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 Ca2+/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 (INaL) alone cannot adequately lead to [Na+] elevation in HF; 3) enhanced sarcoplasmic reticulum (SR) leak current (Ileak) causes disturbed Ca2+ handling and there is little contribution from Na+/Ca2+ exchanger (NCX); 4) at high SR Ca2+ load, a steeper fractional SR Ca2+ release is observed in HF than that in control, causing alternans to occur more easily; and 5) Ileak 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 Ileak block could augment mechanical function and depress alternans, suggesting a new possible therapeutic target for HF treatment.
Published Version
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