## 4 Discussion
Overall, previous studies described increased myocardial metabolic activity associated with the cardiotoxic effects of chemotherapy [13; 14; 15; 16; 19; 20; 21; 22; 23; 24] but with marked differences between them. The first subset of studies described an increase in [18]FFDG PET myocardial uptake following cardiotoxic treatments [13; 20; 22; 21]. However, follow-up studies proposed further patterns of myocardial uptake related to the potential development of CTRCD [14; 15; 16; 19; 23; 24]. In fact, most of these studies show an effect of anthracyclines in the treated population without specifying whether cardiotoxicity developed during or after the treatment. In our series, we found a lack of overall increase in [18]FFDG myocardial uptake during treatment in the CTRCD+ group compared with the CTRCD\(-\) group. [PERSON] et al. [25] suggested that cardiomyocytes may exhibit a potential vulnerability to oxidative damage, mainly related to a lower baseline level of antioxidant enzymes and elevated mitochondria concentration. Indeed, previous research has pointed to the reactive oxygen species as the most accepted mechanism involved in the development of cardiotoxicity [44]. The oxidative stress may eventually lead to structural and functional damage to the cardiomyocytes, and consequently, a reduction in the [18]FFDG uptake in the affected myocardium should be expected [25]. Although initial studies reported an increased uptake of [18]FFDG in the myocardium of patients undergoing chemotherapy [14; 16; 23], these did not include patients with cardiovascular risk factors, whose myocardium could respond differently due to a greater vulnerability to the damage produced by anthracyclines [45]. Moreover, consistent with the hypothesis of oxidative damage and a potential reduction in the capacity of vulnerable myocardium to be responsive to cardiotoxic damage, our results reveal that CTRCD+ patients showed significantly lower uptake values compared to CTRCD\(-\) patients during the intermediate PET imaging studies. Nonetheless, it is important to mention that the mechanisms of cardiotoxicity and glycolytic metabolism in exposed cardiomyocytes have not yet been well established and are mere hypotheses. Similarly, methodologies for the quantification of cardiac metabolism in nuclear imaging are not yet standardized or well-established yet. As a rule, the quantification of cardiac [18]FFDG PET activity is performed based on region/volume of interest manually placed on cardiac structures that show measurable focal uptake. Nevertheless, the assessment of cardiac FDG uptake patterns could benefit from more sophisticated analyses such as radiomic-based quantification methods. Previous studies [26; 27; 28; 29; 30; 31] have shown a potential diagnostic role of radiomic features in various cardiac diseases, such as texture analysis in patients with cardiac sarcoidosis [26; 31], heart failure-like myocarditis [28] or acute infarct-like myocarditis [29], and prediction of long-term outcome in patients with takotsubo syndrome [30]. To the best of our knowledge, this is the first study to extend the concept of the analysis of [18]FFDG PET radiomics to the assessment of cardiac toxicity with routine follow-up scans. A total of 34 radiomic features were identified as potential predictors of cardiotoxicity in the intermediate PET study, which could be a potential tool to support the identification of a predisposition to the subsequent development of cardiac complications after cardiotoxic treatment or the early diagnosis, which would allow for improvement in the clinical management of these patients through the use of other treatment strategies that preserve myocardial functionality. The \(H_{R\!ad}\) uptake heterogeneity index based on the radiomic values revealed that the myocardium of CTRCD+ patients exhibited greater homogeneity in [18]FFDG uptake in the intermediate PET studies combined with lower overall uptake in the intermediate PET associated with cardiotoxic damage (\(p=0.025\)).