RYR2 and congestive heart failure: However, in chronic heart failure, intracellular Ca2+ overload and Ca2+ depletion in SR are due not only to Ca2+ leakage from failing RyR2 but also to decreased Ca2+ uptake, which is caused by down-regulation of sarcoma/endoplasmic reticulum Ca2+-ATPase and decreased PLB phosphorylation [2, 5, 33, 34].