Boosting predictive concepts on arrhythmogenesis resolving and unifying cardiac electrophysiology and structural remodelling at organ-level

Remodelling processes associated with genetic and non-genetic cardiac diseases can cause electrical conduction disturbances and arrhythmias. Current models used to predict functional alterations due to structural remodelling fail to accurately assess arrhythmogenic risk, mainly because they do not draw upon comprehensive functional and structural data and are typically based on low-resolution and non-integrated information. Here, I present HeartCORE, an interdisciplinary approach designed to establish a mechanistic relationship between electrophysiological dysfunction and structural alterations in an animal model that mimics human cardiac electrophysiology. Langendorff-perfused rabbit hearts will first be electrically characterized in terms of conduction, repolarization properties, and arrhythmogenicity using a dual-wavelength panoramic optical mapping system that includes the transmural dimension. The hearts will then be transformed into well-preserved, fully transparent organs and imaged with a high-throughput light sheet mesoscope to reconstruct cardiac muscle organization and collagen deposits with micrometric resolution. Selected high-resolution immunohistochemistry images will be integrated with the structural data of each organ to develop a computational model of cardiac electrical activity and explore the possibility of reproducing in silico experimentally observed electrical behaviour. This methodology will be applied to investigate the impact of cardiac remodelling (including non-myocyte reorganization) on conduction disturbances and arrhythmogenesis in two distinct scenarios: generalized interstitial fibrosis in congenital hypertrophic cardiomyopathy and localized scarring in acquired myocardial infarction. HeartCORE aims to create a unifying model that integrates functional and structural data, enabling a comprehensive investigation of the morphological causes leading to electrical alterations and enhancing predictive concepts in arrhythmogenesis.