收稿日期: 2025-01-03
录用日期: 2025-03-09
网络出版日期: 2025-07-11
基金资助
上海临床重点专科建设项目(shslczdzk03403);瑞金广慈临床技术与创新项目(GCTIP)(YW20220006);山西医科大学精准医学分子影像协同创新中心开放基金
Research progress on positron emission tomography using radionuclide-labeled fibroblast activation protein inhibitor in diagnosis of cardiac diseases
Received date: 2025-01-03
Accepted date: 2025-03-09
Online published: 2025-07-11
成纤维细胞活化蛋白(fibroblast activation protein, FAP)作为一种特异性表达于活化心肌成纤维细胞(cardiac fibroblasts, CFs)表面的Ⅱ型跨膜丝氨酸蛋白酶,在心肌损伤、炎症及纤维化过程中,通过降解细胞外基质和激活转化生长因子β(transforming growth factor-β, TGF-β)等关键通路,驱动心肌间质重塑及胶原沉积,成为心肌纤维化发展的核心效应靶点。FAP仅在活化的CFs中显著上调,在但正常心肌组织中很少表达,这为心肌疾病的无创精准诊断提供了分子基础。近年来,放射性核素标记的FAP抑制剂(FAP inhibitor, FAPI)正电子发射断层扫描(positron emission tomography, PET)技术凭借其无创性、高靶向性和定量评估能力,可在分子层面早期捕获微纤维化信号,突破了传统影像(如心脏磁共振)对结构性改变的依赖,在活动性心肌纤维化的动态评估中展现出独特优势,为心脏疾病的早期诊断、病理机制探索及预后评估提供了新路径。当前研究证实,FAPI-PET在多种心脏疾病中具有重要应用价值,如在急性心肌梗死后左心室重构中动态监测梗死周边区FAP活性,可预测心室扩张及不良重构的趋势;针对放化疗及免疫治疗心脏毒性导致的亚临床纤维化实现早期预警;对于心脏淀粉样变性,可帮助早期量化评估心肌纤维化负荷,并协助评估不同亚型的危险分层和预后;在肺动脉高压及右心室重构中,可全面评估弥漫性纤维化,并显示疾病严重程度;针对不同亚型心肌病(如肥厚型/扩张型等),通过分析纤维化空间分布辅助临床表型的判断;还可评估房颤导管消融术后心房损伤修复反应,以预测心律失常复发风险。本文综述FAPI-PET检查在心脏疾病诊断中应用的国内外研究进展,展望其应用潜力与未来挑战。
贾迎起 , 张敏 , 李彪 . 放射性核素标记的成纤维细胞活化蛋白抑制剂正电子发射断层扫描在心脏疾病诊断中的研究进展[J]. 诊断学理论与实践, 2025 , 24(02) : 220 -225 . DOI: 10.16150/j.1671-2870.2025.02.014
Fibroblast activation protein (FAP) is a type Ⅱ transmembrane serine protease specifically expressed on the surface of activated cardiac fibroblasts (CFs). During myocardial injury, inflammation, and fibrosis, it drives myocardial interstitial remodeling and collagen deposition by degrading the extracellular matrix and activating key pathways such as transforming growth factor-β (TGF-β), thus serving as a central effector target in the development of myocardial fibrosis. FAP is significantly upregulated exclusively in activated CFs, with minimal expression in normal myocardial tissue, provi-ding a molecular basis for the non-invasive and precise diagnosis of cardiac diseases. In recent years, radionuclide-labeled FAP inhibitor (FAPI) positron emission tomography (PET), with its non-invasiveness, high targeting specificity, and quantitative evaluation capability, has enabled the early detection of microfibrosis signals at the molecular level. This technique overcomes the reliance of conventional imaging (e.g., cardiac magnetic resonance) on structural changes, demonstrating unique advantages in the dynamic evaluation of active myocardial fibrosis and providing a novel pathway for early diagnosis, exploration of pathological mechanisms, and prognostic evaluation of cardiac diseases. Current research confirms that FAPI-PET holds significant application value across multiple cardiac diseases. For example, in left ventricular remodeling after acute myocardial infarction, dynamic monitoring of FAP activity in the peri-infarct zone can predict ventricular dilation and adverse remodeling trends. In cardiotoxicity induced by radiotherapy, chemotherapy, or immunotherapy, it achieves early warning of subclinical fibrosis. For cardiac amyloidosis, it facilitates early quantification of myocardial fibrotic burden and assists in risk stratification and prognosis evaluation across different subtypes. In pulmonary hypertension and right ventricular remodeling, it can comprehensively evaluate diffuse fibrosis and reflect the severity of the di-sease. For different subtypes of cardiomyopathy (e.g., hypertrophic/dilated), it assists in clinical phenotype identification by analyzing the spatial distribution of fibrosis. Additionally, it can be used to evaluate the atrial injury repair responses after catheter ablation for atrial fibrillation, thereby predicting the risk of arrhythmia recurrence. This study reviews domestic and international research advances in the application of FAPI-PET in the diagnosis of cardiac diseases, and discusses its application potential and future challenges.
