Cardiac fibroblast activation detected by Ga-68 FAPI PET imaging as a potential novel biomarker of cardiac injury/remodeling

doi:10.1007/s12350-020-02307-w

Journal of Nuclear Cardiology

Volume 28, Issue 3, June 2021, Pages 812-821

https://doi.org/10.1007/s12350-020-02307-w Get rights and content

Abstract

Background

Fibroblast activation protein (FAP) as a specific marker of activated fibroblasts can be visualized by positron emission tomography (PET) using Ga-68-FAP inhibitors (FAPI). Gallium-68-labeled FAPI is increasingly used in the staging of various cancers. In addition, the first cases of theranostic approaches have been reported. In this work, we describe the phenomenon of myocardial FAPI uptake in patients who received a Ga-68 FAPI PET for tumor staging.

Method and results

Ga-68 FAPI PET examinations for cancer staging were retrospectively analyzed with respect to cardiac tracer uptake. Standardized uptake values (SUV) were correlated to clinical covariates in a univariate regression model.

From 09/2018 to 11/2019 N = 32 patients underwent FAPI PET at our institution. Six out of 32 patients (18.8%) demonstrated increased localized myocardial tracer accumulation, with remote FAPI uptake being significantly higher in patients with vs without localized focal myocardial uptake (SUV_max 2.2 ± .6 vs 1.5 ± .4, P < .05 and SUV_mean 1.6 ± .4 vs 1.2 ± .3, P < .05, respectively). Univariate regression demonstrated a significant correlation of coronary artery disease (CAD), age and left ventricular ejection fraction (LVEF) with remote SUV_mean uptake, the latter with a very strong correlation with remote uptake (R² = .74, P < .01).

Conclusion

Our study indicates an association of CAD, age, and LVEF with FAPI uptake. Further studies are warranted to assess if fibroblast activation can be reliably measured and may be used for risk stratification regarding early detection or progression of CAD and left ventricular remodeling.

Spanish Abstract

Antecedentes

Proteína de activación de fibroblastos (FAP) como marcador específico de fibroblastos maduros activados se puede visualizar mediante tomografía por emisión de positrones (PET) usando inhibidores de Ga-68-FAP (FAPI).

El FAPI marcado con galio 68 se usa cada vez más en la estatificación de varios tipos de cáncer.Además, se han reportado los primeros casos de abordajes teranósticos.

En este trabajo describimos el fenómeno de la captación de FAPI miocárdica en pacientes que recibieron Ga-68 FAPI PET para estatificación tumoral.

Método y resultados

Los exámenes de PET Ga-68 FAPI para estadificación de cáncer se analizaron retrospectivamente con respecto a la captación del marcador cardíaco. Los valores de absorción estandarizados (SUV) se correlacionaron con covariables clínicas en un modelo de regresión univariante.

Del 09/2018 al 11/2019 con una n = 32 pacientes fueron sometidos a PET FAPI en nuestra institución. Seis de 32 pacientes (18.8%) demostraron un aumento de acumulación del marcador localizado en el miocardio, con la captación remota de FAPI siendo significativamente mayor en pacientes con aumento de la captación vs sin captación focalizada de miocardio (SUVmax 2.2 ± 0.6 vs. 1.5 ± 0.4, p <0.05 y SUV mean 1.6 ± 0.4 vs. 1.2 ± 0.3, p <0.05, respectivamente).

La regresión univariante demostró una correlación significativa de la enfermedad de la arteria coronaria (CAD), la edad y la fracción de eyección ventricular izquierda (FEVI) con absorción SUV remota, esta última con una muy fuerte correlación con la captación remota (R² = 0.74, p <0.01).

Conclusión

Nuestro estudio indica una asociación de CAD, edad y FEVI con la captación de FAPI.

Se necesitan más estudios para evaluar si la activación de fibroblastos se puede medir de manera confiable y se puede usar para la estratificación de riesgo con respecto a la detección temprana o la progresión de la CAD y la remodelación ventricular izquierda.

Chinese Abstract

背景

成纤维细胞活化蛋白(FAP)作为活化成纤维细胞的一种特异性标志物,可以通过Ga-68-FAP抑制剂(FAPI)的正电子发射断层扫描(PET)显像进行活体可视化。Ga-68标记的FAPI已被越来越多地用于各种癌症的分期。并且已有第一个诊疗一体化的病例报道。本文在接受Ga-68 FAPI PET进行肿瘤分期患者中研究了心肌FAPI摄取结果。

