Mechanistic interpretations of sustained ventricular fibrillation: The role of mapping methodology, model and time

Ventricular fibrillation (VF) is a malignant tachyarrhythmia underlying cardiac arrest, yet the mechanisms maintaining VF remain incompletely understood. Ethical constraints and technical limitations have largely precluded systematic investigation of sustained VF in humans, resulting in a body of evidence derived predominantly from animal models and ex vivo human preparations, often yielding apparently conflicting mechanistic interpretations. This article summarizes the experimental studies and conceptual frameworks that underpin the contemporary understanding of VF maintenance. We discuss evidence derived from frequency- and phase-based mapping approaches in short- and long-duration VF studies across species, highlighting how methodological constraints, animal models, spatial scale and VF duration critically influence mechanistic interpretation. Despite the heterogeneity across studies, overall, the data indicate that VF is not inherently chaotic but exhibits transient spatiotemporal organization that evolves dynamically over time. The underlying drivers sustaining VF throughout its progression are not uniform: multiple at times co-existing mechanisms, including re-entrant activity, self-perpetuating wavelets and rapid focal activation, have been implicated. The predominance and temporal evolution of these mechanisms are shaped by progressive global ischaemia with metabolic deterioration, pre-existing structural remodelling and the involvement as well as architecture of the Purkinje network. Collectively, these observations support the concept of duration-dependent and likely also substrate-specific electrophysiological phenotypes of VF, while also exposing a paucity of studies that have explicitly and systematically evaluated the effect of pre-existing structural and electrical substrate characteristics to examine their reciprocal interaction with VF dynamics. We conclude by outlining future directions, emphasizing the need for true 3D transmural mapping technologies and multimodal integration of structural and functional substrate features to enable mechanistic phenotyping and inform more personalized and effective strategies for VF management and prevention.