Title : Can the heart remember a scar? Mechanical memory of cardiac fibroblasts as a potential driver of delayed arrhythmias

Background: Myocardial injury initiates a repair response involving cardiac fibroblast activation, extracellular matrix deposition, and scar formation. Although fibrosis is essential for maintaining structural integrity, it can disrupt electrical conduction and create a substrate for arrhythmias. An emerging concept in cellular mechanobiology is that cells can retain pathological phenotypes after the mechanical stimuli that induced them have diminished. Whether persistent mechanical memory in cardiac fibroblasts contributes to delayed arrhythmic vulnerability represents an important mechanistic question.

Objective: This conceptual framework proposes that mechanically induced fibroblast reprogramming may act as a temporal bridge between resolved myocardial stress and persistent electrophysiological instability, potentially explaining why arrhythmic risk may remain after the initial injury has stabilized.

Methods: A hypothesis-driven mechanistic model is proposed integrating cardiac mechanobiology, fibrosis, and electrophysiology. The framework examines three interconnected processes: (1) mechanical stress-induced fibroblast activation through mechanotransduction pathways, including integrin-associated signaling and YAP/TAZ regulation; (2) persistence of profibrotic cellular states following normalization of the original mechanical environment; and (3) subsequent effects on myocardial electrical propagation through extracellular matrix remodeling, altered cardiomyocyte–fibroblast interactions, and spatial heterogeneity in conduction. A proposed experimental approach would expose cardiac fibroblasts to transient mechanical stress, subsequently culture them under baseline conditions, and compare their molecular phenotype and profibrotic activity with unstressed controls. Conditioned matrices or fibroblast–cardiomyocyte co-culture systems could then be used to investigate conduction abnormalities and arrhythmia susceptibility.

Proposed outcomes: The model predicts that fibroblasts previously exposed to pathological mechanical stress may retain altered signaling or matrix-producing behavior despite removal of the original stimulus. If demonstrated, this persistent phenotype could contribute to continued tissue remodeling and electrophysiological heterogeneity. Experiments would need to distinguish genuine cellular memory from ongoing biochemical stimulation, irreversible tissue damage, and persistent differences in matrix stiffness. No clinical or experimental outcomes are claimed at this stage.

Conclusion: Mechanical memory may provide a testable explanation for how transient cardiac stress could produce longer-lasting changes in the arrhythmogenic substrate. Establishing a causal relationship between fibroblast memory and delayed arrhythmias could identify new targets for interventions aimed at reversing maladaptive cellular states rather than merely suppressing fibrosis. This framework offers a potential direction for integrating mechanobiology with arrhythmia prevention and warrants validation through controlled experimental studies.

Keywords: Cardiac fibroblasts; mechanical memory; myocardial fibrosis; arrhythmogenesis; mechanotransduction; cardiac electrophysiology.

Dr. Sohaihra Khan is a medical doctor, cardiovascular researcher, and academic editor with a strong interest in cardiology and clinical research. She has authored first-author publications in cardiology and pediatric cardiology and serves as a peer reviewer for Baishideng Publishing Group, having reviewed more than 50 manuscripts across multiple medical specialties. She is also the Editor-in-Chief of the Journal of Emerging Clinical & Health Sciences, contributing to scholarly publishing, editorial development, and the promotion of evidence-based medical research. Her research interests include cardiovascular pathophysiology, emerging concepts in cardiology, and innovative approaches to improving clinical care.