| First Author | Sossalla S | Year | 2011 |
| Journal | Basic Res Cardiol | Volume | 106 |
| Issue | 2 | Pages | 263-72 |
| PubMed ID | 21174213 | Mgi Jnum | J:307005 |
| Mgi Id | MGI:6705192 | Doi | 10.1007/s00395-010-0136-x |
| Citation | Sossalla S, et al. (2011) Diastolic dysfunction and arrhythmias caused by overexpression of CaMKIIdelta(C) can be reversed by inhibition of late Na(+) current. Basic Res Cardiol 106(2):263-72 |
| abstractText | Transgenic (TG) Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) delta(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 mumol/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/mm(2); P < 0.05). Addition of Ran improved diastolic dysfunction to 2.1 +/- 0.2 mN/mm(2) (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 CaMKIIdelta(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 CaMKIIdelta(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. |
