FAPI PET/CT Imaging in Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) (FAPI-ARVC))

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited myocardial disease characterized by progressive fibro-fatty replacement of the ventricular myocardium, predominantly involving the right ventricle, although left ventricular and biventricular forms are increasingly recognized. The disease is associated with ventricular arrhythmias, progressive ventricular dysfunction, heart failure, and sudden cardiac death. Because phenotypic expression is variable and may evolve over time, early diagnosis remains challenging, particularly in patients with subtle structural abnormalities or incomplete expression of conventional diagnostic criteria.

Current diagnostic evaluation relies on a multiparametric approach integrating electrocardiographic, arrhythmic, structural, functional, histopathological, and genetic findings. The revised 2010 Task Force Criteria improved standardization of diagnosis, and the Padua criteria further expanded the disease concept by incorporating left ventricular involvement. However, despite these advances, important limitations remain, especially in the early stages of disease, when conventional imaging may not adequately detect active myocardial remodeling.

Echocardiography and cardiac magnetic resonance imaging are central imaging modalities in ARVC. Echocardiography allows assessment of chamber dimensions, ventricular systolic function, and regional wall motion abnormalities, whereas cardiac magnetic resonance imaging provides more detailed characterization of ventricular volumes, function, and tissue abnormalities. Nevertheless, both techniques primarily reflect structural and functional consequences of disease and may be less sensitive for detecting early or biologically active fibrotic remodeling. This limitation is particularly relevant in a disease in which myocardial fibrosis is a major pathological substrate for electrical instability and arrhythmogenesis. It may also be especially important in patients who are unable to undergo cardiac magnetic resonance imaging because of contraindications or technical limitations. In such cases, 68Ga-DOTA-SA-FAPI PET/CT may provide complementary diagnostic information by enabling non-invasive assessment of active myocardial fibrotic remodeling.

Molecular imaging with fibroblast activation protein inhibitor positron emission tomography/computed tomography (FAPI PET/CT) has emerged as a promising non-invasive technique for visualizing activated fibroblasts in vivo. Fibroblast activation protein is overexpressed in activated fibroblasts involved in tissue remodeling and fibrogenesis. In cardiovascular disease, FAPI-based imaging has attracted growing interest as a potential marker of active fibrosis. In ARVC, where fibro-fatty myocardial replacement is a defining pathological feature, 68Ga-DOTA-SA-FAPI PET/CT may offer additional biological information beyond conventional imaging by identifying active fibroblast-related remodeling.

The present study is a prospective single-group diagnostic imaging study designed to evaluate the incremental value of protocol-specified 68Ga-DOTA-SA-FAPI PET/CT imaging in adult patients with ARVC. The central hypothesis is that FAPI PET/CT may improve the non-invasive assessment of myocardial fibrotic activity and provide complementary information to conventional multimodality evaluation.In particular, the study seeks to explore whether myocardial FAPI uptake is detectable in patients with ARVC and whether uptake patterns correlate with established clinical, electrocardiographic, echocardiographic, and previously obtained cardiac magnetic resonance findings. The study will also explore the potential usefulness of FAPI PET/CT in patients in whom cardiac magnetic resonance imaging is unavailable or cannot be performed.

The study will be conducted through collaboration between the Istanbul University-Cerrahpaşa Institute of Cardiology, Department of Cardiology, and the Istanbul Training and Research Hospital, Department of Nuclear Medicine. Fifteen adult patients with established ARVC who are under clinical follow-up will be enrolled prospectively. Following informed consent, participants will undergo comprehensive clinical evaluation together with electrocardiography, transthoracic echocardiography, review of previously obtained cardiac magnetic resonance imaging findings, and protocol-specified 68Ga-DOTA-SA-FAPI PET/CT imaging. No new cardiac magnetic resonance imaging will be performed as part of the study protocol.

The PET/CT imaging protocol includes intravenous administration of approximately 150-200 MBq of 68Ga-DOTA-SA-FAPI. No fasting or specific dietary preparation is required. After tracer injection, participants will rest during an uptake period of approximately 40-60 minutes. Imaging will then be performed using a hybrid PET/CT scanner. A low-dose CT acquisition will be obtained for attenuation correction and anatomical localization, followed by three-dimensional PET acquisition focused on the thoracic region for cardiac assessment. Images will be reconstructed according to standard institutional protocols using attenuation, scatter, and decay correction methods.

Image analysis will focus on the presence, localization, and pattern of myocardial FAPI uptake. Particular attention will be paid to uptake involving the right ventricular free wall, right ventricular outflow tract, interventricular septum, left ventricular myocardium, or biventricular distribution. Where technically feasible, semi-quantitative parameters such as standardized uptake values may also be recorded. These findings will be interpreted in relation to conventional imaging, including previously available cardiac magnetic resonance imaging, and clinical phenotype in order to assess the potential complementary role of FAPI PET/CT in ARVC characterization.

Participants will also undergo clinical follow-up for 6 months after PET/CT imaging. Follow-up data will include interval symptoms, arrhythmic events, clinical status, routine electrocardiographic findings, echocardiographic reassessment where available, and selected laboratory parameters obtained during standard care. This follow-up is intended to provide preliminary exploratory information regarding possible associations between baseline myocardial FAPI uptake and short-term clinical course.

As an exploratory pilot study, this project is primarily intended to generate early clinical evidence regarding the feasibility and potential usefulness of FAPI PET/CT in ARVC. The study is expected to clarify whether imaging of fibroblast activation may complement current structural and functional assessment, especially in cases where conventional modalities provide limited or equivocal information. It may also provide preliminary evidence regarding the potential role of FAPI PET/CT in the diagnostic evaluation of patients with ARVC who are unable to undergo cardiac magnetic resonance imaging, while also allowing comparison with previously obtained cardiac magnetic resonance data in patients with established ARVC. If myocardial uptake patterns appear biologically and clinically meaningful, the results may support the development of larger prospective studies investigating the diagnostic and prognostic role of FAPI PET/CT in arrhythmogenic cardiomyopathy.

Data will be collected and managed by the study investigators in accordance with institutional ethical standards. Study data will be coded and de-identified before analysis to protect participant confidentiality. Because this is an investigator-initiated academic study, analyses and interpretation will be performed independently by the research team. The results are expected to provide pilot data relevant to future multicentre research and to the broader investigation of molecular imaging biomarkers in inherited cardiomyopathies.