方法和结果

回顾性分析了Ga-68 FAPI PET检查癌症分期的心脏示踪剂摄取情况。摄取值(SUV)作为因变量,临床资料作为协变量,纳入单变量回归模型。

从2018年9月到2019年11月,共纳入32例在我院接受了FAPI PET检查的患者。其中6例患者(18.8%)表现为局灶性心肌摄取。与无局灶性心肌摄取的患者相比,有局灶性摄取患者远处心肌FAPI摄取值更高(SUV_max 2.2±0.6 vs. 1.5±0.4,P<0.05,SUV_mean 1.6±0.4 vs. 1.2±0.3,P<0.05)。单因素回归分析表明,冠状动脉疾病(CAD)病史、年龄和左心室射血分数(LVEF)与远处心肌SUV_mean摄取显著相关,其中LVEF的相关性最高(R²=0.74,P<0.01)。

结论

本研究表明,CAD病史、年龄和LVEF与FAPI的摄取值有关。需要进一步的研究评估FAPI能否可靠地测定成纤维细胞的活化,并用于CAD的早期诊断或进展以及左心室重构的风险分层。

French Abstract

Contexte

La protéine d’activation des fibroblastes (FAP) activés et matures peut être visualisée par tomographie à émission de positons (TEP) à l’aide d’inhibiteurs de l’activation des fibroblastes (FAPI). FAPI marqué au gallium 68 est de plus en plus utilisé dans la stratification de divers cancers. De plus, les premiers exemples d’approches théranostiques ont été rapportés. Dans ce travail nous décrivons la captation myocardique de FAPI chez les patients qui bénéficié d’une TEP au Ga-68 FAPI pour stratification tumorale.

Méthode et résultats

Les examens TEP Ga-68 FAPI pour la stratification oncologique ont été analysés rétrospectivement pour l’absorption du traceur au niveau cardiaque. Les valeurs d’absorption normalisées (SUV) font été corrélées aux variables cliniques selon un modèle de régression univarié. A partir de septembre 2018 jusqu’en novembre 2019, 32 patients ont bénéficié d’une TEP FAPI dans notre établissement. Six de nos 32 patients (18,8%) ont démontré une augmentation focale de captation du tracer au niveau myocardique. Les foyers systémiques se sont révélés significativement plus élevé chez les patients avec foyers myocardiques localisés (SUV max 2,2 ± 0,6 vs 1,5 ± 0,4, p <0,05 et SUV mean 1,6 ± 0,4 vs 1,2 ± 0,3, p <0,05, respectivement). Nous avons observé une corrélation significative entre la maladie coronarienne, l’âge, la fraction d’éjection du ventricule gauche et la présence de foyer myocardiques FAPI (R² = 0,74, p <0,01)

Conclusion

Notre étude indique une association entre la maladie cardiovasculaire coronarienne, l’âge et la FEVG et la captation myocardique de FAPI. Des études additionnelles sont nécessaires pour déterminer si l’activation des fibroblastes peut être mesurée de manière fiable et utilisée pour la détection et la progression de la maladie coronarienne et le remodelage du ventricule gauche

Introduction

Activation of fibroblasts is mandatory for repair and regeneration after myocardial injury including myocardial infarction (MI), progressive heart failure, or chemotherapy-induced injury, with the main mechanism of extracellular matrix remodeling.¹^,² Several pathways and mediators are suggested to play a role in fibrosis development, among others the renin-angiotensin-aldosterone (RAA) system, fibrogenic growth factors like transforming growth factor beta (TGF-β), or inflammatory cytokines and chemokines.³^,⁴ In addition, fibroblast activation protein (FAP) alpha has been demonstrated to be a specific marker of activated mature fibroblasts.⁵ The fibroblast activation protein, also known as dipeptidyl peptidase (DPP) 4, is an enzyme and represents a serine proteinase. During embryonic development, FAP expression can be detected in a variety of tissues.⁶ However, in adult humans, intensive expression is only found in the setting of wound healing, in fibrotic remodeling processes like in liver fibrosis and cirrhosis⁷ and in the stroma of the majority of malignant cancer types.8, 9, 10 The highest FAPI uptake was reported in sarcoma, esophageal, breast and lung cancer, and cholangiocarcinoma pointing at the dominant expression of FAP in solid tumors.⁹ A study analyzing brain samples could even demonstrate increased FAP expression in high-grade gliomas.¹¹ For this reason, it is not only a very promising target in the diagnosis and potentially also in radio-ligand therapy of various tumor types, but it also represents a highly interesting target to diagnose and monitor tissue alterations such as remodeling processes due to different noxious agents including ischemia, chemo-, or radiation therapy. Recently, a Ga-68-labeled tracer has been developed, which has already been increasingly used in the diagnosis and staging of malignancy.¹² The quinolone-based FAP inhibitors can be labeled using the chelator DOTA. Of the Ga-68-labeled FAP inhibitors described, FAPI-04 has been considered the most promising one due to its characteristics such as low nano-molar affinity, an almost complete internalization of more than 90% and rapid blood clearance. Advantages of FAPI over FDG are, among other things, that it represents a more specific signal with very low uptake in healthy organs and thus a very low background, which also provided the possibility for first theranostic concepts using Y-90 FAPI.¹² Furthermore, FAPI could be used in tumors that often have no or only limited increased FDG uptake resulting in a low sensitivity, such as pancreatic cancer or hepatocellular carcinoma.¹³ As there is no approved tracer so far, FAPI can only be used on a compassionate use basis. As many aspects of ventricular fibrosis development are still unclear,³ this novel imaging technique has the potential to significantly improve the understanding of ventricular fibrosis development under various clinical settings (e.g., cardiac side effects of modern cancer therapy). The latter consists of radio-, conventional chemo-, immuno-, and targeted therapy.¹⁴ Heart failure is among the most common side effects of these multimodal approaches and has been related to the development of fibrosis.¹⁵ Early detection of myocardial remodeling and fibrosis may be critical to prevent development of overt heart failure.

