Therapeutic strategy involving FKBP12.6-mediated stabilization of RyR. A small influx of Ca²⁺ through the LTCC leads to the release of a large amount of Ca²⁺ from the SR through RyR in the normal heart. In HF, however, PKA-mediated hyperphosphorylation of RyR2 occurs, and this in turn dissociates FKBP12.6 from RyR2, leading to a diastolic Ca²⁺ leak through RyR2. This results in the Ca²⁺ transient being diminished (due to the reduced SR Ca²⁺ content and dyssynchronous Ca²⁺ release). Administration of a new compound, the 1,4-benzothiazepine derivative JTV519, normalizes this abnormal channel gating by restoring the conformational state of RyR and by rebinding FKBP12.6 to the channel complex. Thereby, JTV519 normalizes Ca²⁺ cycling and contractile function in failing cardiac myocytes and hence provides chronic suppression of progressive left ventricular dysfunction in HF. P, PKA phosphorylation at serine 2809; [Ca²⁺]_i, intracellular [Ca²⁺].