Gallium-68 fibroblast activation protein inhibitor positron emission tomography in cardiovascular disease

Gallium-68 fibroblast activation protein inhibitor [(⁶⁸Ga)Ga-FAPI] is a new radiopharmaceutical positioning itself as the preferred agent in patients with malignant tumours, competing with 2-Deoxy-2-[18F]fluoro-d-glucose [2-(¹⁸F)FDG] using positron emission tomography (PET). While imaging oncology patients with [⁶⁸Ga]Ga-FAPI PET, incidental uptake of [⁶⁸Ga]Ga-FAPI has been detected in the myocardium. This review summarises original research studies associating the visualisation of FAPI-based tracers in the myocardium with underlying active cardiovascular disease.

1. Introduction

Gallium-68 fibroblast activation protein inhibitor [⁶⁸Ga]Ga-FAPI is a new radiopharmaceutical widely used when imaging patients with various malignancies, inflammatory and pre-fibrotic conditions. The tumour environment predominantly consists of cancer-associated fibroblasts (CAF) and non-malignant cells that play a role in cancer metabolism and regulate tumour growth and aggressiveness (1). These CAF overexpress the fibroblast activation protein, a binding site for [⁶⁸Ga]Ga-FAPI. Similarly, increased fibroblast activation protein (FAP) expression in patients with cardiac disease has been identified at day seven post myocardial infarction (2). When a myocardial injury occurs, fibroblasts differentiate into myofibroblasts which produce components of the extracellular matrix (ECM), predominantly collagen, to allow healing and maintaining the structural integrity of the heart.

2. Gallium-68 fibroblast activation protein inhibitor positron emission tomography

Fibroblasts are elongated spindle-shaped cells with a basophilic cytoplasm, an oval nucleus, a well-developed Golgi apparatus, and an abundantly rough endoplasmic reticulum (Figure 1). Fibroblasts originate from mesenchymal cells derived from stem cells. They are the most abundant cell type in the connective tissue of various organs. The cellular membrane of activated fibroblasts expresses FAP, a transmembrane serine protease composed of amino acids with an intracellular domain of six amino acids, and a transmembrane domain of 20 amino acids (3).

Figure 1

Figure 1. Morphological transformation of fibroblasts after myocardial infarction. Fibroblasts transform from a resting state into proto-myofibroblasts and myofibroblasts expressing fibroblast activation protein, the binding site for fibroblast activation protein inhibitor-based imaging agents.

Gallium-68 fibroblast activation protein inhibitor positron emission tomography (PET) has positioned itself as the preferred imaging modality for the staging and restaging of various oncological malignancies such as head, neck, and abdominal tumours, almost overthrowing 2-Deoxy-2-[¹⁸F]fluoro-d-glucose [2-(18F)FDG] PET (4). The ease of onsite preparation and the high tissue-to-background contrast ratio of gallium-labelled ligands render them ideal imaging agents over [2-(18F)FDG]. In some studies, [⁶⁸Ga]Ga-FAPI PET has been used for radiation treatment planning and evaluation of biodistribution kinetics (5).

The synthesis of FAPI precursors for tumour binding and potential therapy, FAPI-02 up to FAPI-15, has been reported by Linder et al. (6). In their study, FAPI-04 had a favourable tumour-to-blood volume in patients with metastatic breast cancer. Also, FAPI-04 was more stable in human serum (6). Other FAPI precursors include FAP-34, which has been labelled with technetium-99m, FAPI-74, and FAPI-46 (7). Novel techniques for synthesising [⁶⁸Ga]Ga-FAPI-46 involve mixing a buffer solution with ascorbic acid and 50 micrograms (µ) of FAPI-46 and transferring the mixture into the reactor vial. Gallium-68 is eluted from a Germanium-68/Gallium-68 generator, typically with 5 millilitres of 0.1 M hydrochloric acid, and then preheated. The [⁶⁸Ga]GaCl₃ solution eluted from the generator is mixed with 50 µg of the FAPI-46 precursor and heated at 90° C for 4 min (8).

Once the radiopharmaceutical has been administered intravenously, it travels in the bloodstream and enters the myocardium. Eventually, the [⁶⁸Ga]Ga-FAPI complex binds to the fibroblast activation protein expressed on the cell membrane of activated fibroblasts. On the PET images of the myocardium, the localisation of the radiopharmaceutical in actively healing tissue will manifest as focal and sometimes diffuse increased uptake of [⁶⁸Ga]Ga-FAPI as seen in cardiac amyloidosis. This has been demonstrated in case reports and retrospective studies conducted on patients with malignant or inflammatory diseases (9–11).

