Diastolic dysfunction and arrhythmias caused by overexpression of CaMKIIdC can be reversed by inhibition of late Na+ current
- نوع فایل : کتاب
- زبان : انگلیسی
- مؤلف : Samuel Sossalla Ulrike Maurer Hanna Schotola Nico Hartmann Michael Didie´ Wolfram-H. Zimmermann Claudius Jacobshagen Stefan Wagner Lar
- چاپ و سال / کشور: 2011
Description
Transgenic (TG) Ca2?/calmodulin-dependent protein kinase II (CaMKII) dC mice develop systolic heart failure (HF). CaMKII regulates intracellular Ca2? 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 INa) 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 INa inhibitor ranolazine (Ran, 5 lmol/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 INa 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 CaMKIIdC overexpression induces diastolic dysfunction and arrhythmogenic triggers possibly via an enhanced late INa. Inhibition of elevated late INa had beneficial effects on arrhythmias as well as diastolic function in papillary muscles from CaMKIIdC TG mice. Thus, late INa inhibition appears to be a promising option for diastolic dysfunction and arrhythmias in HF where CaMKII is found to be increased
Basic Res Cardiol (2011) 106:263–272 Received: 7 July 2010 / Revised: 13 October 2010 / Accepted: 8 November 2010 / Published online: 21 December 2010
