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心脏淀粉样变(cardiac amyloidosis,CA)是一种由于错误折叠的淀粉样蛋白沉积并浸润心脏各部位导致的疾病,可引起心肌病、心力衰竭、心律失常和瓣膜性心脏病[1]。轻链型CA(light chain CA,AL-CA)和转甲状腺素蛋白相关CA(transthyretin-related CA,ATTR-CA)是CA的主要常见类型。系统性AL-CA是由免疫球蛋白轻链异常引起的,这些患者大多都合并多发性骨髓瘤(multiple myeloma,MM)[2]。然而,高达38%的MM患者存在临床隐匿性AL-CA [3-6]。当临床怀疑CA时,可通过心内膜心肌活检确认是否存在淀粉样蛋白沉积。然而,心内膜心肌活检具有有创、难以获得活检组织、可能存在并发症等缺点,因此需要寻找一种诊断性能与组织活检相当的无创影像方法。
心脏无创影像方法包括心脏超声、心脏磁共振成像(cardiac magnetic resonance imaging,CMR)和心脏核素显像。心脏超声和CMR的局限性在于只能评估心脏自身病变,无法区分CA与其他原因引起的肥厚性心肌病[7]。11C标记的匹兹堡化合物B(11C-PIB)和18F标记的氟贝他吡、氟比他班已被证明可以无创识别CA,但无法区分AL-CA与ATTR-CA[8-10]。99Tcm标记的焦磷酸盐和羟基亚甲基二磷酸盐均对ATTR-CA有很强的亲和力,可通过SPECT鉴别AL-CA与ATTR-CA,其诊断ATTR-CA的灵敏度和特异度均较高,而AL-CA患者心肌对99Tcm标记的焦磷酸盐和羟基亚甲基二磷酸盐的摄取均较少甚至无摄取[11]。综上,目前临床上缺乏可早期诊断AL-CA的方法。AL-CA易被误诊及漏诊,导致诊疗延迟,患者病死率高。因此,临床上迫切需要寻找一种可早期识别AL-CA的无创、有效的诊断方法。
成纤维细胞活化蛋白由活化的成纤维细胞特异性表达。近年来,放射性核素标记的成纤维细胞激活蛋白抑制剂(fibroblast activation protein inhibitor,FAPI)被开发并应用于多种心脏疾病的PET/CT显像,以评估心肌纤维化[12]。有研究者发现,放射性核素标记的FAPI PET/CT可用于检测AL-CA患者的心肌成纤维细胞活化[13-15]。本研究旨在探讨AL-CA患者心脏Al18F-1,4,7-三氮杂环壬烷-1,4,7-三乙酸(1, 4, 7-triazacyclononane-1, 4, 7-triacetic acid,NOTA)-FAPI PET/CT显像对AL-CA的诊断价值。
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由表1可知,AL-CA+MM组、AL-only组、MM对照组、健康对照组受试者的性别、年龄、BMI的差异均无统计学意义(均P>0.05)。AL-CA+MM组的病程数为6.0(4.0,35.0)个月;AL-only组的病程数为(5.7±2.1)个月;MM对照组的病程数为18.0(12.0,73.0)个月,3组病程数的差异无统计学意义(P>0.05)。AL-CA+MM组中,3例(3/5,60.0%)患者分期为ISS Ⅲ期,2例(2/5,40.0%)患者分期为ISS Ⅱ期;MM对照组中2例(2/5,40.0%)患者分期为ISS Ⅲ期,1例(1/5,20.0%)患者分期为ISS Ⅱ期,2例(2/5,40.0%)患者分期为ISS Ⅰ期,AL-CA+MM组和MM对照组患者ISS分期的差异无统计学意义(P>0.05)。
组别 性别[例(%)] 年龄
(岁, ±s)$ \bar{{x}} $ BMI
(kg/m2, ±s)$ \bar x $ 病程数
[月,M(Q1,Q3)
或 ±s]$ \bar x $ ISS分期[例(%)] 视觉评估左心室Al18F-NOTA-FAPI PET/CT摄取阳性
[例(%)]男性 女性 Ⅰ期 Ⅱ期 Ⅲ期 AL-CA+MM组(n=5) 5(100.0) 0(0.0) 61.4±6.3 27.6±8.1 6.0(4.0,35.0) 0(0.0) 2(40.0) 3(60.0) 3(60.0) AL-only组(n=3) 2(66.7) 1(33.3) 65.3±4.0 22.2±1.7 5.7±2.1 − − − 3(100.0)a MM对照组(n=5) 5(100.0) 0(0.0) 60.8±9.5 24.7±1.9 18.0(12.0,73.0) 2(40.0) 1(20.0) 2(40.0) 1(20.0) 健康对照组(n=5) 4(80.0) 1(20.0) 61.6±6.4 24.1±4.9 − − − − 0(0.0) 检验值 χ2=3.150 F=0.278 F=0.775 F=1.085 χ2=2.533 χ2=9.584 P值 0.369 0.84 0.527 0.374 0.282 0.022 组别 左心室SUVmax
( ±s)$ \bar x $ 左心室T/B