3. Preclinical studies supporting the use of a Gallium-68 fibroblast activation protein inhibitor post myocardial infarction

Preclinical studies have shown promising results on the role of [⁶⁸Ga]Ga-FAPI in studying cardiac remodelling after myocardial infarction (MI) and in heart failure. Varasteh et al. induced MI in 20 rats by ligating the left anterior descending coronary artery, and a sham procedure was performed in four rats (2). A series of [⁶⁸Ga]Ga-FAPI-04 positron emission tomography/computerised tomography (PET/CT) images were acquired on days 1, 3, 6, 14, 23, and 30 after MI, and the [⁶⁸Ga]Ga-FAPI uptake peaked on day 6 and decreased rapidly by day 14. Immunofluorescence staining analyses on infarcted hearts on day 7 showed selective accumulation of FAP-positive cells in the peri-infarct zone (2).

Also, Qiao et al. noninvasively monitored reparative fibrosis in rats using [⁶⁸Ga]Ga-FAPI PET/CT. In their study, they induced myocardial infarction in 16 rats by performing a thoracotomy and ligating the left anterior descending coronary artery (12). A thoracotomy was done on another 17 rats without ligating any coronary arteries (sham procedure). Serial imaging with [⁶⁸Ga]Ga-FAPI PET/CT was performed in rats at different time points, from day 1 to day 35 post-surgery. Also, the excised cardiac tissue specimens from two rats with induced myocardial infarction and two sham-operated rats were subjected to histological examination, autoradiography, and immunofluorescence staining.

In the rats with MI, the excised cardiac tissue revealed an infiltrate of inflammatory cells, dissolved and broken muscle fibres, necrosis, and features of replacement fibrosis. Autoradiography showed an accumulation of FAPI in the infarcted myocardium and infarct border zone (12). Similarly, FAP-positive cells were identified in the infarcted area, specifically on days 3, 6, and 15 after the infarction. The myocardium of sham-operated rats exhibited normal morphology with neatly arranged myocardial fibres (12). Both of these studies demonstrated the feasibility of monitoring ventricular remodelling after MI.

Gallium-68 FAPI PET/CT findings have also been correlated with histopathological changes in rats with heart failure. Serial imaging was performed on the experimental and control groups of mice on day 0 before inducing heart failure with isoproterenol hydrochloride and 7, 14, 21, and 28 days thereafter (13). In rats with heart failure, [⁶⁸Ga]Ga-FAPI uptake increased on days 7 and 14 and declined on days 21 and 28. Histological evaluation of heart tissue specimens showed fibrotic activity, which increased from day 0 to day 28 in rats with heart failure. No tracer uptake was seen on day 0, and a peak uptake was observed on day 7. Serial echocardiography findings showed a decline in systolic function on day 7. After day 7, ventricular chamber enlargement, ventricular wall thinning, and a reduction in myocardial contractility were observed. Also, the heart-to-muscle uptake ratio was the highest on day 7, gradually decreasing over time (13).

4. Clinical studies demonstrating the use of a Gallium-68 fibroblast activation protein inhibitor positron emission tomography in patients with various cardiovascular diseases

We conducted a systematic literature search on PubMed and Web of Science to identify original research studies and case reports demonstrating the use of FAPI on subjects known or suspected to have underlying cardiovascular diseases (CVD). The following search terms and associated Medical Subject Headings (MeSH) were used: “Gallium-68 AND Fibroblast activation protein” OR “Flourine-18 AND Fibroblast activation protein.” We retrieved 15 studies focused on the clinical utility of FAPI-based PET tracers labelled with either Gallium-68 or Flourine-18 on conditions such as coronary artery diseases, cardiomyopathies, infiltrative heart diseases, immune checkpoint inhibitor-related myocarditis, systemic sclerosis, and other pathologies such as pulmonary arterial hypertension, which may lead to fibrotic changes in the right ventricle (Table 1). Most of the evidence supporting the potential role of FAPI-based tracers in identifying active cardiac disease and managing CVD originates from original research studies with small sample sizes, case reports, or a retrospective review of FAPI PET images in patients with malignancies referred for PET imaging. In studies reporting incidental visualisation of cardiac uptake of FAPI in patients with underlying malignancies, logistic regression analysis reporting odds ratios and correlation studies reporting correlation coefficients were used to associate the visualisation of FAPI with CVD or its risk factors.

Table 1

Table 1. Summary of original clinical research studies evaluating the uptake of fibrin-activating protein inhibitors in the myocardium of subjects with known or suspected cardiovascular disease.

