. Because atherosclerotic plaques that are precursors of acute coronary events harbor abundant macrophage infiltration, we hypothesized that the detection of a high concentration of MCP-1 receptors on inflammatory cells should noninvasively identify vulnerable plaques. METHODS: Atherosclerotic lesions were induced by balloon deendothelialization of the abdominal aorta, which was followed by a 0.5% cholesterol diet for 16 wk in 7 New Zealand White rabbits; 5 unmanipulated rabbits, fed normal chow for 16 wk, were used as controls. Radionuclide imaging was performed immediately after intravenous (99m)Tc-labeled MCP-1 administration and 3 h later. At the end of imaging session, aortas were explanted and submitted for estimation of quantitative MCP-1 uptake (in percentage injected dose per gram, %ID/g) and pathologic characterization. RESULTS: Atherosclerotic lesions were clearly visible in all hyperlipidemic animal gamma-imaging. No tracer uptake was seen in the control rabbits. The mean quantitative MCP-1 uptake in atherosclerotic lesions was 4-fold higher than that of the aortic specimens from the control rabbits (0.065 +/- 0.005 vs. 0.016 +/- 0.006; P < 0.0001). Histology confirmed a strong correlation between MCP-1 uptake and the number of macrophages in American Heart Association type II-IV lesions (r = 0.87, P < 0.0001). CONCLUSION: Noninvasive radionuclide imaging of inflammation is feasible by MCP-1 in experimentally induced atherosclerosis. It is proposed that detection of the extent of inflammation in advanced atherosclerotic plaques may allow identification of unstable plaques.     

MRI study of atherosclerotic plaque progression using ultrasmall superparamagnetic iron oxide in Watanabe heritable hyperlipidemic rabbits

Objective:

The purpose of this study was to evaluate plaque progression by using MRI with ultrasmall superparamagnetic iron oxide (USPIO) and by histopathological studies.

Methods:

We divided 12 Watanabe heritable hyperlipidemic (WHHL) rabbits into 4 groups based on their age (3, 9, 14 and 26 months) and injected them intravenously with 0.8 mmol (Fe) kg⁻¹ of USPIO (size, 32 nm; concentration, 15 mg dl⁻¹). On the fifth post-injection day, they were again given an intravenous injection with 40 μmol kg⁻¹ of the same USPIO, and MR angiography (MRA) was performed. The signal-to-noise ratio (SNR) in regions of interest in the wall of the upper abdominal aorta was calculated on coronal images. Specimens from the same level of the aorta were subjected to iron staining and RAM-11 immunostaining and used for histopathological study. For statistical analysis of the MRA and histopathological findings, we used analysis of variance [Tukey''s honest significant difference (HSD) test].

Results:

In 9-month-old rabbits, the SNR was significantly lower than in rabbits of the other ages (p < 0.01), and the area of RAM-11 (DAKO Corporation, Glostrup, Denmark) and iron uptake in the aortic wall was significantly larger (RAM-11, p < 0.01; iron, p < 0.05). These areas were the smallest in 3-month-old rabbits.

Conclusion:

Histopathologically, the number of macrophages was the greatest in 9-month-old rabbits. Our findings indicate that the SNR on MRI scans reflects the number of macrophages in the aortic wall of WHHL rabbits.

Advances in knowledge:

USPIO-enhanced MRI visualized the accumulation of macrophages in early atherosclerotic plaques of WHHL rabbits in the course of natural progression.     

Molecular imaging of atherosclerotic plaques with technetium-99m-labelled antisense oligonucleotides

Purpose The purpose of this study was to visualise experimental atherosclerotic lesions using radiolabelled antisense oligonucleotides (ASONs).Methods Atherosclerosis was induced in New Zealand White rabbits fed 1% cholesterol for approximately 60 days. In vivo and ex vivo imaging was performed in atherosclerotic rabbits and normal control rabbits after i.v. injection of 92.5±18.5 MBq ^99mTc-labelled ASON or ^99mTc-labelled sense oligonucleotides. Immediately after the in vivo imaging, the animals were sacrificed and ex vivo imaging of the aortic specimens was performed. Biodistribution of radiolabelled c-myc ASON was evaluated in vivo in atherosclerotic rabbits.Results Planar imaging revealed accumulation of ^99mTc-labelled c-myc ASON in atherosclerotic lesions along the artery wall. Ex vivo imaging further demonstrated that the area of activity accumulation matched the area of atherosclerotic lesions. In contrast, no atherosclerotic lesions were found in the vessel wall and no positive imaging results were obtained in animals of the control group.Conclusion This molecular imaging approach has potential for non-invasive imaging of atherosclerotic plaques at an early stage.     

