Abstract:

Cardiac fibrosis is a key factor in electrical conduction disturbances, yet its specific impact on conduction remains unclear, hindering predictive insight of cardiac electrophysiology and arrhythmogenesis. Among the different cardiac disorders, arrhythmogenic cardiomyopathy (ACM) is known to be associated with massive fibrotic remodelling of the myocardium, and it accounts for most cases of stress-related arrhythmic sudden death. To explore ACM further, we employed a Desmoglein-2-mutant mouse model and developed a correlative imaging approach to integrate macro-scale cardiac electrophysiology with 3D micro-scale reconstructions of the ventricles, to characterise the dynamics of conduction wavefronts and relate them to the underlying structural substrate. Our findings confirm that this ACM model shows localised replacement of cardiomyocytes with collagen and non-myocytes, contributing to electrical dysfunction. Moreover, we observed that conduction through fibrotic tissue areas shows a frequency-dependent behaviour, where conduction fails at high stimulation frequencies, promoting re-entrant arrhythmias, even in regions that were electrophysiologically inconspicuous at lower stimulation rates. Using a computational model, informed by high- resolution structural data, we found that frequency-dependent conduction through fibrotic tissue cannot be explained solely by collagen deposition or cardiomyocyte re-organisation. Indeed, fibrotic areas feature electrophysiological remodelling which acts as a low-pass filter for conduction, which can be quantitatively explained by electrotonic coupling of cardiomyocytes with non-myocytes. Collectively, our study provides a novel structure-function mapping pipeline and describes a previously unrecognised pro-arrhythmogenic mechanism in ACM, underscoring the need for dynamic assessment of functional conduction block in fibrotic myocardium using multiple diagnostic pacing protocols.