title: Theoretical investigation of the mechanism of heart failure using a canine ventricular cell model: especially the role of up-regulated CaMKII and SR Ca(2+) leak.
abstract: Heart failure (HF) is associated with susceptibility to sudden cardiac death. However, the underlying mechanism of electrical instability and mechanical dysfunction associated with HF remains poorly understood. In this study, a new canine ventricular cell model based on the Hund-Rudy dynamic (HRd) model and recently published experimental data was developed to investigate the electrical changes and calcium handling dysfunction in HF. Simulation results suggest that: 1) acute Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) over-expression (CaMKII-OE) affects the action potential (AP) profile, while AP prolongation is mainly caused by the down-regulation of K(+) currents; 2) enhanced late Na(+) current (I(NaL)) alone cannot adequately lead to [Na(+)] elevation in HF; 3) enhanced sarcoplasmic reticulum (SR) leak current (I(leak)) causes disturbed Ca(2+) handling and there is little contribution from Na(+)/Ca(2+) exchanger (NCX); 4) at high SR Ca(2+) load, a steeper fractional SR Ca(2+) release is observed in HF than that in control, causing alternans to occur more easily; and 5) I(leak) block restores the contraction and relaxation function, but cannot eliminate alternans. By inhibiting CaMKII, alternans is eliminated, but contractility is not improved. Partial CaMKII inhibition in combination with I(leak) block could augment mechanical function and depress alternans, suggesting a new possible therapeutic target for HF treatment.
authors.affiliation: Department of Biomedical Engineering, Zhejiang University, Hangzhou 310027, China.
authors.forename: Yunliang
authors.initials: Y
authors.lastname: Zang
authors.forename: Ling
authors.initials: L
authors.lastname: Dai
authors.forename: Heqing
authors.initials: H
authors.lastname: Zhan
authors.forename: Jianhong
authors.initials: J
authors.lastname: Dou
authors.forename: Ling
authors.initials: L
authors.lastname: Xia
authors.forename: Henggui
authors.initials: H
authors.lastname: Zhang
mesh_terms: D000200:Action Potentials; D000818:Animals; D002118:Calcium / Q000502:physiology*; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000502:physiology*; D003198:Computer Simulation; D004285:Dogs; D006333:Heart Failure / Q000201:enzymology* / Q000503:physiopathology; D006352:Heart Ventricles / Q000473:pathology; D007700:Kinetics; D008954:Models, Biological; D009200:Myocardial Contraction; D032383:Myocytes, Cardiac / Q000201:enzymology / Q000502:physiology; D012519:Sarcoplasmic Reticulum / Q000502:physiology*
chemical_list: D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D002118:Calcium