| [1] | VARASTEH Z, MOHANTA S, ROBU S, et al. Molecular imaging of fibroblast activity after myocardial infarction using a 68Ga-labeled fibroblast activation protein inhibitor, FAPI-04[J]. J Nucl Med,2019,60(12):1743-1749. |
| [2] | NAGARAJU C K, DRIES E, POPOVIC N, et al. Global fibroblast activation throughout the left ventricle but localized fibrosis after myocardial infarction[J]. Sci Rep,2017,7(1):10801. |
| [3] | HUMEREZ C, FRANGOGIANNIS N G. Fibroblasts in the infarcted, remodeling, and failing heart[J]. JACC Basic Transl Sci,2019,4(3):449-467. |
| [4] | VAN HOUT G P, ARSLAN F, PASTERKAMP G, et al. Targeting danger-associated molecular patterns after myocardial infarction[J]. Expert Opin Ther Targets,2016,20(2):223-239. |
| [5] | BLANKESTEIJN W M. Has the search for a marker of activated fibroblasts finally come to an end?[J]. J Mol Cell Cardiol,2015,88:120-123. |
| [6] | ROG-ZIELINSKA E A, NORRIS R A, KOHL P, et al. The living scar—cardiac fibroblasts and the injured heart[J]. Trends Mol Med,2016,22(2):99-114. |
| [7] | KESSLER L, KUPUSOVIC J, FERDINANDUS J, et al. Visualization of fibroblast activation after myocardial infarction using 68Ga-FAPI PET[J]. Clin Nucl Med,2021,46(10):807-813. |
| [8] | DIEKMANN J, KOENIG T, THACKERAY J T, et al. Cardiac fibroblast activation in patients early after acute myocardial infarction: integration with MR tissue characteri-zation and subsequent functional outcome[J]. J Nucl Med,2022,63(9):1415-1423. |
| [9] | SIEBERMAIR J, K?HLER M I, KUPUSOVIC J, et al. Cardiac fibroblast activation detected by Ga-68 FAPI PET imaging as a potential novel biomarker of cardiac injury/remodeling[J]. J Nucl Cardiol,2021,28(3):812-821. |
| [10] | XIE B, WANG J, XI X Y, et al. Fibroblast activation protein imaging in reperfused ST-elevation myocardial infarction: comparison with cardiac magnetic resonance imaging[J]. Eur J Nucl Med Mol Imaging,2022,49(8):2786-2797. |
| [11] | ZHANG M, QUAN W, ZHU T, et al. [68Ga]Ga-DOTA-FAPI-04 PET/MR in patients with acute myocardial infarction: potential role of predicting left ventricular remodeling[J]. Eur J Nucl Med Mol Imaging,2023,50(3):839-848. |
| [12] | SHARMA P, SINGH S S, GAYANA S. Fibroblast activation protein inhibitor PET/CT: a promising molecular imaging tool[J]. Clin Nucl Med,2021,46(3):e141-e150. |
| [13] | PRABHU S D, FRANGOGIANNIS N G. The biological basis for cardiac repair after myocardial infarction: from inflammation to fibrosis[J]. Circ Res,2016,119(1):91-112. |
| [14] | IBANEZ B, ALETRAS A H, ARAI A E, et al. Cardiac MRI endpoints in myocardial infarction experimental and clinical trials: JACC scientific expert panel[J]. J Am Coll Cardiol,2019,74(2):238-256. |
| [15] | VAZIR A, FOX K, WESTABY J, et al. Can we remove scar and fibrosis from adult human myocardium?[J]. Eur Heart J,2019,40(12):960-966. |
| [16] | HOFFMANN D B, FRACCAROLLO D, GALUPPO P, et al. Genetic ablation of fibroblast activation protein alpha attenuates left ventricular dilation after myocardial infarction[J]. PLoS One,2021,16(3):e0248196. |
| [17] | TAPIO S. Pathology and biology of radiation-induced cardiac disease[J]. J Radiat Res,2016,57(5):439-448. |
| [18] | CHANG H M, MOUDGIL R, SCARABELLI T, et al. Cardiovascular complications of cancer therapy: best practices in diagnosis, prevention, and management: Part 1[J]. J Am Coll Cardiol,2017,70(20):2536-2551. |
| [19] | GABRIELS K, HOVING S, SEEMANN I, et al. Local heart irradiation of ApoE(-/-) mice induces microvascular and endocardial damage and accelerates coronary atherosclerosis[J]. Radiother Oncol,2012,105(3):358-364. |
