In addition, in a canine model of heart failure progression, an early and continuous increase in RyR2-mediated SR Ca2+ leak has been proposed (Belevych et al, 2011), although this defect has been mainly assigned to decreased coupling of Ca2+ influx and RyR2-mediated Ca2+ release evidenced by a loss of canonical dyadic nanodomain organization (Manfra et al, 2017) and increased junctophilin-2 cleavage by calpain (Lehnart & Wehrens, 2022; Weninger et al, 2022). The gene discussed is RYR2; the disease is heart failure.