Transverse tubular network structures in the genesis of intracellular calcium alternans and triggered activity in cardiac cells

The major role of a transverse-tubular (TT) network in a cardiac cell is to facilitate effective excitation-contraction coupling and signaling. The TT network structures are heterogeneous within a single cell, and vary between different types of cells and species. They are also remodeled in cardiac diseases. However, how different TT network structures predispose cardiac cells to arrhythmogenesis remains to be revealed. To systematically investigate the roles of TT network structure and the underlying mechanisms in the genesis of intracellular calcium (Ca2+) alternans and triggered activity (TA). Based on recent experimental observations, different TT network structures, including uniformly and non-uniformly random TT distributions, were modeled in a cardiac cell model consisting of a three-dimensional network of Ca2+ release units (CRUs). Our simulations showed that both Ca2+ alternans and Ca2+ wave-mediated TA were promoted when the fraction of orphaned CRUs was in an intermediate range, but suppressed in cells exhibiting either well-organized TT networks or low TT densities. Ca2+ alternans and TA could be promoted by low TT densities when the cells were small or the CRU coupling was strong. Both alternans and TA occurred more easily in uniformly random TT networks than in non-uniformly random TT networks. Subcellular spatially discordant Ca2+ alternans was promoted by non-uniformly random TT networks but suppressed by increasing CRU coupling strength. These mechanistic insights provide a holistic understanding of the effects of TT network structure on the susceptibility to arrhythmogenesis. The TT network plays important roles in promoting Ca2+ alternans and TA, and different TT network structures may predispose cardiac cells differently to arrhythmogenesis. •T-tubular density and structure are heterogeneous among different types of cardiac cells.•T-tubular networks in failing ventricular myocytes are disrupted and become more heterogeneous.•Ca2+ alternans and triggered activity are promoted by intermediate T-tubular density.•Susceptibility to alternans and triggered activity depends on the T-tubular network heterogeneity.•T-tubular difference in different cell types may contribute to different susceptibility to alternans and triggered activity.