4.1. Coronary artery disease

FAPI for ST-segment elevation myocardial infarction (STEMI) has been primarily used in patients with coronary artery disease. Zhang et al. studied 26 patients with STEMI after percutaneous coronary intervention referred for imaging with [⁶⁸Ga]Ga-DOTA-FAPI Positron emission tomography/magnetic resonance imaging (PET/MRI) and found that both the volume and intensity of FAPI decreased over time when comparing the baseline and follow-up scan performed 12 months later. However, on the PET/MR images acquired 12 months after the acute myocardial infarction, FAPI uptake persisted in all patients studied (17). Similarly, in another study involving 35 patients with STEMI, [⁶⁸Ga]Ga-DOTA-FAPI uptake was significantly elevated in the territory of the stenosed coronary artery (18).

Atherosclerotic coronary artery disease, presenting as chronic coronary or acute unstable syndromes, results from traditional risk factors such as hypertension and smoking, known to cause coronary vascular endothelial damage by inducing inflammation, as evidenced by elevated C-reactive protein plasma levels (27). In addition, atherosclerosis may occur as a secondary element of vascular inflammation, despite the absence of cardiovascular risk factors (28, 29). Acute coronary syndromes are precipitated by the thrombotic occlusion of an unstable, complicated atherosclerotic plaque. During myocardial ischaemia, the reduction in blood flow and subsequent delivery of oxygen to the heart muscle induces necrosis in the myocyte. Once the vessel is damaged, it attempts to “seal” the damaged area by depositing lipids and recruiting inflammatory cells (30). The diameter of the vessel where the atheroma is located narrows over time.

In response to myocardial ischaemia, a series of signalling mechanisms lead to the transformation of the structure of fibroblasts from the resting state to an activated proto-myofibroblast, which ultimately transforms into a myofibroblast (Figure 1).

Recurrent, small thrombotic non-occlusive ischaemic episodes and reperfusion or occlusive non-reperfused episodes are usually followed by the recruitment of macrophages and fibroblasts to the injured area of the myocardium or endocardium, a hallmark of myocardial fibrosis. As demonstrated by Zhang and colleagues, the persistent activation of fibroblasts may suggest the presence of underlying ventricular remodelling, in which the heart attempts to repair the infarcted area, or adverse ventricular remodelling, where the recruitment of fibroblasts will result in excessive deposition of collagen, which will eventually impair the contractility of the heart muscles.

Non-invasive fibroblast activation detection after acute myocardial infarction may identify areas of adverse ventricular remodelling depicted by persistent [⁶⁸Ga]Ga-FAPI-04 uptake despite re-perfusion therapy. This persistent uptake has been demonstrated by Diekmann et al., who studied 35 patients with post acute STEMI. These patients were referred for imaging with single photon emission computed tomography (SPECT), PET, and CMR after percutaneous coronary intervention and dual-antiplatelet therapy (18). Despite receiving reperfusion therapy, [⁶⁸Ga]Ga-FAPI-04 PET images showed uptake in the anterior and septal walls and, partially, in the apex (Figure 2)(18). The clinical significance of cardiac fibroblast activation after reperfusion therapy needs further exploration, as this finding may be indicative of adverse or expected ventricular remodelling after restoring myocardial perfusion.

Figure 2

Figure 2. Cardiac images acquired after reperfusion therapy for acute myocardial infarction. The first row depicts single photon emission computed tomography (SPECT) myocardial perfusion images acquired at rest using [^99mTc]Tc-tetrofosmin, followed by [⁶⁸Ga]Ga-FAPI-04 PET images in the second row. The third row depicts cardiovascular magnetic resonance imaging. There are no perfusion defects visualised after reperfusion therapy in the SPECT resting perfusion images. However, a large area of cardiac fibroblast activation is visualised in the anterior and septal walls and partially in the apex. There is no evidence of late gadolinium enhancement in the corresponding myocardial images on CMR. HLA, horizontal long axis; SA, short axis; VLA, vertical long axis. This research was originally published in JNM. Johanna Diekmann et al. (18). © SNMMI.

4.2. Hypertrophic cardiomyopathy

Fibroblast activation has been studied in patients with dilated and hypertrophic cardiomyopathies (14, 15). In patients with hypertrophic cardiomyopathy (HCM), interstitial fibrosis is one of the typical histological features predisposing patients to arrhythmias and heart failure (31). Wang et al. performed PET imaging with Fluorine 18 [¹⁸F]-AlF-NOTA-FAPI (¹⁸F-FAPI) on 50 patients with HCM and 22 age and sex-matched healthy volunteers (14). They found intense and inhomogeneous tracer uptake in all patients with HCM, and the uptake was weakly correlated (r = 0.32) with a 5-year risk of sudden cardiac death (14). The potential role of FAPI-based tracers in HCM is for the selection of patients at high risk of sudden cardiac death (SCD), where an implantable cardioverter-defibrillator (ICD) may be implanted prophylactically to prevent lethal arrhythmias and heart failure in patients exhibiting FAPI uptake on imaging.

