InsP₃R-RyR channel crosstalk augments sarcoplasmic reticulum Ca²⁺ release and arrhythmogenic activity in post-MI pig cardiomyocytes

Ca²⁺ transients (CaT) underlying cardiomyocyte (CM) contraction require efficient Ca²⁺ coupling between sarcolemmal Ca²⁺ channels and sarcoplasmic reticulum (SR) ryanodine receptor Ca²⁺ channels (RyR) for their generation; reduced coupling in disease contributes to diminished CaT and arrhythmogenic Ca²⁺ events. SR Ca²⁺ release also occurs via inositol 1,4,5-trisphosphate receptors (InsP₃R) in CM. While this pathway contributes negligeably to Ca²⁺ handling in healthy CM, rodent studies support a role in altered Ca²⁺ dynamics and arrhythmogenic Ca²⁺ release involving InsP₃R crosstalk with RyRs in disease. Whether this mechanism persists in larger mammals with lower T-tubular density and coupling of RyRs is not fully resolved. We have recently shown an arrhythmogenic action of InsP₃-induced Ca²⁺ release (IICR) in end stage human heart failure (HF), often associated with underlying ischemic heart disease (IHD). How IICR contributes to early stages of disease is however not determined but highly relevant. To access this stage, we chose a porcine model of IHD, which shows substantial remodelling of the area adjacent to the infarct. In cells from this region, IICR preferentially augmented Ca²⁺ release from non-coupled RyR clusters that otherwise showed delayed activation during the CaT. IICR in turn synchronised Ca²⁺ release during the CaT but also induced arrhythmogenic delayed afterdepolarizations and action potentials. Nanoscale imaging identified co-clustering of InsP₃Rs and RyRs, thereby allowing Ca²⁺-mediated channel crosstalk. Mathematical modelling supported and further delineated this mechanism of enhanced InsP₃R-RyRs coupling in MI. Our findings highlight the role of InsP₃R-RyR channel crosstalk in Ca²⁺ release and arrhythmia during post-MI remodelling.