Persistent activation of myocardial fibroblasts was observed in patients with heart failure with reduced ejection fraction (HFrEF), with distinct spatial patterns related to the etiology of the cardiomyopathy, according to results from a prospective study published April 15 in JAMA Cardiology. These findings suggest that noninvasive imaging of fibroblast activation may provide mechanistic insights, aid risk stratification and support the development of targeted antifibrotic therapies in HF.

In this case-control study with 81 participants, whose mean age was 66 years and a third were women, 42 had HF (half were ischemic cardiomyopathy and half were nonischemic), 20 had a prior myocardial infarction but preserved left ventricular systolic function and 19 were healthy volunteers. Data analysis was conducted from January 2024 to January 2025.

To evaluate myocardial fibroblast activation, the main outcome of the study, Shruti S. Joshi, MBBS, PhD, et al., used gallium 68-labeled fibroblast activation protein inhibitor 46 ([⁶⁸Ga]FAPI-46) PET and MRI. The researchers conducted repeat imaging in a subset of 19 patients with HF after more than six months.

Results showed there was no myocardial fibroblast activation in healthy volunteers. In contrast, in patients with HF, there was increased myocardial uptake of [⁶⁸Ga]FAPI-46 (mean SUVmax, 2.7 [1.5] vs. 1.5 [0.3]; p<0.001).

Notably, the highest uptake was among patients with ischemic cardiomyopathy, which was localized to regions of established MI (mean SUVmax, 3.2 [1.1]), whereas in patients with nonischemic cardiomyopathy there was diffuse uptake of a lower intensity (mean SUVmax, 2.3 [0.5]), with the highest signal in the basal septum, independent of the presence of late gadolinium enhancement.

Additionally, the uptake of [⁶⁸Ga]FAPI-46 was higher in patients with ischemic cardiomyopathy than those with a prior MI without HF, even though the infarct size was comparable (mean SUVmax, 3.2 [1.1] vs. 2.5 [0.3]; p=0.03).

Looking at the patients with HF who underwent repeat imaging, higher baseline ([⁶⁸Ga]FAPI-46 uptake was associated with less improvement in ejection fraction following optimal medical therapy over time (p=0.02).

Despite several study limitations including the modest size of the study population and limited availability of the radiotracer used, "these findings support an important pathophysiological role for activated fibroblasts in [HF] and identify them as a potential therapeutic target," write the authors. "Importantly, [⁶⁸Ga]FAPI-46 uptake provides information different from but complementary to that of cardiac MRI."

"These studies confirm prior investigations suggesting a direct role of cardiac fibroblast activation in the remodeling process of [HF] and indicate that cardiac fibrosis is an important marker of long-term adverse clinical outcomes," write Peter S. Natov, MD, and James E. Udelson, MD, FACC, in an accompanying editorial. "The cardiac fibroblast may emerge as the next critical target of cardiovascular diagnostics and therapeutics."

In a related brief report, results from the EVOLVED clinical trial showed that in asymptomatic patients with severe aortic stenosis, higher fibrosis burden was associated with adverse outcomes. According to study authors Neil J. Craig, PhD, et al., benefits of early valve intervention were similar between patients with high and low fibrosis burden.