4.3. Amyloidosis

Amyloidosis is a systemic infiltrative disease characterised by the extracellular deposition of insoluble proteins in various organs, including the heart, and the abnormal accumulation of amyloid proteins in solid organs may lead to organ dysfunction (32). Non-invasive imaging modalities such as echocardiography and CMR imaging help to identify cardiac involvement in subjects with systemic amyloidosis (32). In a study involving 30 patients with biopsy-proven systemic light-chain amyloidosis, [⁶⁸Ga]Ga-FAPI-04 PET/CT was used to assess cardiac fibroblast activation (16). Patchy and diffuse uptake patterns were found in 80% of patients, suggesting active cardiac remodelling (16). Gou and Chen explored the clinical utility of staging multiple myeloma with [⁶⁸Ga]Ga-FAPI-04 PET/CT. Diffuse and inhomogeneous FAPI uptake was visualised in the left ventricle, suggesting cardiac amyloidosis (21). In patients with cardiac involvement, FAPI-based imaging may also play a role in identifying patients at risk for SCD requiring ICDs.

5. Assessment of myocardial fibrosis

Fibrosis in the heart indicates an area in the myocardium that cannot contract effectively, leading to myocardial contractile dysfunction, heart failure, a possible nidus for ventricular arrhythmias, and SCD (33–35). The endomyocardial biopsy allows for histological, immunohistochemical, and molecular evaluation of a specimen of cardiac tissue (36). Ideally, the biopsy should be performed under image guidance to increase the probability of sampling abnormal tissue. The major drawback of performing an endomyocardial biopsy is the limited access to cardiac catheterisation laboratories in most low-and middle-income countries.

Newer imaging techniques, such as the visualisation of late gadolinium enhancement and the quantification of the extracellular volume using CMR imaging, have proven to be helpful in identifying fibrotic tissue in patients with ischaemic and non-ischaemic dilated cardiomyopathy (37–39). In research settings, human cardiac tissue has been excised during coronary artery bypass graft (CABG) surgery, left ventricular assist device implantation, and cardiac transplant surgery to assess for micro- and macroscopic evidence of myocardial fibrosis (40). The characteristics of non-invasive imaging methods for evaluating myocardial fibrosis are summarised in Table 2.

Table 2

Table 2. Non-invasive imaging modalities for the assessment of myocardial fibrosis.

6. Future Studies and Recommendations

Cardiac fibroblast activation has been studied in patients with various CVDs, mostly in patients with ischaemic heart disease. Whether the visualisation of FAPI uptake on the myocardium suggests the presence of an underlying normal response to myocardial injury or adverse remodelling remains to be elucidated. Future studies should attempt to perform non-invasive imaging at multiple time points and correlate imaging findings with inflammatory markers. The frequency of imaging could be extrapolated from animal models. In addition, subjects known to have coronary artery diseases should be subjected to coronary angiography and subsequently randomised to imaging with FAPI-based tracers and CMR imaging to evaluate the clinical impact of FAPI in defining clinically relevant outcomes such as cardiovascular death, all-cause mortality, and the rate of rehospitalisation. Furthermore, considering that the activation of fibroblasts is a momentary phase in the life cycle of fibroblasts, the window of opportunity for intervening should be clearly defined. Moreover, the utility of FAPI-based tracers could be further explored in patients with chronic coronary syndromes, potentially selecting candidates for coronary revascularisation.

7. Conclusions

Evidence supporting the application of FAPI-based radiopharmaceuticals in cardiac diseases is still in its infancy, comprising data collated from original research studies with small sample sizes, case reports, and retrospective studies on patients with oncological conditions. After a myocardial injury, the heart attempts to repair the damaged tissue and maintain its structural integrity by orchestrating a series of processes, including the deposition of extracellular matrix components and the activation of fibroblasts. Unresolved pertinent issues related to imaging activated fibroblasts include the appropriate timing for imaging and the need for a definitive management plan in patients with FAPI uptake in the myocardium.

Author contributions

Conceptualisation of the study: DM, MS, and NT. Literature review: DM, MS, SM, and JD. All authors contributed to the article and approved the submitted version. DM wrote the first draft of the manuscript. NT, MS, EK, SM, JD, BH, and MV edited the manuscript.

Acknowledgments

Figure 1 was created with Biorender software. The authors would like to thank the Society of Nuclear Medicine and Molecular Imaging for permission to reuse Figure 2 was originally published in the Journal of Nuclear Medicine by Johanna Diekmann et al. Cardiac Fibroblast Activation in Patients Early After Acute Myocardial Infarction: Integration with MR Tissue Characterization and Subsequent Functional Outcome. J Nucl Med 2022;63:1415-1423. © SNMMI

Conflict of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

The author MS declared that they were an editorial board member of Frontiers at the time of submission. This had no impact on the peer review process or the final decision.

Publisher's note

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