Cardiac fibroblast activation as a novel molecular imaging biomarker in hypertrophic cardiomyopathy: a prospective positron emission tomography study

Abstract Background Hypertrophic cardiomyopathy (HCM) is the commonest inherited cardiomyopathy. Whilst many patients remain asymptomatic, some progress to advanced hypertrophy, heart failure and sudden cardiac death1. Current imaging markers do not reliably predict disease progression, an unmet need in the era of emerging targeted therapies. Myocardial fibrosis, driven by activated fibroblasts, is a hallmark of HCM, and associated with adverse outcomes2. The novel PET tracer Gallium-68 Fibroblast Activation Protein Inhibitor [68Ga]FAPI-46 binds to activated fibroblasts, providing a readout of their activity in the myocardium3. We prospectively investigated its role across the HCM disease spectrum. Methods In this single-centre observational cohort study, patients with established HCM, pathogenic gene variant carriers without overt left ventricular hypertrophy (LVH) and healthy volunteers underwent hybrid [68Ga]FAPI-46 PET and magnetic resonance imaging. Myocardial tracer uptake was visually assessed and quantified using global and segmental analysis. [68Ga]FAPI-46 uptake was quantified as maximum target-to-background ratio (TBRmax). Total myocardial FAPI burden (CMV%) was defined as signal exceeding 1.5× blood pool activity. Associations between myocardial uptake, HCM phenotype, and clinical and imaging markers of adverse remodelling were evaluated. Results 56 patients with established HCM (median age 56 [IQR 42, 65] years, 71% male), 5 MYBPC3 gene carriers without overt LVH (age 48 [45, 54], 100% male) and 21 healthy volunteers (age 57 [54, 61], 71% male) were included. Left ventricular myocardial [68Ga]FAPI-46 uptake was absent in controls but present in all patients with established HCM and MYBPC3 gene carriers without LVH (Figure1a&1b). [68Ga]FAPI-46 uptake localised to and extended beyond regions of LVH and LGE, with a greater burden FAPI-positive than LGE-positive segments (Figure 1b). The intensity of [68Ga]FAPI-46 uptake increased across each group (TBRmax healthy 1.15 [1.07–1.23] vs gene carrier 1.60 [1.57–2.08] vs established HCM 3.21 [2.31–4.22], p<0.001) (Figure 2a) and correlated with biomarker and imaging metrics of adverse remodelling (LV mass ρ=0.42; GLS ρ=0.54; troponin ρ=0.53; LGE burden ρ=0.69; all p<0.001) (Figure 2b). Among patients with HCM, total myocardial [68Ga]FAPI-46 burden correlated with ESC 5-year sudden cardiac death risk score (ρ=0.38, p=0.003) and demonstrated moderate discrimination for ESC ≥3% risk (AUC 0.72, 95% CI 0.58–0.87) (Figure 2c). Conclusion For the first time, we demonstrate that cardiac fibroblast activation is increased across the HCM disease spectrum, preceding overt hypertrophy and established fibrosis. Intensity and burden of fibroblast activation correlate with markers of disease severity, supporting [68Ga]FAPI-46 as a potential novel imaging biomarker for early disease detection, risk stratification and identifying patients most likely to benefit from disease-modifying therapies.