BACKGROUND: Sarcoplasmic reticulum (SR) Ca(2+) leak through ryanodine receptor 
type 2 (RyR2) dysfunction is of major pathophysiological relevance in human 
heart failure (HF); however, mechanisms underlying progressive RyR2 
dysregulation from cardiac hypertrophy to HF are still controversial.
METHODS AND RESULTS: We investigated healthy control myocardium (n=5) and 
myocardium from patients with compensated hypertrophy (n=25) and HF (n=32). In 
hypertrophy, Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) and protein 
kinase A (PKA) both phosphorylated RyR2 at levels that were not different from 
healthy myocardium. Accordingly, inhibitors of these kinases reduced the SR 
Ca(2+) leak. In HF, however, the SR Ca(2+) leak was nearly doubled compared with 
hypertrophy, which led to reduced systolic Ca(2+) transients, a depletion of SR 
Ca(2+) storage and elevated diastolic Ca(2+) levels. This was accompanied by a 
significantly increased CaMKII-dependent phosphorylation of RyR2. In contrast, 
PKA-dependent RyR2 phosphorylation was not increased in HF and was independent 
of previous β-blocker treatment. In HF, CaMKII inhibition but not inhibition of 
PKA yielded a reduction of the SR Ca(2+) leak. Moreover, PKA inhibition further 
reduced SR Ca(2+) load and systolic Ca(2+) transients.
CONCLUSIONS: In human hypertrophy, both CaMKII and PKA functionally regulate 
RyR2 and may induce SR Ca(2+) leak. In the transition from hypertrophy to HF, 
the diastolic Ca(2+) leak increases and disturbed Ca(2+) cycling occurs. This is 
associated with an increase in CaMKII- but not PKA-dependent RyR2 
phosphorylation. CaMKII inhibition may thus reflect a promising therapeutic 
target for the treatment of arrhythmias and contractile dysfunction.