( ±s)$ \bar x $ BNP [pg/ml,M(Q1,Q3)或 ±s]$ \bar x $ LVEF
(%, ±s)$ \bar x $ 左心室IVST
(mm, ±s)$ \bar x $ 左心室PWT
(mm, ±s)$ \bar x $ LAVI
(ml/m2, ±s)$ \bar x $ 左心室EDV (ml, ±s)$ \bar x $ 左心室ESV
(ml, ±s)$ \bar x $ AL-CA+MM组(n=5) 4.2±1.8 4.2±2.1 398(42.5,595.0) 67.8±6.7 13.9±1.1b 13.7±0.9b 25.5±6.7 101.6±37.8 32.2±12.4 AL-only组(n=3) 4.1±1.1 4.7±0.6a 259.0±40.0b 67.0±5.3 13.3±2.3 13.0±1.7 25.2±10.0 79.0±17.1 25.3±5.8 MM对照组(n=5) 2.5±1.4 3.0±1.2 19.2±15.7 71.8±7.5 10.8±0.3 10.3±0.6 19.6±8.7 133.5±4.9 41.9±16.8 健康对照组(n=5) 2.1±0.2 2.2±0.4 − − − − − − − 检验值 F=3.341 F=3.011 F=6.198 F=0.635 F=8.584 F=13.995 F=0.755 F=1.979 F=1.194 P值 0.050 0.066 0.045 0.550 0.007 0.001 0.498 0.208 0.358 注:a表示与健康对照组相比,差异均有统计学意义(χ2=4.302,P=0.018;t=6.748,P=0.001);b表示与MM对照组相比,差异均有统计学意义(t=9.928、6.197、6.774,均P<0.05);−表示无此项数据。AL-CA为轻链型心脏淀粉样变;AL-only为轻链型心脏淀粉样变不伴多发性骨髓瘤;MM为多发性骨髓瘤;NOTA为1,4,7-三氮杂环壬烷-1,4,7-三乙酸;FAPI 为成纤维细胞激活蛋白抑制剂;PET为正电子发射断层显像术;CT为计算机体层摄影术;BMI为身体质量指数;ISS为国际分期体系;SUVmax为最大标准化摄取值;T/B为靶本底比值;BNP为B型利钠肽;LVEF为左室射血分数;IVST为室间隔厚度;PWT为后壁厚度;LAVI为左心房容积指数;EDV为舒张末期容积;ESV为收缩末期容积 表 1 AL-CA+MM组、AL-only组、MM对照组和健康对照组一般资料、Al18F-NOTA-FAPI PET/CT显像、实验室检查和心脏超声结 果的比较
Table 1. Comparison of general data, Al18F-1, 4, 7-triazacyclononane-1, 4, 7-triacetic acid (NOTA)-fibroblast activation protein inhibitor (FAPI) PET/CT imaging, laboratory examination and cardiac ultrasound results among light chain cardiac amyloidosis (AL-CA)+multiple myeloma (MM) group, light chain (AL)-only group, MM control group and healthy control group
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与MM对照组相比,AL-only组BNP水平升高,差异有统计学意义[(259.0±40.0) pg/ml 对(19.2±15.7) pg/ml,t=9.928,P<0.05);AL-CA+MM组左心室室间隔厚度和左心室后壁厚度增加,差异均有统计学意义[(13.9±1.1) mm对(10.8±0.3) mm,t=6.197,P<0.05;(13.7±0.9) mm 对(10.3±0.6) mm,t=6.774,P<0.05]。MM对照组、AL-only组、AL-CA+MM组的左心室射血分数、左心房容积指数、左心室舒张末期容积、左心室收缩末期容积的差异均无统计学意义(均P>0.05)。
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AL-CA+MM组、AL-only组、MM对照组和健康对照组左心室心肌Al18F-NOTA-FAPI摄取情况如图1所示。Al18F-NOTA-FAPI PET/CT显像结果显示,AL-CA+MM组3例(3/5,60.0%)患者和AL-only组3例(3/3,100.0%)患者左心室心肌Al18F-NOTA-FAPI摄取均为阳性;MM对照组4例(4/5,80.0%)患者和健康对照组5名(5/5,100.0%)受试者左心室心肌Al18F-NOTA-FAPI摄取均为阴性。
图 1 AL-CA+MM组、AL-only组、MM对照组和健康对照组所有受试者心脏Al18F-NOTA-FAPI PET显像图