Aim of this study was to descriptively assess patterns of cardiac Ga-68 FAPI uptake in consecutive patients having undergone this imaging technique for staging after cancer treatment. Furthermore, we aimed to link this tracer uptake to clinical characteristics with respect to a cardiac disease history of the study cohort.

Section snippets

Patient Enrollment

We retrospectively analyzed patients having undergone FAPI PET imaging for cancer staging at the University Hospital Essen, Germany. According to the local standard, patients receiving anti-cancer treatment undergo cardiac diagnostic work-up before chemotherapy as well as half-annually after initiation of therapy to identify potential complications at an early stage. This standardized diagnostic work-up includes assessment of medical records, assessment of NYHA state and medical history by

Baseline Characteristics

From 09/2018 to 11/2019 N = 32 patients underwent PET imaging for staging after systemic anti-cancer treatment for different kinds of cancers. The majority of patients was female (17/32, 53.1%), with an overall mean age of 58.7 ± 15.0 years at time of PET scan. Left ventricular EF was preserved in the majority of patients, with an overall mean LVEF of 57.5 ± 7.3 %. The most frequent tumor entities were pancreatic cancer (18/32 (56.3%)), melanoma (2/32 (6.3%)), and osteosarcoma (2/32 (6.3%)).

Visual and Quantitative Assessment of Myocardial FAPI Uptake in the Overall Cohort

Six

Discussion

This is the first in-human study describing the pattern of cardiac FAPI uptake in a cohort of patients who underwent Ga-68 FAPI PET imaging for cancer staging. The main findings are that patients with visual detectable (focal) tracer uptake (6/32 patients, 18.8%) were older, with a higher prevalence of CAD/MI and lower LVEF. In patients with CAD, the visual tracer uptake seemed to correlate with the area of primarily diseased myocardium. In patients with increased uptake in certain myocardial

Conclusion

This is the first report to assess cardiac FAPI uptake in cancer patients. Higher age, a history of CAD/MI as well as impaired LVEF seem to be associated with increased localized uptake. These results point towards the potential role of FAPI imaging to assess myocardial localized as well as generalized injury. Further research efforts are needed to clearly link myocardial FAPI uptake to myocardial fibroblast activation. Finally, studies are warranted to assess if FAPI uptake might be used to

Funding

The authors have not received funding for the present study. Open Access funding provided by Projekt DEAL.

Disclosures

Wolfgang P. Fendler is a consultant for Ipsen, Endocyte, and BTG, and received personal fees from RadioMedix outside of the submitted work. J.T.S. is supported by the German Cancer Consortium (DKTK), the Deutsche Forschungsgemeinschaft (DFG; SFB824/C04 and KFO337/SI1549/3-1). J.T.S. has received consulting fees/ honoraria and has served as a speaker or advisory board member for AstraZeneca, Baxalta, Bristol-Myers Squibb, Celgene, Roche, Shire and has received research support from Bristol-Myers

