A 3D Integrated Model of Cardiomyocytes Revealed the Important Role of Cardiac T-Tubule Structure for the Maintenance of Contractile Function

Abstract

T-tubules in mammalian ventricular myocytes are invaginations of the surface membrane which couple membrane depolarization with intracellular Ca2+ signaling to facilitate the coordinated contraction. Deletion of t-tubules (detubulation) has been reported in heart diseases, although the complex nature of the cardiac excitation-contraction (E-C) coupling process makes it difficult to experimentally establish causal relationships between detubulation and cardiac dysfunction. Alternatively, numerical simulations have been proposed, however, the majority of models treat the subcellular spaces as lumped compartments, and are thus unable to dissect the impact of morphological changes in t-tubules. We developed a 3D finite element model of cardiomyocytes in which subcellular components including t-tubules, myofibrils, sarcoplasmic reticulum, and mitochondria were modeled and arranged realistically. Based on this framework, electrophysiology, E-C coupling, metabolism and mechanical deformation are simulated by simultaneously solving the multiple reaction diffusion equations for Ca2+ and energy metabolites, and the mechanical equilibrium. The model reproduced the Ca2+ transients and contraction observed in experimental studies with and without the t-tubule system and revealed that the asynchronous contraction caused by a large area of detubulated region can impair contractile efficiency.View Large Image | View Hi-Res Image | Download PowerPoint Slide