InsPR-RyR channel crosstalk augments sarcoplasmic reticulum Ca release and arrhythmogenic activity in post-MI pig cardiomyocytes.

Ca transients (CaT) underlying cardiomyocyte (CM) contraction require efficient Ca coupling between sarcolemmal Ca channels and sarcoplasmic reticulum (SR) ryanodine receptor Ca channels (RyR) for their generation; reduced coupling in disease contributes to diminished CaT and arrhythmogenic Ca events. SR Ca release also occurs via inositol 1,4,5-trisphosphate receptors (InsPR) in CM. While this pathway contributes negligeably to Ca handling in healthy CM, rodent studies support a role in altered Ca dynamics and arrhythmogenic Ca release involving InsPR 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 InsP-induced Ca 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 Ca release from non-coupled RyR clusters that otherwise showed delayed activation during the CaT. IICR in turn synchronised Ca release during the CaT but also induced arrhythmogenic delayed afterdepolarizations and action potentials. Nanoscale imaging identified co-clustering of InsPRs and RyRs, thereby allowing Ca-mediated channel crosstalk. Mathematical modelling supported and further delineated this mechanism of enhanced InsPR-RyRs coupling in MI. Our findings highlight the role of InsPR-RyR channel crosstalk in Ca release and arrhythmia during post-MI remodelling.