Myocardial Fibroblast Activation in Ischemic and Nonischemic Cardiomyopathy

IMPORTANCE: Adverse myocardial remodeling and fibrosis contribute to heart failure progression and are thought to be driven by activated fibroblasts. Noninvasive assessment of myocardial fibroblast activation may improve phenotyping and risk stratification in heart failure. OBJECTIVE: To evaluate myocardial fibroblast activation in patients with heart failure with reduced ejection fraction using gallium 68-labeled fibroblast activation protein inhibitor 46 (68GaFAPI-46) positron emission tomography (PET) and magnetic resonance imaging (MRI). DESIGN, SETTING, AND PARTICIPANTS: This was a prospective case-control study including patients with heart failure with reduced ejection fraction, patients with prior myocardial infarction without heart failure, and healthy volunteers. A subset of patients with heart failure underwent repeat imaging after more than 6 months. Data analysis was conducted from January 2024 to January 2025. EXPOSURE: All participants underwent 68GaFAPI-46 PET/MRI. MAIN OUTCOMES AND MEASURES: Myocardial fibroblast activation quantified using maximum standardized uptake values (SUVmax) of 68GaFAPI-46. RESULTS: A total of 81 participants were included (mean SD age, 66.2 9.7 years; 22 27% female): 42 with heart failure (21 with heart failure due to ischemic cardiomyopathy from a previous myocardial infarction and 21 with a nonischemic etiology; mean SD left ventricular ejection fraction, 41% 9%), 20 with a prior myocardial infarction but preserved left ventricular systolic function, and 19 healthy volunteers. No myocardial fibroblast activation was observed in healthy volunteers. All patients with heart failure demonstrated increased myocardial 68GaFAPI-46 uptake compared with healthy volunteers (mean SD SUVmax, 2.7 1.5 vs 1.5 0.3; P < .001). Uptake was highest in patients with ischemic cardiomyopathy, localizing to regions of established myocardial infarction (mean SD SUVmax, 3.2 1.1). Patients with nonischemic cardiomyopathy exhibited a different pattern of diffuse, lower-intensity uptake (mean SD SUVmax, 2.3 0.5), with the highest signal in the basal septum irrespective of late gadolinium enhancement. Patients with ischemic cardiomyopathy had higher uptake than patients with prior myocardial infarction without heart failure (n = 20) despite no major difference in infarct size (mean SD SUVmax, 3.2 1.1 vs 2.5 0.3; P = .03). Among patients with heart failure who underwent repeat imaging, higher baseline 68GaFAPI-46 uptake was associated with less improvement in ejection fraction with optimal medical therapy over time (r = -0.52; P = .02). CONCLUSIONS AND RELEVANCE: In this case-control study, patients with heart failure demonstrated persistent myocardial fibroblast activation with distinct spatial patterns according to cardiomyopathy etiology. Noninvasive imaging of fibroblast activation may provide mechanistic insights, aid risk stratification, and support the development of targeted antifibrotic therapies in heart failure.