A maze‐like electrical substrate: arrhythmogenic vulnerability in doxorubicin‐damaged ventricles

Doxorubicin (DOX) was isolated in Italy in the 1960s, and was rapidly adopted for breast cancer, sarcoma, neuroblastoma and lung malignancies, and is considered a cornerstone of chemotherapy for the treatment of various types of cancer to this day (Bhutani et al., 2025). It is a molecule designed to save lives by intercalating DNA and halting topoisomerase II, arresting replication – a biochemical sword dividing the malignant lineage from surviving cells. Yet even swords cast light and shadow. The same molecular elegance that kills tumour cells fragments cardiomyocytes, destabilizes ion homeostasis, and leaves behind a heart that remembers injury through collagen and silence. Clinically, the paradox lies in the dual outcome whereby a life-saving anticancer therapy ultimately contributes to cardiovascular disease, shifting the cause of mortality from malignancy to cardiac dysfunction – indeed, cardiovascular disease is the leading cause of death among cancer survivors, a reality that forces cardio-oncology to confront a battle fought long after the tumour is gone. This difficulty arises partly because DOX cardiotoxicity is multicausal – oxidative stress, mitochondrial dysfunction, calcium mishandling, inflammation, oedema, early electrical disarray and only then fibrosis (Bhutani et al., 2025). That complexity may be precisely why preventing the adverse effects has remained so elusive: there is no single doorway to block when the house has many entrances. Over the past decades, advances in cardiac magnetic resonance imaging (MRI), aligned with the rise of computational electrophysiology, has reshaped how we look at the heart (Barison et al., 2025). Although the understanding that the heart is electrically controlled long predates these developments, recent improvements in imaging acquisition, analysis and integration with computational methods have transformed the ventricle from a conceptual electrical organ into a quantitatively mapped, three-dimensional substrate, enabling more detailed phenotyping and mechanistic insight across cardiac conditions. From this perspective, the ventricle emerges as an electrical structure whose geometry can sustain memory, complexity, failure and, under specific conditions, re-entry. Through this conceptual lens, what appears as collagen deposition represents the first macroscopic manifestation of an underlying alteration in electrical propagation. Fibrosis does not merely increase stiffness; it modifies tissue geometry in ways that reshape conduction pathways, alter source–sink relationships, and predispose the myocardium to conduction delay and block. The mechanical consequence simply follows the electrical injury – though the reverse also occurs, as mechanical stress alters electrophysiology, and sometimes both unravel simultaneously, making it impossible to decide which came first in this cardiac version of the chicken-or-the-egg riddle. In this context, the recent article by Villar-Valero et al. (2026) in The Journal of Physiology stands out not as a new drug, not a new cure, but a new way of seeing. The authors reconstruct porcine left ventricles using MRI-derived anatomy and in vivo electrophysiological mapping, then simulate action potential propagation under DOX-induced remodelling (Villar-Valero et al., 2026). Rather than observing arrhythmias directly, the question is subtler and more fascinating: when structure breaks, does electricity learn new routes? A major strength of this work lies in the deliberate methodological design. The lattice Boltzmann method enables tissue-level electrical behaviour to emerge from local interactions between cellular geometry and conductivity, providing a computationally efficient framework to link microscopic structure with macroscopic propagation patterns. Through 96 parametrized simulations, the authors systematically vary excitability, conductivity and fibrotic distribution; the parameter λ captures fundamental requirements for arrhythmia – excitability, action potential duration (APD) and conduction velocity (CV) (Rapaka et al., 2012; Villar-Valero et al., 2026). The model is intentionally minimalistic, focusing on the specific features it set out to investigate, without delving into the richer landscape of ionic currents, channel dynamics and the broader biophysical machinery – which, although absent here, also shapes cardiac vulnerability. What the authors find is striking: DOX does not merely weaken myocardium – it introduces a maze-like conduction geometry. Fibrosis forms corridors, blind alleys, fragile bridges of surviving tissue through which depolarization waves accelerate, stall, collide and return. Perhaps more subtle is the observation that electrical impairment is not confined to collagen-rich regions. In the model, tissue oedema surrounding fibrotic areas is sufficient to distort local geometry and slow conduction, indicating that arrhythmogenic substrates can emerge even in regions with limited collagen deposition. Even hearts with modest fibrotic burden may sustain re-entry if geometry aligns. And here, a piece of conceptual brilliance: fibrosis is not only a residual marker of injury but an active determinant of the electrical behaviours the tissue can sustain, effectively redefining the range of conduction patterns and arrhythmic possibilities. But the model is a mirror, and mirrors distort as much as they reveal. Two ventricles with the same collagen fraction may have entirely different arrhythmic futures because one provides a pathway while the other provides only a trap. The authors themselves acknowledge the unavoidable limitation: even a high-fidelity digital twin cannot entirely replace biological reality, because anatomy – the actual spatial distribution of fibrosis – matters profoundly. Although the accomplishment is undeniable, the model does not explicitly model the cellular and subcellular ionic mechanisms known to be affected by DOX, such as RyR2 leak, SERCA depression, potassium current remodelling and oxidative signalling. Instead, the electrophysiological consequences of these processes are incorporated indirectly through DOX-specific parameters (e.g., λ), allowing their net effects on propagation to be represented without modelling their molecular origins (Bhutani et al., 2025). Action potentials in vivo arise from tightly coordinated ionic processes, many of which are altered by DOX but are not explicitly represented at the mechanistic level in the model. Thus, the model captures how electrical waves propagate and fail at the tissue level, including the emergence of unidirectional block and re-entrant activation. However, it does not address the upstream cellular mechanisms that initiate electrical instability, focusing instead on its structural and geometric consequences. Yet perhaps that is enough. After all, arrhythmia is always a marriage between structure and electricity, and this work dissects their interaction with unusual clarity. The study by Villar-Valero et al. feels like a glimpse of the future. One can envision digital-twin risk stratification, predicting vulnerable circuits before symptoms appear, adjusting DOX dose based on patient-specific vulnerability, or identifying micro-circuits for preventive modulation. Arrhythmia would become something detected before it happens – not after syncope. The philosophical implication is seductive: fibrosis is not merely consequence – it may be premonition. Geometry is destiny. A heart is not only what it is, but what paths it allows electricity to take. If so, cardiotoxicity is not about the destruction of myocardium but about reshaping the heart's internal landscape into something capable of spiralling. The next frontier may not depend on removing scar, but on learning how to read it – and perhaps intervene before it writes its own ending. And that is a question deep enough to sustain years of research. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. The authors declare they have no competing interests. Each author made significant contributions to the conception, drafting, and critical revision of the manuscript. All authors have read and approved the final version of this manuscript and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All persons designated as authors qualify for authorship, and all those who qualify for authorship are listed. None of the authors received funding for this work specifically. A.O.D. holds a fellowship from São Paulo Research Foundation (FAPESP – no. 2023/11912-2). D.S.S. is supported by the National Council for Scientific and Technological Development (CNPq nos 406492/2024-7, 405631/2024-3 and 409449/2024-5).