Background-Potassium currents contribute to action potential duration (APD) and arrhythmogenesis. In heart failure, Ca/calmodulin-dependent protein kinase II (CaMKII) is upregulated and can alter ion channel regulation and expression. Methods and Results-We examine the influence of overexpressing cytoplasmic CaMKII␦ C , both acutely in rabbit ventricular myocytes (24-hour adenoviral gene transfer) and chronically in CaMKII␦ C -transgenic mice, on transient outward potassium current (I to ), and inward rectifying current (I K1 ). Acute and chronic CaMKII overexpression increases I to,slow amplitude and expression of the underlying channel protein K V 1.4. Chronic but not acute CaMKII overexpression causes downregulation of I to,fast , as well as K V 4.2 and KChIP2, suggesting that K V 1.4 expression responds faster and oppositely to K V 4.2 on CaMKII activation. These amplitude changes were not reversed by CaMKII inhibition, consistent with CaMKII-dependent regulation of channel expression and/or trafficking. CaMKII (acute and chronic) greatly accelerated recovery from inactivation for both I to components, but these effects were acutely reversed by AIP (CaMKII inhibitor), suggesting that CaMKII activity directly accelerates I to recovery. Expression levels of I K1 and Kir2.1 mRNA were downregulated by CaMKII overexpression. CaMKII acutely increased I K1 , based on inhibition by AIP (in both models). CaMKII overexpression in mouse prolonged APD (consistent with reduced I to,fast and I K1 ), whereas CaMKII overexpression in rabbit shortened APD (consistent with enhanced I K1 and I to,slow and faster I to recovery). Computational models allowed discrimination of contributions of different channel effects on APD. Key Words: action potentials Ⅲ potassium Ⅲ arrhythmia Ⅲ electrophysiology Ⅲ heart failure H eart failure (HF) is accompanied by arrhythmogenic changes related to electric remodeling. This is associated with prolongation of action potential duration (APD) 1 and downregulation of transient outward K-current (I to ) and inward rectifying K-current (I K1 ). I K1 is responsible for stabilizing the diastolic membrane potential (E m ), such that decreased I K1 increases the propensity for triggered arrhythmias. 2 I to is important in early repolarization and influences the effects of other currents and transporters by affecting AP voltage-time trajectory. There are at least 2 components of I to generated by different K-channel isoforms, which can be distinguished according to their recovery and inactivation kinetics. 3,4 The fast component (I to,fast ) recovers and inactivates with time constants () of Ͻ100 ms, whereas the slow component (I to,slow ) recovers with of hundreds of milliseconds up to several seconds and inactivates with of Ϸ200 ms. 3-5 Downregulation of I to has been described in animal models of hypertrophy and human HF, 2,6,7 is associated with APD prolongation, 8 and predisposes to early afterdepolarizations.
Conclusion-CaMKII
Clinical Perspective on p 294In HF, expression and activity of Ca/cal...