Subthreshold delayed afterdepolarizations mediated by reduced tissue conductivity form a substrate for unidirectional block and reentry within the infarcted heart

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): British Heart Foundation, Wellcome Trust Background Delayed afterdepolarizations (DADs) due to spontaneous calcium release (SCR) events at the subcellular scale have been associated with arrhythmia formation in the border zone (BZ) of infarcted hearts. DADs may not only summate to form ectopic focal sources but may also inactivate sodium channels forming a substrate for unidirectional conduction block and reentry. The role played by infarct anatomy and altered intracellular coupling in facilitating this phenomenon is not fully understood. Purpose To use computational modelling to investigate the role of anatomical properties of the infarct BZ in creating a substrate for DAD-mediated conduction block and reentry. Methods MRI data from a porcine post-infarction heart was used to build the computational model. A phenomenological model was used to simulate SCRs in the BZ. Arrhythmia susceptibility was quantified by pacing the model followed by a pause, to see whether DADs would occur, and an extra S2 beat with different coupling intervals (CIs). Tissue conductivity in the BZ was decreased to investigate the effect of uncoupling on DAD-mediated conduction block. Results Subthreshold DADs occurring within the infarct BZ inactivated the fast sodium channels which resulted in block of S2 beats. This occurred most readily in narrow isthmuses where electrotonic load was attenuated by the non-conducting scar. DADs rendered the entire isthmus area refractory establishing a substrate for unidirectional block and reentry (see Fig. A). Reduced tissue conductivity in the BZ reduced electrotonic load on cells undergoing DADs. This led to more local tissue depolarization (Vm) as uncoupling prevented current from flowing to neighboring cells at rest (Fig. B-C). Reduced tissue conductivity also enhanced DAD-mediated block by increasing the vulnerable window for reentry initiation (700ms < S2 CI < 900ms as shown in Fig. D). Conclusion Subthreshold DADs provide a substrate for arrhythmogenesis in the infarct BZ. Tissue uncoupling enhanced the arrhythmogenic risk by increasing the time window of unidirectional block.