Constructing dyadic geometries from super-resolution imaging for computing structure-function relationships in cardiac contraction

Time: 10:30 - 10:50  The microanatomical structures responsible for cardiac excitation-contraction (EC) coupling in ventricular myocytes are degraded in many cardiac diseases. How these structural changes impact function is... [ view full abstract ]

Time: 10:30 - 10:50  

The microanatomical structures responsible for cardiac excitation-contraction (EC) coupling in ventricular myocytes are degraded in many cardiac diseases. How these structural changes impact function is not well understood. The small size of the structures, combined with the multi-scale nature of EC coupling, makes computations a fundamental tool for understanding structure-function relationships across these scales. A major bottleneck, however, is the lack of detailed geometric data to properly constrain computational models. We are developing a pipeline to construct detailed and structurally accurate geometries from three dimensional super-resolution dSTORM imaging of ryanodine receptor (RyR) localization. Beginning with the dSTORM-defined RyR distributions and a t-tubule map identified from caveolin 3 labeling, we use rule-based heuristics to define t-tubular and sarcoplasmic membrane structures. We then combine the generated geometries with a finite volume reaction-diffusion model of calcium-induced calcium release (CICR) to explore the impact of structural degradation occurring within and between dyads, on microscopic and macroscopic EC coupling. Importantly, our model combined spatially distributed calcium diffusion and buffering at sub-dyadic resolution (non-compartmental dyadic dynamics) with stochastic RyR release, both of which are necessary to capture how dyadic break-up affects spark dynamics. We have used our pipeline at the dyad-level to explore how changing the shape and size of local membranes affects RyR-triggered spark fidelity, amplitude, duration, and termination. We will use our pipeline and calcium model to move to larger volumes and explore ensembles of calcium release units to better understand structural impact on emergent multi-scale EC properties.