Cardiac fibroblast activation in anthracycline related cardiac injury

Abstract Introduction Anthracyclines are used in the effective treatment of a wide range of cancers. Their administration can however lead to cardiotoxicity and the development of heart failure often several years following their administration. The mechanisms underlying this process and delayed presentation remain unclear, however they involve adverse remodelling and myocardial fibrosis, two key process driven by activated myocardial fibroblasts. Gallium-68 Fibroblast Activation Protein Inhibitor (68Ga-FAPI) is a novel PET tracer that binds specifically to activated fibroblasts providing a readout of their activity in the myocardium across a range of cardiomyopathies. In this study we sought to investigate the role of activated fibroblasts in the development of cardiotoxicity non-invasively for this first time. Methods In this prospective observational cohort study, patients with a history of anthracycline exposure with and without related cardiotoxicity and control volunteers underwent hybrid 68Ga-FAPI positron emission tomography and magnetic resonance imaging. 68Ga-FAPI uptake was quantified as the maximum standardised uptake value (SUVmax) in the interventricular septum, divided by the mean blood pool uptake to calculate a target-to-background ratios (TBRmax). We investigated the relationship of myocardial 68Ga-FAPI uptake with anthracycline exposure and cardiotoxicity, as well as established cardiac magnetic resonance metrics of adverse left ventricular remodelling. Results Nineteen age-matched healthy volunteers (age 59 ± 6, 30% female) were recruited alongside 23 patients (age 59 ± 9, 78% female) with previous anthracycline exposure (dose 547 ± 136mg, imaged 3.3 years following last anthracycline exposure) including 7 with a clinical diagnosis of chemotherapy related-cardiotoxicity. Intensity of myocardial fibroblast activation was highest in those with chemotherapy related cardiotoxicity but was also higher in patients with previous anthracycline exposure, but no cardiotoxicity compared to control participants (Figure 1a, TBRmax 1.61 ± 0.51 versus 1.34 ± 0.22 versus 1.19 ± 0.08 respectively, ANOVA p=0.001). In all patients with prior anthracycline exposure, increasing 68Ga-FAPI uptake correlated with increased extracellular volume (r=0.509, p=0.013), and reduced global longitudinal strain (r=-0.421, p=0.046) and left ventricular ejection fraction (r=-0.510, p=0.013). Conclusion Fibroblast activation is increased in the myocardium of patients with established cardiotoxicity versus healthy controls. However, it is also increased in patients with a history of anthracycline exposure and no cardiotoxicity even several years following cancer treatment, likely reflecting ongoing myocardial injury. This would support a multi-hit hypothesis to cardiotoxicity development, with anthracycline exposure priming activated fibroblasts in the myocardium, which may then tigger over cardiotoxicity on exposure to subsequent insults.