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Cardiovascular disease is the leading cause of morbidity and mortality worldwide. Myocardial fibrosis plays an important role in adverse outcomes such as heart failure and arrhythmias. As the pathological response and degree of scarring, and therefore clinical presentation varies from patient to patient, early detection of fibrosis is crucial for identifying the appropriate treatment approach and forecasting the progression of a disease along with the likelihood of disease-related mortality. Current imaging modalities provides information about either decreased function or extracellular signs of fibrosis. Targeting activated fibroblasts represents a burgeoning approach that could offer insights prior to observable functional alterations, presenting a promising focus for potential anti-fibrotic therapeutic interventions at cellular level. In this article, we provide an overview of imaging cardiac fibrosis and discuss the role of different advanced imaging modalities with the focus on novel non-invasive imaging of activated fibroblasts.
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An important mechanism for cancer progression is degradation of the extracellular matrix (ECM) which is accompanied by the emergence and proliferation of an activated fibroblast, termed the cancer associated fibroblast (CAF). More specifically, an enzyme pathway identified to be amplified with local cancer progression and proliferation of the CAF, is fibroblast activation protein (FAP). The development and progression of heart failure (HF) irrespective of the etiology is associated with left ventricular (LV) remodeling and changes in ECM structure and function. As with cancer, HF progression is associated with a change in LV myocardial fibroblast growth and function, and expresses a protein signature not dissimilar to the CAF. The overall goal of this review is to put forward the postulate that scientific discoveries regarding FAP in cancer as well as the development of specific chemotherapeutics could be pivoted to target the emergence of FAP in the activated fibroblast subtype and thus hold translationally relevant diagnostic and therapeutic targets in HF.
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Noninvasive cardiovascular imaging plays a key role in diagnosis and patient management including monitoring treatment efficacy. The usefulness of noninvasive cardiovascular imaging has been extensively studied and shown to have high diagnostic reliability and prognostic significance, while the nondiagnostic results frequently encountered with single imaging modality require complementary or alternative imaging techniques. Hybrid cardiac imaging was initially introduced to integrate anatomical and functional information to enhance the diagnostic performance, and lately employed as a strategy for comprehensive assessment of the underlying pathophysiology of diseases. More recently, the utility of computed tomography has grown in diversity, and emerged from being an exploratory technique allowing functional measurement such as stress dynamic perfusion. Cardiac magnetic resonance imaging (CMR) is widely accepted as a robust tool for evaluation of cardiac function, fibrosis, and edema, yielding high spatial resolution and soft-tissue contrast. However, the use of intravenous contrast materials is typically required for accurate diagnosis with these imaging modalities, despite the associated risk of renal toxicity. Nuclear cardiology, established as a molecular imaging technique, has advantages in visualization of the disease-specific biological process at cellular level using numerous probes without requiring contrast materials. Various imaging modalities should be appropriately used sequentially to assess concomitant disease and the progression over time. Therefore, simultaneous evaluation combining high spatial resolution and disease-specific imaging probe is a useful approach to identify the regional activity and the stage of the disease. Given the recent advance and potential of multiparametric CMR and novel nuclide tracers, hybrid positron emission tomography MR is becoming an ideal tool for disease-specific imaging.
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Pulsed-field ablation (PFA) is a novel ablation modality for atrial fibrillation (AF) ablating myocardium by electroporation without tissue-heating. With its different mechanism of tissue ablation, it is assumed that lesion creation is divergent to thermal energy sources. ⁶⁸Ga-fibroblast-activation protein inhibitor (FAPI) PET/CT targets FAP-alpha expressed by activated fibroblasts. We aimed to assess ⁶⁸Ga-FAPI uptake in pulmonary veins as surrogate for ablation damage after PFA and cryoballoon ablation (CBA).
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Translators: Zhuo He, B.S., College of Computing, Michigan Technological University Min Zhao, M.D., Ph.D., Department of Nuclear Medicine, Xiangya Hospital Weihua Zhou, Ph.D., College of Computing, Michigan Technological University.

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Original ArticleCardiac fibroblast activation detected by Ga-68 FAPI PET imaging as a potential novel biomarker of cardiac injury/remodeling

Abstract

Background

Method and results

Conclusion

Spanish Abstract

Antecedentes

Método y resultados

Conclusión

Chinese Abstract

背景

方法和结果

结论

French Abstract

Contexte

Méthode et résultats

Conclusion

Introduction

Section snippets

Patient Enrollment

Baseline Characteristics

Visual and Quantitative Assessment of Myocardial FAPI Uptake in the Overall Cohort

Discussion

Conclusion

Funding

Disclosures

JACC Basic Transl Sci

J Am Coll Cardiol

Int J Cardiol

Int J Cardiol

J Mol Cell Cardiol

Is myocardial fibrosis a new frontier for discovery in cardiotoxicity related to the administration of anthracyclines?

Circ Cardiovasc Imaging

Myofibroblast-mediated mechanisms of pathological remodelling of the heart

Nat Rev Cardiol

Global fibroblast activation throughout the left ventricle but localized fibrosis after myocardial infarction

Sci Rep

Understanding fibroblast activation protein (FAP): Substrates, activities, expression and targeting for cancer therapy

Proteomics Clin Appl

Fibroblast activation protein: A cell surface dipeptidyl peptidase and gelatinase expressed by stellate cells at the tissue remodelling interface in human cirrhosis

Hepatology

Cell surface glycoprotein of reactive stromal fibroblasts as a potential antibody target in human epithelial cancers

Proceedings of the National Academy of Sciences of the United States of America

Original Article
Cardiac fibroblast activation detected by Ga-68 FAPI PET imaging as a potential novel biomarker of cardiac injury/remodeling