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- Title
Diastolic dysfunction and arrhythmias caused by overexpression of CaMKIIδ can be reversed by inhibition of late Na current.
- Authors
Sossalla, Samuel; Maurer, Ulrike; Schotola, Hanna; Hartmann, Nico; Didié, Michael; Zimmermann, Wolfram-H.; Jacobshagen, Claudius; Wagner, Stefan; Maier, Lars
- Abstract
Transgenic (TG) Ca/calmodulin-dependent protein kinase II (CaMKII) δ mice develop systolic heart failure (HF). CaMKII regulates intracellular Ca 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) 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 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/mm; P < 0.05). Addition of Ran improved diastolic dysfunction to 2.1 ± 0.2 mN/mm (at 10 Hz; P < 0.05) without negative inotropic effects. Mechanistically, the late I 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 overexpression induces diastolic dysfunction and arrhythmogenic triggers possibly via an enhanced late I. Inhibition of elevated late I had beneficial effects on arrhythmias as well as diastolic function in papillary muscles from CaMKIIδ TG mice. Thus, late I inhibition appears to be a promising option for diastolic dysfunction and arrhythmias in HF where CaMKII is found to be increased.
- Subjects
HEART failure; ARRHYTHMIA; CARDIAC contraction; CALMODULIN; PROTEIN kinases; INTRACELLULAR calcium; ECHOCARDIOGRAPHY; EXCITATION (Physiology)
- Publication
Basic Research in Cardiology, 2011, Vol 106, Issue 2, p263
- ISSN
0300-8428
- Publication type
Article
- DOI
10.1007/s00395-010-0136-x