RYR2 and heart failure: No less, they provided a plausible and detailed mechanism, as RyRs were proposed to become hyperactive, even near resting cytosolic Ca2+ concentration, and thus “leaky.” However, along with those details, Marks had made the relatively bold claim that this particular phosphorylation may represent a nexus for a range of CICR dysfunction in disease, based largely on the observation that RyR was hyperphosphorylated at this site in heart failure.