RYR2 and heart failure: Increased SR Ca2+ leak has been molecularly attributed to RyR2 overactivity mediated by several mechanisms including (i) RyR2 hyper-phosphorylation by PKA because of a chronic hyper-adrenergic state in heart failure (Marx et al, 2000; Potenza et al, 2019), (ii) RyR2 hyper-phosphorylation by Ca2+–calmodulin-dependent kinase (CaMKII) involving exchange protein directly activated by cAMP (Epac2) and nitric oxide synthase 1 (Wehrens et al, 2004; Sag et al, 2009; Pereira et al, 2017), and (iii) increased RyR2 oxidation (Andersson et al, 2011; Huang et al, 2021).