Figure 1. Al18F-1, 4, 7-triazacyclononane-1, 4, 7-triacetic acid (NOTA)-fibroblast activation protein inhibitor (FAPI) PET images of hearts in light chain cardiac amyloidosis (AL-CA)+multiple myeloma (MM) group, light chain (AL)-only group, MM control group and healthy control group
AL-only组左心室心肌SUVmax 和T/B均高于健康对照组[SUVmax:(4.1±1.1)对(2.1±0.2),t=3.234,P=0.081;T/B:(4.7±0.6)对(2.2±0.4),t=6.748,P=0.001]。AL-CA+MM组左心室心肌SUVmax和T/B均高于MM对照组 [SUVmax:(4.2±1.8)对(2.5±1.4),t=1.699,P=0.128;T/B:(4.2±2.1)对(3.0±1.2),t=1.120,P=0.295]。AL-CA+MM 组左心室心肌SUVmax和T/B均高于健康对照组[SUVmax:(4.2±1.8)对(2.1±0.2),t=2.642,P=0.056;T/B:(4.2±2.1)对(2.2±0.4),t=2.047,P=0.104](图2)。
图 2 AL-CA+MM组、AL-only组、MM对照组和健康对照组的Al18F-NOTA-FAPI PET/CT显像的SUVmax和T/B结果分析
Figure 2. Analysis of maximum standardized uptake value (SUVmax) and target to background ratio (T/B) results of Al18F-1, 4, 7-triazacyclononane-1, 4, 7-triacetic acid (NOTA)-fibroblast activation protein inhibitor (FAPI) PET/CT imaging in light chain cardiac amyloidosis (AL-CA)+multiple myeloma (MM) group, light chain (AL)-only group, MM control group and healthy control group
Al18F-NOTA-FAPI PET/CT显像在轻链型心脏淀粉样变中的诊断价值
Diagnostic value of Al18F-NOTA-FAPI PET/CT imaging in light chain cardiac amyloidosis
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摘要:
目的 探讨Al18F-1,4,7-三氮杂环壬烷-1,4,7-三乙酸(NOTA)-成纤维细胞激活蛋白抑制剂(FAPI) PET/CT显像对轻链型心脏淀粉样变(AL-CA)的诊断价值。 方法 前瞻性研究2021年9至12月于首都医科大学附属北京朝阳医院确诊为AL-CA的8例[5例合并多发性骨髓瘤(MM)]患者的临床资料,其中男性7例、女性1例,年龄(62.9±5.6)岁。分别招募与AL-CA患者性别和年龄匹配的5名健康志愿者和5例MM患者作为对照。研究共分为4组: AL-CA+MM组(AL-CA伴MM )5例、AL-only组(AL-CA不伴MM)3例、MM对照组(MM不伴AL-CA )5例、健康对照组5名。所有受试者均接受Al18F-NOTA-FAPI PET/CT显像。分析4组受试者的实验室检查指标[B型利钠肽(BNP)水平]、心脏超声数据和Al18F-NOTA-FAPI PET/CT显像结果。多组间计量资料的比较采用LSD检验或Kruskal Wallis检验。2组间计量资料的比较采用两独立样本t检验(方差齐),计数资料的比较采用χ2检验。 结果 与MM对照组相比,AL-only组BNP水平升高,差异有统计学意义[(259.0±40.0) pg/ml 对(19.2±15.7) pg/ml,t=9.928,P<0.05];AL-CA+MM组左心室室间隔厚度和左心室后壁厚度增加,差异均有统计学意义[(13.9±1.1) mm对(10.8±0.3) mm,t=6.197,P<0.05;(13.7±0.9) mm 对(10.3±0.6) mm,t=6.774,P<0.05]。Al18F-NOTA-FAPI PET/CT显像结果显示:AL-CA+MM组3例(3/5,60.0%)患者和AL-only组3例(3/3,100.0%)患者左心室心肌Al18F-NOTA-FAPI摄取均为阳性;MM对照组4例(4/5,80.0%)患者和健康对照组5名(5/5,100.0%)受试者左心室心肌Al18F-NOTA-FAPI摄取均为阴性。