Transgenic (TG) Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) δ(C) mice 
develop systolic heart failure (HF). CaMKII regulates intracellular Ca(2+) 
handling proteins as well as sarcolemmal Na(+) channels. We hypothesized that 
CaMKII also contributes to diastolic dysfunction and arrhythmias via 
augmentation of the late Na(+) current (late I(Na)) in early HF (8-week-old TG 
mice). Echocardiography revealed severe diastolic dysfunction in addition to 
decreased systolic ejection fraction. Premature arrhythmogenic contractions 
(PACs) in isolated isometrically twitching papillary muscles only occurred in TG 
preparations (5 vs. 0, P < 0.05) which could be completely terminated when 
treated with the late I(Na) inhibitor ranolazine (Ran, 5 μmol/L). 
Force-frequency relationships revealed significantly reduced twitch force 
amplitudes in TG papillary muscles. Most importantly, diastolic tension 
increased with raising frequencies to a greater extent in TG papillary muscles 
compared to WT specimen (at 10 Hz: 3.7 ± 0.4 vs. 2.5 ± 0.3 mN/mm²; P < 0.05). 
Addition of Ran improved diastolic dysfunction to 2.1 ± 0.2 mN/mm² (at 10 Hz; P 
< 0.05) without negative inotropic effects. Mechanistically, the late I(Na) was 
markedly elevated in myocytes isolated from TG mice and could be completely 
reversed by Ran. In conclusion, our results show for the first time that TG 
CaMKIIδ(C) overexpression induces diastolic dysfunction and arrhythmogenic 
triggers possibly via an enhanced late I(Na). Inhibition of elevated late I(Na) 
had beneficial effects on arrhythmias as well as diastolic function in papillary 
muscles from CaMKIIδ(C) TG mice. Thus, late I(Na) inhibition appears to be a 
promising option for diastolic dysfunction and arrhythmias in HF where CaMKII is 
found to be increased.