The sarcoplasmic reticulum (SR) Ca²⁺ leak is an important pathomechanism in heart failure (HF). It has been suggested that Ca²⁺/calmodulin‐dependent protein kinase II (CaMKII) is only relevant for the induction of the SR Ca²⁺ leak in non‐ischaemic but not in ischaemic HF. Therefore, we investigated CaMKII and its targets as well as the functional effects of CaMKII inhibition in human ischaemic cardiomyopathy (ICM, n = 37) and dilated cardiomyopathy (DCM, n = 40).

Western blots showed a significantly increased expression (by 54 ± 9%) and autophosphorylation at Thr286 (by 129 ± 29%, P < 0.05 each) of CaMKII in HF compared with healthy myocardium. However, no significant difference could be detected in ICM compared with DCM as to the expression and autophosphorylation of CaMKII nor the phosphorylation of the target sites ryanodine receptor 2 (RyR2)‐S2809, RyR2‐S2815, and phospholamban‐Thr17. Isolated human cardiomyocytes (CMs) of patients with DCM and ICM showed a similar frequency of diastolic Ca²⁺ sparks (confocal microscopy) as well as of major arrhythmic events (Ca²⁺ waves, spontaneous Ca²⁺ transients). Despite a slightly smaller size of Ca²⁺ sparks in DCM (P < 0.01), the calculated SR Ca²⁺ leak [Ca²⁺ spark frequecy (CaSpF) × amplitude × width × duration] did not differ between CMs of ICM vs. DCM. Importantly, CaMKII inhibition by autocamide‐2‐related inhibitory peptide (AIP, 1 µmol/L) reduced the SR Ca²⁺ leak by ∼80% in both aetiologies (P < 0.05 each) and effectively decreased the ratio of arrhythmic cells (P < 0.05).

Functional and molecular measures of the SR Ca²⁺ leak are comparable in human ICM and DCM. CaMKII is equally responsible for the induction of the ‘RyR2 leakiness’ in both pathologies. Thus, CaMKII inhibition as a therapeutic measure may not be restricted to patients suffering from DCM but rather may be beneficial for the majority of HF patients.