Zebrafish Model Reveals Early Electrocardiographic and Molecular Signatures of Doxorubicin-Induced Cardiotoxicity.

Abstract

Doxorubicin (DOX) is a highly effective anthracycline widely used in cancer therapy but limited by its dose-dependent cardiotoxicity, which may result in arrhythmia, dilated cardiomyopathy, and heart failure. Conventional surveillance tools, including echocardiography and serum biomarkers, often identify injury only after substantial cardiac dysfunction has occurred. This underscores the need for early markers with mechanistic relevance. In this study, we developed an integrated zebrafish platform combining pathophysiological evaluation, electrocardiography (ECG), and transcriptomic profiling to establish a novel approach for early detection of DOX-induced cardiotoxicity (DIC). Consistent with human and mammalian models, DOX administration in adult zebrafish resulted in ventricular enlargement, myocardial fiber disarray, and elevated troponin I levels. ECG recordings revealed dose-dependent conduction disturbances, notably progressive PR interval and QRS prolongation, with P wave widening at higher doses. These findings identify the PR interval as a sensitive, early index of conduction impairment in the zebrafish DIC model, consistent with clinical reports linking PR prolongation to adverse outcomes. RNA sequencing further identified transcriptional pathways associated with conduction delay, with dysregulation of sodium channels (scn5lab, scn1lab), gap junction proteins (cx43, cx40.8), and transcriptional regulators (nkx2.5, tbx family). Notably, scn1lab expression declined progressively, cx43 and nkx2.5 were upregulated, showing temporal changes that co-occurred with the observed ECG and structural phenotypes. Together, these results support adult zebrafish as a scalable platform for cardiotoxicity screening and highlight PR interval prolongation as an early electrophysiological marker of DOX-associated conduction disturbance. The transcriptomic signatures are presented as correlative, hypothesis-generating candidates relevant to cardiac conduction and remodeling.