AL-only组左心室心肌最大标准化摄取值(SUVmax) 和靶本底比值(T/B)均高于健康对照组[SUVmax:(4.1±1.1)对(2.1±0.2),t=3.234,P=0.081;T/B:(4.7±0.6)对(2.2±0.4),t=6.748,P=0.001]。AL-CA+MM组左心室心肌SUVmax和T/B均高于MM对照组 [SUVmax:(4.2±1.8)对(2.5±1.4),t=1.699,P=0.128;T/B:(4.2±2.1)对(3.0±1.2),t=1.120,P=0.295]。AL-CA+MM 组左心室心肌SUVmax和T/B均高于健康对照组[SUVmax:(4.2±1.8)对(2.1±0.2),t=2.642,P=0.056;T/B:(4.2±2.1)对(2.2±0.4),t=2.047,P=0.104]。 结论 Al18F-NOTA-FAPI PET/CT显像具有无创、有效检测AL-CA患者心脏成纤维细胞活化的能力,其对AL-CA患者具有一定的诊断价值。 Abstract:Objective To explore the diagnostic value of Al18F-1, 4, 7-triazacyclononane-1, 4, 7-triacetic acid (NOTA)-fibroblast activation protein inhibitor (FAPI) PET/CT imaging in light chain cardiac amyloidosis (AL-CA). Methods The clinical data of 8 patients (7 males and 1 female, aged (62.9±5.6) years) diagnosed with AL-CA in Beijing Chao-Yang Hospital, Capital Medical University from September to December 2021 were prospectively studied. Five healthy volunteers and 5 patients with multiple myeloma (MM), who matched the gender and age with AL-CA patients, were recruited as controls. All subjects were divided into 4 groups: 5 cases in the AL-CA+MM group (AL-CA with MM), 3 cases in the AL-only group (AL-CA without MM), 5 cases in the MM control group (MM without AL-CA), and 5 cases in the healthy control group. All subjects underwent Al18F-NOTA-FAPI PET/CT imaging. Laboratory index type B natriuretic peptide (BNP) level, echocardiography data, and Al18F-NOTA-FAPI PET/CT imaging results were analyzed. Measurement data were compared among the 4 groups by using LSD or Kruskal-Wallis test and between 2 groups by independent samples t-test (homogeneity of variance). Enumeration data were compared by χ2 test. Results BNP level in the AL-only group was higher than that in the MM control group, and the difference was statistically significant ((259.0±40.0) pg/ml vs. (19.2±15.7) pg/ml, t=9.928, P<0.05). The left ventricular interventricular septum thickness and the left ventricular posterior wall thickness increased in the AL-CA+MM group, and the differences were statistically significant ((13.9±1.1) mm vs. (10.8±0.3) mm, t=6.197, P<0.05; (13.7±0.9) mm vs. (10.3±0.6) mm, t=6.774, P<0.05). Al18F-NOTA-FAPI PET/CT imaging results showed that the Al18F-NOTA-FAPI uptake of the left ventricular