Evaluation of the early enhancement of coronary atherosclerotic plaque by contrast-enhanced MR angiography

Purpose

To evaluate the early enhancement of coronary atherosclerotic plaque using contrast-enhanced MR angiography (CE-MRA) and investigate the association between unstable angina pectoris (UAP) and early enhancement of the plaque.

Methods

Forty-one patients presenting with angina pectoris and demonstrating single-vessel disease with non-calcified plaque and significant coronary stenosis (≥50%) on CTA were consecutively recruited for coronary CE-MRA. Contrast-to-noise ratio of the culprit plaque guided by CTA was measured on a cross-sectional multi-planar reconstruction image of the plaque on both pre- and post-CE-MRA. A 50% increasing of CNR was defined as plaque enhancement. The association between early enhancement of the plaques and UAP was analyzed.

Results

Thirty-seven non-calcified plaques with significant coronary stenosis were detected in the 37 patients on MRA. 4 subjects were excluded because coronary atherosclerotic plaques were inadequate for identification on MRA. Of the 37 patients, 18 patients had UAP and other 19 patients presented stable angina pectoris (SAP). Of the 37 plaques on CE-MRA, 13 and 24 plaques presented early enhancement and no enhancement, respectively. Of the 13 early-enhanced plaques, 11 (85%) and 2 (15%) were found in the patients with UAP and SAP, respectively (p < 0.01). Of the 37 patients, 11 (61%) with UAP and 2 (11%) with SAP had early-enhanced plaques, respectively (p < 0.01).

Conclusion

CE-MRA allows detection of early enhancement of coronary atherosclerotic plaque. The early enhancement is common in unstable angina and could be a sign of vulnerability.     

激光诱导荧光光谱区分正常和斑块动脉及对其生物学机制的研究

采用３３７ｎｍＮ２激光诱导动脉荧光，以荧光光谱区分粥样硬化斑块和正常动脉壁的阳性率８４％，阴性率１００％，正确率８９．５％。弹性蛋白和胶原蛋白是动脉的主要荧光物质。弹性蛋白是构成正常动脉荧光光谱的主要成分。胶原蛋白增生导致粥样硬化斑块的荧光光谱异于正常动脉。钙和胆固醇也可能影响粥样硬化斑块的荧光光谱。     

Acetylated low-density lipoprotein-encapsulated cholesteryl 1,3-diiopanoate glyceryl ether for the detection of atherosclerosis in rabbits.

A cholesteryl ester analog, cholesteryl 1,3-diiopanoate glyceryl ether (C2I), was synthesized and investigated for its potential use for the detection of atherosclerotic lesions in rabbits. METHODS: (125)I-labeled C2I was incorporated into acetylated low-density lipoprotein (AcLDL). The resultant complex, (125)I-C2I-AcLDL, was injected intravenously into 2 groups of rabbits, fed cholesterol and normal chow, at a dose of 555 kBq/kg. Tissue samples were taken 24 h after injection for the biodistribution study. Atherosclerotic lesions and C2I deposition in aortic samples were examined by Sudan IV staining and autoradiography, respectively. RESULTS: The levels of C2I in blood and aortic samples in cholesterol-fed animals were 2- to 3-fold higher than those in the control group (P < 0.05). The autoradiography results correlated well with the Sudan IV staining results, indicating sites of C2I deposition superimposed on lesion sites. CONCLUSION: C2I was preferentially taken up and retained at atherosclerotic lesion sites, suggesting its potential use for the detection of early atherosclerosis.     

68Ga-DOTA-RGD peptide: biodistribution and binding into atherosclerotic plaques in mice

Purpose

Increased expression of αvβ3/αvβ5 integrin is involved in angiogenesis and the inflammatory process in atherosclerotic plaques. The novel ⁶⁸Ga-DOTA-RGD peptide binds with high affinity to αvβ3/αvβ5 integrin. The aim of this study was to investigate the uptake of the ⁶⁸Ga-DOTA-RGD peptide in atherosclerotic plaques.

