Introduction: The Cardio-Oncology Dilemma
Anthracyclines, including doxorubicin and epirubicin, remain a cornerstone of chemotherapy for various malignancies, notably breast cancer and lymphomas. However, their clinical utility is frequently shadowed by the risk of dose-dependent, irreversible cardiotoxicity. For decades, clinicians have sought a reliable biomarker to identify patients at the highest risk of developing left ventricular (LV) dysfunction before overt heart failure occurs. High-sensitivity cardiac troponin I (hs-cTnI) has emerged as a leading candidate, given its ability to detect minute levels of myocardial injury. Current guidelines often suggest troponin monitoring for risk stratification. However, the exact relationship between these biomarker elevations and long-term functional changes remains a subject of intense clinical debate.
The Cardiac CARE Trial: Study Design and Objectives
The Cardiac CARE trial was a prospective, multicenter, randomized, open-label study designed to investigate the role of cardioprotective therapy in patients undergoing high-dose anthracycline chemotherapy who exhibited evidence of early myocardial injury. In this specific sub-analysis, researchers aimed to determine how hs-cTnI concentrations relate to the cumulative dose of anthracyclines, the number of treatment cycles, and subsequent changes in LV function as measured by cardiac magnetic resonance (CMR).
The study population included 175 participants with a mean age of 52 years. The cohort was predominantly female (86.5%), reflecting the high prevalence of breast cancer patients treated with these agents. Participants were required to be undergoing high-dose therapy, with a median cumulative epirubicin-equivalent dose of 600 mg/m2. To ensure high-resolution data, hs-cTnI was measured before every chemotherapy cycle and at 2, 4, and 6 months post-treatment. LV function was assessed using CMR at baseline and 6 months post-chemotherapy, providing a more sensitive and reproducible measurement than standard echocardiography.
Key Findings: Dissociation Between Dose and Injury
One of the most striking findings of the study was the temporal pattern of myocardial injury. Peak hs-cTnI concentrations were not observed during the peak of treatment, but rather 2 months after the completion of chemotherapy. The median peak concentration was 14.0 ng/L. Interestingly, while the peak hs-cTnI levels statistically correlated with the number of treatment cycles, they did not correlate with the total cumulative dose of anthracyclines. This suggests that the frequency of the ‘hits’ to the myocardium might be more relevant to biomarker release than the total mass of the drug administered.
Regarding functional outcomes, the results were somewhat reassuring but also complex. None of the 171 patients who completed the follow-up developed a left ventricular ejection fraction (LVEF) below 50%. However, 14.0% (24 patients) experienced what is clinically defined as a significant decline—a drop in LVEF of more than 10%. Despite the high sensitivity of the assay, hs-cTnI showed only a weak correlation with this LVEF change. Furthermore, the biomarker was not predictive of changes in global longitudinal strain (GLS), which is often considered a more sensitive early marker of systolic impairment than LVEF.
Clinical Implications and Pathophysiological Insights
These findings challenge the prevailing assumption that any elevation in troponin during chemotherapy is a harbinger of significant cardiac decline. The weak association between hs-cTnI and LVEF reduction suggests that the ‘injury’ detected by high-sensitivity assays may represent a transient stress response or a low level of cardiomyocyte turnover that the heart can physiologically compensate for, at least in the short term.
For the clinician, this study suggests that while troponin monitoring can detect myocardial injury, its utility as a standalone tool for predicting which patients will develop functional impairment is limited. It highlights a potential ‘prognostic gap’ where the presence of a biomarker does not necessarily translate into a clinically actionable decrease in cardiac output. This may lead to unnecessary anxiety for patients and potentially premature cessation of life-saving oncological treatments if interpreted too conservatively.
Expert Commentary: Rethinking Biomarker Surveillance
The Cardiac CARE trial provides a high-quality, CMR-validated dataset that brings much-needed nuance to cardio-oncology. The lack of correlation with cumulative dose is particularly interesting, as it may point toward individual genetic susceptibility or varying mechanisms of injury that are not strictly dose-dependent in every patient.
However, limitations must be considered. The 6-month follow-up period may be too short to capture the full trajectory of anthracycline-induced cardiomyopathy, which can sometimes manifest years after the conclusion of therapy. Additionally, because the study focused on those with ‘elevated’ troponin for its primary intervention, the results primarily speak to the predictive value within a higher-risk subset.
Future research should focus on whether combining hs-cTnI with other markers, such as B-type natriuretic peptide (BNP) or advanced imaging techniques like T1 mapping on CMR, could provide a more robust predictive model. For now, the results of the Cardiac CARE trial suggest that clinicians should exercise caution when making major treatment decisions based solely on mild elevations in high-sensitivity troponin.
Summary and Conclusion
The Cardiac CARE trial demonstrates that in patients receiving high-dose anthracyclines, hs-cTnI elevations are common and peak post-treatment, but they do not correlate with cumulative drug dose. Most importantly, these elevations are poor predictors of both LVEF decline and changes in global longitudinal strain at 6 months. While hs-cTnI remains a valuable tool for detecting acute myocardial stress, its role as a gatekeeper for cardioprotective intervention or chemotherapy modification requires further refinement. The study underscores the need for a multi-modal approach to cardiac surveillance in cancer survivors.
References
Loganath K, Lee KK, Oikonomidou O, et al. Anthracycline Dose, Myocardial Injury, and Change in Left Ventricular Function in the Cardiac CARE Trial. JACC CardioOncol. 2025 Oct;7(6):725-735. doi: 10.1016/j.jaccao.2025.06.003.
