Chronic diastolic SR Ca2+ leak due to stress-induced remodeling (caused by PKA phosphorylation and oxidation) of RyR2 (cardiac muscle) and RyR1 (skeletal muscle) channels depletes SR Ca2+, reduces contractility, promotes heart failure (HF) progression (2), is arrhythmogenic (3–6), and impairs skeletal muscle function (7). This evidence concerns the gene RYR2 and heart failure.