Methods

Uptake of intravenously administered ⁶⁸Ga-DOTA-RGD peptide was studied ex vivo in excised tissue samples and aortic sections of LDLR^?/?ApoB^100/100 atherosclerotic mice. The uptake of the tracer in aortic cryosections was examined by using digital autoradiography. Subsequently, the autoradiographs were combined with histological and immunohistological analysis of the sections.

Results

DOTA-RGD peptide was successfully labelled with the generator-produced ⁶⁸Ga. The tracer had reasonably good specific radioactivity (8.7?±?1.1 GBq/μmol) and was quite stable in vivo. According to ex vivo biodistribution results, ⁶⁸Ga-DOTA-RGD was cleared rapidly from the blood circulation and excreted through the kidneys to the urine with high radioactivity in the intestine, lungs, spleen and liver. Autoradiography results showed significantly higher uptake of ⁶⁸Ga-DOTA-RGD peptide in the atherosclerotic plaques compared to healthy vessel wall (mean ratio ± SD 1.4?±?0.1, p?=?0.0004).

Conclusion

We observed that ⁶⁸Ga-DOTA-RGD is accumulated into the plaques of atherosclerotic mice. However, this data only shows the feasibility of the approach, while the clinical significance still remains to be proven. Further studies are warranted to assess the uptake of this tracer into human atherosclerotic plaques.     

Evaluation and comparison of <Superscript>11</Superscript>C-choline uptake and calcification in aortic and common carotid arterial walls with combined PET/CT

Purpose  

Inflamed atherosclerotic plaques may rupture and cause acute myocardial infarction, stroke and other thrombotic events. Early detection of these unstable plaques could, in many cases, prevent such potentially fatal events. ¹¹C-choline or ¹⁸F-labelled choline derivatives for visualizing the synthesis of phospholipids, are promising markers of plaque inflammation with potential advantages over ¹⁸F-FDG. Their potential for plaque characterization in humans is, however, unclear. In this study the prevalence and distribution of ¹¹C-choline uptake in the aortic and common carotid arterial walls of elderly male patients was evaluated with combined PET/CT. Additionally, the localization of radiotracer uptake and calcification was correlated in various vessel segments.     

Gadofluorine-enhanced magnetic resonance imaging of carotid atherosclerosis in Yucatan miniswine

OBJECTIVE: The aim of this study was to determine whether gadofluorine, a paramagnetic magnetic resonance imaging (MRI) contrast agent, selectively enhances carotid atherosclerotic plaques in Yucatan miniswine. METHODS: Atherosclerotic plaques were induced in the left carotid arteries (LCA) of Yucatan miniswine (n=3) by balloon denudation and high cholesterol diet. T1-weighted MRI was performed before and 24 hours after gadofluorine injection (at a dose of 100 micromol/kg) to assess the enhancement of the balloon-injured LCA wall relative to healthy, uninjured right carotid artery (RCA) wall. Histopathology was performed to verify the presence and composition of the atherosclerotic plaques imaged with MRI. RESULTS: Gadofluorine was found to enhance LCA atherosclerotic lesions relative to RCA wall by 21% (P<0.025) 24 hours after contrast injection. Enhancement of healthy LCA wall relative to healthy RCA wall was not observed. CONCLUSION: Gadofluorine selectively enhances carotid atherosclerotic plaques in Yucatan miniswine. Gadofluorine appears to be a promising MR contrast agent for detection of atherosclerotic plaques in vivo.     

Perfusion of tumor-bearing kidneys as a model for scintigraphic screening of monoclonal antibodies

Tumor-bearing human kidneys were used in an ex vivo perfusion model to screen monoclonal antibodies, recognizing renal cell carcinoma-associated antigens for diagnostic potential in vivo. Perfusion of tumor-bearing kidneys with 99mTc-labeled G250 and RC38 antibody resulted in visualization of the tumor, whereas perfusion with two other monoclonal antibodies, RC2 and RC4, did not lead to tumor visualization. Uptake of radiolabel in normal kidney tissue was low for G250 and RC38 antibody. Tumor-to-kidney tissue ratios after perfusion with G250 and RC38 antibody were 2.7 and 2.2, respectively. After rinsing for 3 hr with unlabeled perfusion fluid the tumor-to-kidney tissue ratios increased to 8.6 for G250 antibody and to 2.7 for RC38 antibody. We conclude that perfusion of tumor-bearing human kidneys with radiolabeled monoclonal antibodies is a relatively simple way to evaluate renal cell carcinoma associated monoclonal antibodies as diagnostic agents in vivo.