| [20] | HECKMANN M B, REINHARDT F, FINKE D, et al. Relationship between cardiac fibroblast activation protein activity by positron emission tomography and cardiovascular disease[J]. Circ Cardiovasc Imaging,2020,13(9):e010628. |
| [21] | JOHNSON D B, BALKO J M, COMPTON M L, et al. Fulminant myocarditis with combination immune checkpoint blockade[J]. N Engl J Med,2016,375(18):1749-1755. |
| [22] | NIU N, HUO L, ZHANG S, et al. Immune checkpoint inhibitor-associated cardiotoxicity detected by 68Ga-DOTATATE PET/CT and 68Ga-FAPI PET/CT[J]. Eur Heart J Cardiovasc Imaging,2022,23(3):e123. |
| [23] | WANG H, WEI J, ZHENG Q, et al. Radiation-induced heart disease: a review of classification, mechanism and prevention[J]. Int J Biol Sci,2019,15(10):2128-2138. |
| [24] | FONTANA M, COROVIC A, SCULLY P, et al. Myocardial amyloidosis: the exemplar interstitial disease[J]. JACC Cardiovasc Imaging,2019,12(11 Pt 2):2345-2356. |
| [25] | GROGAN M, DISPENZIERI A, GERTZ M A. Light-chain cardiac amyloidosis: strategies to promote early diagnosis and cardiac response[J]. Heart,2017,103(14):1065-1072. |
| [26] | RUBERG F L, BERK J L. Transthyretin (TTR) cardiac amyloidosis[J]. Circulation,2012,126(10):1286-1300. |
| [27] | FALK R H, QUARTA C C. Echocardiography in cardiac amyloidosis[J]. Heart Fail Rev,2015,20(2):125-131. |
| [28] | MARTINEZ-NAHARRO A, TREIBEL T A, ABDEL-GADIR A, et al. Magnetic resonance in transthyretin cardiac amyloidosis[J]. J Am Coll Cardiol,2017,70(4):466-477. |
| [29] | YANG M, ARSANJANI R, ROARKE M C. Advanced nuclear medicine and molecular imaging in the diagnosis of cardiomyopathy[J]. Am J Roentgenol,2020,215(5):1208-1217. |
| [30] | YAMAMOTO Y, ONOGUCHI M, HARAMOTO M, et al. Novel method for quantitative evaluation of cardiac amyloidosis using 201TlCl and 99mTc-PYP SPECT[J]. Ann Nucl Med,2012,26(8):634-643. |
| [31] | WANG X, GUO Y, GAO Y, et al. Feasibility of 68Ga-labeled fibroblast activation protein inhibitor PET/CT in light-chain cardiac amyloidosis[J]. JACC Cardiovasc Imaging,2022,15(11):1960-1970. |
| [32] | DORBALA S. Fibroblast activation: a novel mechanism of heart failure in light chain cardiac amyloidosis?[J]. JACC Cardiovasc Imaging,2022,15(11):1971-1973. |
| [33] | GUO W, CHEN H. 68Ga FAPI PET/MRI in cardiac amyloidosis[J]. Radiology,2022,303(1):51. |
| [34] | CAHILL T J, ASHRAFIAN H, WATKINS H. Genetic cardiomyopathies causing heart failure[J]. Circ Res,2013,113(6):660-675. |
| [35] | CHALHOUB S M, LOH P, HAUER R N, et al. The role of connexin40 in atrial fibrillation[J]. Cardiovasc Res,2009,84(1):15-23. |
| [36] | MORAVSKY G, OFEK E, RAKOWSKI H, et al. Myocardial fibrosis in hypertrophic cardiomyopathy: accurate reflection of histopathological findings by CMR[J]. JACC Cardiovasc Imaging,2013,6(5):587-596. |
| [37] | ALMAAS V M, HAUGAA K H, STR?M E H, et al. Noninvasive assessment of myocardial fibrosis in patients with obstructive hypertrophic cardiomyopathy[J]. Heart,2014,100(8):631-638. |
| [38] | ZHANG Y, DONG Z, WANG L, et al. Functional significance of myocardial activity at 18F-FAPI PET/CT in hypertrophic cardiomyopathy identified by cardiac magnetic resonance feature-tracking strain analysis[J]. Eur J Nucl Med Mol Imaging,2023,51(1):110-122. |
| [39] | SHI X, LIN X, HUO L, et al. Cardiac fibroblast activation in dilated cardiomyopathy detected by positron emission tomography[J]. J Nucl Cardiol,2022,29(2):881-884. |
