Figure 1. Diastolic SR Ca²⁺ leak in ventricular myocytes from failing hearts.

Representative line scan of Ca²⁺ sparks recorded in ventricular cardiomyocytes from normal (A) and failing murine hearts (B). Representative RyR2 single-channel tracings under conditions that simulate diastole when the cytosolic Ca²⁺ concentration is low (e.g. 100–150 nM), in normal (C) and heart failure (D) cardiomyocytes ²⁴³. Schematic representation of intracellular Ca²⁺ release in EC coupling in normal (E) and heart failure (F) cardiomyocytes. There is little or no diastolic SR Ca²⁺ leak in ventricular cardiomyocytes from normal non-failing hearts (panels A,C and E). In contrast, ventricular cardiomyocytes from failing hearts exhibit increased spontaneous Ca²⁺ sparks, increased RyR2 open probability, diastolic SR Ca²⁺ leak and reduced SR Ca²⁺ stores, all consistent with a pathologic leak of SR Ca²⁺via RyR2 remodeled (including PKA hyperphosphorylation, oxidation, nitrosylation and dissociation of calstabin2 from the RyR2 channel complex) resulting in RyR2 channels that do not close properly during diastole. (panels B,D and F). This results in reduced SR Ca²⁺ content. AP, action potential; TT, transverse tubule; cAMP, cyclic adenosine monophosphate; Cav1.2, L-type Ca²⁺ channel; NCX, Na⁺/Ca²⁺ exchanger; RyR2, ryanodine receptor type-2; SERCA2a, sarco/endoplasmic reticulum ATPase type-2a; PLB, phospholamban; PKA, protein kinase A; CaMKII, Ca^2+/calmodulin-dependent protein kinase II; ROS, reactive oxygen species.