RYR2 and heart failure: Heart failure (HF) is a major global health problem,1 and heart failure with reduced ejection fraction (HFrEF) represents 50% of HF.2 Current therapies fail to adequately address a principal issue: loss of contractile force.3,4 Myocardial calcium is a major contributor to cardiac inotropy and targeting calcium dysregulation in HF is an active area of investigation with targets including RyR2, NCX, SERCA, and TRP channels.5 LTCC hyperactivity has dogmatically been considered contributory to pathological signalling.