myocardium was positive in 3 cases (3/5, 60.0%) of the AL-CA+MM group and 3 cases (3/3, 100.0%) of the AL-only group. The left ventricular myocardium Al18F-NOTA-FAPI uptake was negative in 4 patients (4/5, 80.0%) of the MM control group and 5 subjects (5/5, 100.0%) of the healthy control group. The left ventricular myocardium maximum standardized uptake value (SUVmax) and target to background ratio (T/B) in the AL-only group were higher than those in the healthy control group (SUVmax: (4.1±1.1) vs. (2.1±0.2), t=3.234, P=0.081; T/B: (4.7±0.6) vs. (2.2±0.4), t=6.748, P=0.001). The SUVmax and T/B of the left ventricular myocardium in the AL-CA+MM group were higher than those in the MM control group (SUVmax: (4.2±1.8) vs. (2.5±1.4), t=1.699, P=0.128; T/B: (4.2±2.1) vs. (3.0±1.2), t=1.120, P=0.295). The SUVmax and T/B of left ventricular myocardium in the AL-CA+MM group were higher than those in the healthy control group (SUVmax: (4.2±1.8) vs. (2.1±0.2), t=2.642, P=0.056; T/B: (4.2±2.1) vs. (2.2±0.4), t=2.047, P=0.104). Conclusion Al18F-NOTA-FAPI PET/CT imaging can detect cardiac fibroblast activation non-invasively and effectively and has a certain diagnostic value in patients with AL-CA. -
Key words:
- Amyloidosis /
- Myocardium /
- Membrane proteins /
- Fibroblasts /
- Fluorine radioisotopes /
- Positron-emission tomography /
- Multiple myeloma
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图 1 AL-CA+MM组、AL-only组、MM对照组和健康对照组所有受试者心脏Al18F-NOTA-FAPI PET显像图
Figure 1. Al18F-1, 4, 7-triazacyclononane-1, 4, 7-triacetic acid (NOTA)-fibroblast activation protein inhibitor (FAPI) PET images of hearts in light chain cardiac amyloidosis (AL-CA)+multiple myeloma (MM) group, light chain (AL)-only group, MM control group and healthy control group
图 2 AL-CA+MM组、AL-only组、MM对照组和健康对照组的Al18F-NOTA-FAPI PET/CT显像的SUVmax和T/B结果分析
Figure 2. Analysis of maximum standardized uptake value (SUVmax) and target to background ratio (T/B) results of Al18F-1, 4, 7-triazacyclononane-1, 4, 7-triacetic acid (NOTA)-fibroblast activation protein inhibitor (FAPI) PET/CT imaging in light chain cardiac amyloidosis (AL-CA)+multiple myeloma (MM) group, light chain (AL)-only group, MM control group and healthy control group
