The improvement in survival rates in pediatric malignancies has led to an increase in the number of cancer survivors who are at risk of developing cardiotoxicity and heart failure. Cardiac dysfunction in these patients can occur asymptomatically, and the diagnosis in a symptomatic phase is associated with reduced treatment response and worse prognosis. For this reason, it is essential to establish protocols to follow up on these patients and identify those at risk of cardiotoxicity in order to start early and effective therapies. This review aims to summarize the latest findings in the diagnosis and treatment of cancer therapy-related cardiac disease in long-term survivors of childhood cancer, with a focus on heart failure.

Background: Patients with heart failure and reduced ejection fraction (HFrEF) who achieve improved ejection fraction (HFimpEF) after guideline-directed medical therapy exhibit superior prognosis. However, functional impairment remains a hallmark of HF. Aims: To characterize and compare exercise capacity profiles via cardiopulmonary exercise testing (CPET) between patients with HFimpEF and those with persistently reduced ejection fraction (HFprEF) using a baseline-adjusted analysis. Methods: Data from a longitudinal cohort of 111 HFrEF patients with baseline and follow-up CPET data (minimum 6-month follow-up) were analyzed. Patients were stratified into HFimpEF and HFprEF groups, according to the Universal Definition of HF. Changes between groups were evaluated using Analysis of Covariance (ANCOVA) adjusted for baseline values, with non-parametric Bootstrapping (2000 resamples) and multiplicity. Results: We included 111 patients: 69 with HFimpEF (62.2%) and 42 with HFprEF (37.8%). At a median follow-up of 8.7 months, the HFimpEF group showed significantly greater reverse remodeling (adjusted ΔLVEF +19.9%, p < 0.001) and a greater reduction in NT-proBNP levels (−557.6 pg/mL, p = 0.042). Both groups demonstrated intra-group functional improvements. However, in adjusted between-group ANCOVA models, HFimpEF achieved a significantly greater recovery in percentage of predicted peak oxygen consumption (adjusted difference: +8.5%; 95% CI: 1.2 to 16.1; p = 0.021). Net adjusted between-group differences for absolute VO₂peak gain, submaximal threshold, ventilatory efficiency and recovery kinetics did not reach statistical significance. Multivariate analysis identified older age (beta −0.261, p = 0.010), diabetes mellitus (beta −0.210, p = 0.023) and baseline VO₂peak (beta −0.569, p < 0.001) as negative predictors of improvement. Conclusions: Comprehensive HFrEF management improves exercise capacity across all patients. Although HFimpEF yields superior gains in normalized aerobic capacity, overall functional trajectories are largely comparable between phenotypes. This structural-functional decoupling underscores persistent residual limitations in HFimpEF, supporting CPET for longitudinal risk stratification.