| [40] | LIN K, CHEN X, XUE Q, et al. Diffuse uptake of [68Ga]Ga-FAPI in the left heart in a patient with hypertensive heart disease by PET/CT[J]. J Nucl Cardiol,2022,29(6):3596-3598. |
| [41] | HO C Y, LOPEZ B, COELHO-FILHO O R, et al. Myocardial fibrosis as an early manifestation of hypertrophic cardiomyopathy[J]. N Engl J Med,2010,363(6):552-563. |
| [42] | WANG L, WANG Y, WANG J, et al. Myocardial activity at 18F-FAPI PET/CT and risk for sudden cardiac death in hypertrophic cardiomyopathy[J]. Radiology,2023,306(2):e221052. |
| [43] | AGHAJANIAN H, KIMURA T, RURIK J G, et al. Targe-ting cardiac fibrosis with engineered T cells[J]. Nature,2019,573(7774):430-433. |
| [44] | WANG J, HUO L, LIN X, et al. Molecular imaging of fibroblast activation in multiple non-ischemic cardiomyo-pathies[J]. EJNMMI Res,2023,13(1):39. |
| [45] | ZENG X, ZHAO R, WU Z, et al. [18F]-FAPI-42 PET/CT assessment of progressive right ventricle fibrosis under pressure overload[J]. Respir Res,2023,24(1):270. |
| [46] | XING H Q, GONG J N, CHEN B X, et al. Comparison of 68Ga-FAPI imaging and cardiac magnetic resonance in detection of myocardial fibrosis in a patient with chronic thromboembolic pulmonary hypertension[J]. J Nucl Cardiol,2022,29(5):2728-2730. |
| [47] | PATEL R B, LI E, BENEFIELD B C, et al. Diffuse right ventricular fibrosis in heart failure with preserved ejection fraction and pulmonary hypertension[J]. ESC Heart Fail,2020,7(1):253-263. |
| [48] | WANG L, ZHANG Z, ZHAO Z, et al. 68Ga-FAPI right heart uptake in a patient with idiopathic pulmonary arterial hypertension[J]. J Nucl Cardiol,2022,29(3):1475-1477. |
| [49] | GONG J N, CHEN B X, XING H Q, et al. Pulmonary artery imaging with 68Ga-FAPI-04 in patients with chronic thromboembolic pulmonary hypertension[J]. J Nucl Cardiol,2023,30(3):1166-1172. |
| [50] | GU Y, HAN K, ZHANG Z, et al. 68Ga-FAPI PET/CT for molecular assessment of fibroblast activation in right heart in pulmonary arterial hypertension: a single-center, pilot study[J]. J Nucl Cardiol,2023,30(2):495-503. |
| [51] | CHEN B X, XING H Q, GONG J N, et al. Imaging of cardiac fibroblast activation in patients with chronic thromboembolic pulmonary hypertension[J]. Eur J Nucl Med Mol Imaging,2022,49(4):1211-1222. |
| [52] | KUPUSOVIC J, KESSLER L, NEKOLLA S G, et al. Visua-lization of thermal damage using 68Ga-FAPI-PET/CT after pulmonary vein isolation[J]. Eur J Nucl Med Mol Imaging,2022,49(5):1553-1559. |
| [53] | LINHART M, ALARCON F, BORRàS R, et al. Delayed gadolinium enhancement magnetic resonance imaging detected anatomic gap length in wide circumferential pulmonary vein ablation lesions is associated with recurrence of atrial fibrillation[J]. Circ Arrhythm Electrophysiol,2018,11(12):e006659. |
| [54] | HARRISON J L, SOHNS C, LINTON N W, et al. Repeat left atrial catheter ablation: cardiac magnetic resonance prediction of endocardial voltage and gaps in ablation lesion sets[J]. Circ Arrhythm Electrophysiol,2015,8(2):270-278. |
| [55] | KUCK K H, HOFFMANN B A, ERNST S, et al. Impact of complete versus incomplete circumferential lines around the pulmonary veins during catheter ablation of paroxysmal atrial fibrillation: results from the Gap-Atrial Fibrillation-German Atrial Fibrillation Competence Network 1 Trial[J]. Circ Arrhythm Electrophysiol,2016,9(1):e003337. |
| [56] | KUPUSOVIC J, KESSLER L, BRUNS F, et al. Visualization of fibroblast activation using 68Ga-FAPI PET/CT after pulmonary vein isolation with pulsed field compared with cryoballoon ablation[J]. J Nucl Cardiol,2023,30(5):2018-2028. |
/
| 〈 |
|
〉 |