表 1 AL-CA+MM组、AL-only组、MM对照组和健康对照组一般资料、Al18F-NOTA-FAPI PET/CT显像、实验室检查和心脏超声结 果的比较
Table 1. Comparison of general data, Al18F-1, 4, 7-triazacyclononane-1, 4, 7-triacetic acid (NOTA)-fibroblast activation protein inhibitor (FAPI) PET/CT imaging, laboratory examination and cardiac ultrasound results among light chain cardiac amyloidosis (AL-CA)+multiple myeloma (MM) group, light chain (AL)-only group, MM control group and healthy control group
组别 性别[例(%)] 年龄
(岁, ±s)$ \bar{{x}} $ BMI
(kg/m2, ±s)$ \bar x $ 病程数
[月,M(Q1,Q3)
或 ±s]$ \bar x $ ISS分期[例(%)] 视觉评估左心室Al18F-NOTA-FAPI PET/CT摄取阳性
[例(%)]男性 女性 Ⅰ期 Ⅱ期 Ⅲ期 AL-CA+MM组(n=5) 5(100.0) 0(0.0) 61.4±6.3 27.6±8.1 6.0(4.0,35.0) 0(0.0) 2(40.0) 3(60.0) 3(60.0) AL-only组(n=3) 2(66.7) 1(33.3) 65.3±4.0 22.2±1.7 5.7±2.1 − − − 3(100.0)a MM对照组(n=5) 5(100.0) 0(0.0) 60.8±9.5 24.7±1.9 18.0(12.0,73.0) 2(40.0) 1(20.0) 2(40.0) 1(20.0) 健康对照组(n=5) 4(80.0) 1(20.0) 61.6±6.4 24.1±4.9 − − − − 0(0.0) 检验值 χ2=3.150 F=0.278 F=0.775 F=1.085 χ2=2.533 χ2=9.584 P值 0.369 0.84 0.527 0.374 0.282 0.022 组别 左心室SUVmax
( ±s)$ \bar x $ 左心室T/B
( ±s)$ \bar x $ BNP [pg/ml,M(Q1,Q3)或 ±s]$ \bar x $ LVEF
(%, ±s)$ \bar x $ 左心室IVST
(mm, ±s)$ \bar x $ 左心室PWT
(mm, ±s)$ \bar x $ LAVI
(ml/m2, ±s)$ \bar x $ 左心室EDV (ml, ±s)$ \bar x $ 左心室ESV
(ml, ±s)$ \bar x $ AL-CA+MM组(n=5) 4.2±1.8 4.2±2.1 398(42.5,595.0) 67.8±6.7 13.9±1.1b 13.7±0.9b 25.5±6.7 101.6±37.8 32.2±12.4 AL-only组(n=3) 4.1±1.1 4.7±0.6a 259.0±40.0b 67.0±5.3 13.3±2.3 13.0±1.7 25.2±10.0 79.0±17.1 25.3±5.8 MM对照组(n=5) 2.5±1.4 3.0±1.2 19.2±15.7 71.8±7.5 10.8±0.3 10.3±0.6 19.6±8.7 133.5±4.9 41.9±16.8 健康对照组(n=5) 2.1±0.2 2.2±0.4 − − − − − − − 检验值 F=3.341 F=3.011 F=6.198 F=0.635 F=8.584 F=13.995 F=0.755 F=1.979 F=1.194 P值 0.050 0.066 0.045 0.550 0.007 0.001 0.498 0.208 0.358 注:a表示与健康对照组相比,差异均有统计学意义(χ2=4.302,P=0.018;t=6.748,P=0.001);b表示与MM对照组相比,差异均有统计学意义(t=9.928、6.197、6.774,均P<0.05);−表示无此项数据。AL-CA为轻链型心脏淀粉样变;AL-only为轻链型心脏淀粉样变不伴多发性骨髓瘤;MM为多发性骨髓瘤;NOTA为1,4,7-三氮杂环壬烷-1,4,7-三乙酸;FAPI 为成纤维细胞激活蛋白抑制剂;PET为正电子发射断层显像术;CT为计算机体层摄影术;BMI为身体质量指数;ISS为国际分期体系;SUVmax为最大标准化摄取值;T/B为靶本底比值;BNP为B型利钠肽;LVEF为左室射血分数;IVST为室间隔厚度;PWT为后壁厚度;LAVI为左心房容积指数;EDV为舒张末期容积;ESV为收缩末期容积 -
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