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JACC CardioOncol
JACC CardioOncol
JACC: CardioOncology
2666-0873
Elsevier

S2666-0873(24)00202-3
10.1016/j.jaccao.2024.04.008
Letters
To the Editor
Probing the Anthracycline-Induced Myocardial Injury
A Glimpse Through the Lens of the PRADA Trial
Statescu Claudius MD clstatescu@yahoo.com
∗
El Blidi-Rahmani Manel MD
∗ Hôpital Antoine Béclère, Service de Cardiologie, 157 rue de la Porte de Trivaux, 92140 Clamart, France clstatescu@yahoo.com
25 6 2024
8 2024
25 6 2024
6 4 628629
© 2024 The Authors
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
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pmcWe were intrigued by the lack of correlation reported in the recent PRADA (Prevention of Cardiac Dysfunction During Adjuvant Breast Cancer Therapy) trial analysis1 between the long-term evolution of left ventricular (LV) functional parameters (ejection fraction and global longitudinal strain) over the 2-year observation period and “early” cardiomyocyte injury, reflected by the change in high-sensitivity cardiac troponin (hs-cTn) from baseline to anthracycline completion.

The uncoupling of structural and functional aspects of cardiotoxicity, as currently defined, suggests that “early” cardiomyocyte injury, although prevalent, does not reach the threshold required to trigger hemodynamic anomalies,2 neurohormonal activation, and subsequent cardiomyopathy; however, at 2 years, a significant decline in LV systolic function of 3.9% was observed.1 Consequently, while recognizing the role of extracellular matrix remodeling in cardiomyopathy development, we further identify “late” cardiomyocyte injury as a complementary category of anthracycline-induced myocellular damage of potential pathogenic and clinical relevance.

In anthracycline-exposed cohorts, average hs-cTn levels greater than baseline are persistently detected for months following a peak at course completion;3 this observation indicates protracted, low-grade myocellular damage continuing after the last anthracycline cycle (ie, “late” cardiomyocyte injury). “Early” hs-cTn change from baseline to course completion may therefore provide an insufficient approximation of overall anthracycline-related myocellular damage. In a cohort exposed to epirubicin and/or trastuzumab (n = 40), an index of cumulative cardiomyocyte injury integrating serial hs-cTn assessments at baseline, “early,” and multiple “late” time points demonstrated accuracy for the diagnosis of significant LV ejection fraction decline, with a single cutoff yielding 100% sensitivity and specificity.4

We postulate “late” cardiomyocyte injury to be prominent in patients with altered myocellular repair mechanisms exposed to low-dose anthracyclines. The hs-cTn increase induced by sequential human epidermal growth factor receptor 2 inhibition in anthracycline-pretreated patients3 provides proof of concept; other relevant instances may pertain to the presence of cardiovascular risk factors or disease. Conversely, a correlation between “early” cardiomyocyte injury and long-term change in LV functional parameters may emerge within the PRADA cohort subgroup of human epidermal growth factor receptor 2–negative patients at minimal cardiovascular risk; this hypothesis warrants investigation.

To the investigators’ legitimate plea for “caution when interpreting isolated troponin elevations during adjuvant therapy,”1 we add, drawing on prior arguments, that defining a clinically meaningful metric for cardiomyocyte injury may require consideration of myocellular damage occurring both during and after the course of anthracycline-based chemotherapy (eg, corroboration of the hs-cTn peak value with subsequent measurements and/or clinical risk indexes).

The authors have reported that they have no relationships relevant to the contents of this paper to disclose. The authors are indebted to Elena Statescu, MD, for advice and discussions.

The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the Author Center.
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References

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2 Bristow M.R. Mason J.W. Billingham M.E. Daniels J.R. Dose-effect and structure-function relationships in doxorubicin cardiomyopathy Am Heart J 102 4 1981 709 718 7282516
3 Demissei B.G. Hubbard R.A. Zhang L. Changes in cardiovascular biomarkers with breast cancer therapy and associations with cardiac dysfunction J Am Heart Assoc 9 2 2020 e014708
4 Kitayama H. Kondo T. Sugiyama J. High-sensitive troponin T assay can predict anthracycline- and trastuzumab-induced cardiotoxicity in breast cancer patients Breast Cancer 24 6 2017 774 782 28434150
