Molecular characterization of the extracellular matrix (ECM) in NICM may help identify therapeutic pathways to attenuate cardiomyocyte dysfunction and enhance myocardial regeneration. Fibroblast activation protein is one of the matricellular ECM proteins, which is involved in fibroblast activation and myofibroblast generation underlying myocyte injury. Cardiac fibroblasts activation and expansion significantly contribute to the pathogenesis of multiple cardiac diseases [2]. Pioneering basic and clinical research demonstrated intensive focal FAPI signals in the infarcted myocardium, which showed good agreement with the affected coronary territory [7]. Nowadays, the evidence of FAPI imaging in the evaluation of non-ischemic cardiomyopathies (NICM) was limited, so we aimed to quantify and characterize fibroblast activation in multiple NICMs and investigate whether the cardiac FAPI activity is a surrogate biomarker of myocardial dysfunction.

In this study, we observed in vivo molecular imaging of 68Ga-FAPI-04 PET targeting FAP in different subtypes of NICM patients. We found that most enrolled patients presented elevated myocardial uptake with heterogeneous patterns and FAPI signal density is associated with cardiac contractility. In our previous cohort conducting 68Ga-FAPI-04 PET in patients with noncardiovascular indications, we did not observe elevated cardiac FAPI signal [8].

In this preliminary study, we found heterogeneous diffused elevated FAPI signals within the left ventricular wall in different subtypes of NICM patients, and a distinct FAPI uptake value was observed within the same category of disease. We thought various disease pathogeny might be an explanation. For instance, for the enrolled inflammatory cardiomyopathies patients, the underlying diseases include inflammatory myopathy, vasculitis, systemic sclerosis, and systemic lupus erythematosus. Although inflammatory cardiomyopathies are associated with inflammatory cell infiltration into the myocardium, the underlying mechanism of the autoimmune response might be different [9]. FAPI signal could be transient and not associated with disease staging. In addition, DCM is a heterogeneous disease that presents the manifestation of multiple non-ischemic disorders, e.g., genetic mutations, metabolic and endocrine disturbances, exposure to alcohol, drugs, and toxins [10]. The disease severity and duration were also different. These could eventually lead to different FAPI signals in the same type of disease. Interestingly, we observed elevated right ventricular uptake in a few patients, including 1 RCM patient, 2 DCM patients, all 3 HCM patients, and 4 inflammatory cardiomyopathy patients. This might indicate that disease-related fibrotic activation could also occur in the entire heart. In the correlation analysis, the cardiac uptake parameters were significantly associated with enlarged ventricular volume. Due to the limited patient number in our data, further subgroup analysis could not be achieved.

All in all, NICMs are essential and heterogeneous groups of diseases. Conventional imaging features for defined describing disease entities of cardiomyopathies may be limited with low sensitivity. FAPI PET imaging might provide essential information regarding the derivation and function of cardiac tissue or disease severity, potentially implicating a preferable strategy for visualizing cardiac diseases. The prognostic value of cardiac FAPI PET imaging in multiple NICMs post-systemic or targeted therapy also needs to be investigated. Although our study has some limitations, including a relatively small sample size and lack of a control group, we believe it provides important preliminary data on the potential use of the FAPI signal as a noninvasive biomarker for NICMs and warrants further investigation in larger and more diverse patient populations. Another limitation is that the fibro-activation signal in cardiac disease is transient, disease-dependent, and cannot be accurately associated with disease staging. The limitations of FAPI imaging underscore the need for a more comprehensive and nuanced approach to evaluating cardiac disease, which takes into account the dynamic changes in macrophage and fibroblast activity over time.