Remodeling processes associated with genetic and non-genetic cardiac diseases can cause alterations of electrical conduction and electro-mechanical dysfunction, eventually leading to arrhythmias. These alterations consist mainly in collagen deposition (fibrosis) and cellular disorganization (myofilament alignment), and their predictive models are often based on non-integrated and low-resolution information. Here, we combine advances in tissue clearing, immunostaining and high-resolution optical microscopy to reconstruct the three-dimensional organization of cardiac conduction system in the whole mouse heart. We developed a passive 2’2-thiodiethanol - Clarity protocol for clearing the heart and for achieving antibody penetration into the whole tissue. We simultaneously reconstructed the cellular organization stained by immunostaining and imaged the collagen distribution by second-harmonic generation deep in the cardiac tissue. A cytoarchitectonic analysis was applied to identify cells and to map myofilaments alignment in three dimensions, defining the conduction pathway of action potential propagation at intercellular level. We investigated the three-dimensional cytoarchitectonic remodeling in a transgenic mouse model of hypertrophic cardiomyopathy characterized by a severe degree of left ventricle hypertrophy and interstitial fibrosis. First, using a recently-developed ultra-fast optical system we mapped the propagation of electrical activity in whole diseased hearts. Then, we correlated the propagation maps with the pathological disorganization of myofilaments and collagen deposition using the three-dimensional high-resolution optical reconstruction. This innovative experimental approach will allow to dissect the morphological causes leading to alterations of electrical conduction and to electro-mechanical dysfunction, and, more generally, will represent a whole new paradigm for diagnostic and therapeutic investigations.
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