Abstract 1401: CaMKII-Dependent Increases in ICa and Heart Failure-Associated Arrhythmias
Background: Recent studies have implicated CaMKII (Ca/calmodulin-dependent protein kinase II) in the pathological electrical remodeling of pressure-overload heart failure (HF). To probe proximal activators of CaMKII, we examined changes in ICa.
Methods: Using the whole-cell patch clamp technique, we studied freshly dissociated ventricular myocytes from a model of pressure-overload heart failure. In addition, we employed a unique coupling-clamp technique to electrically couple (Gsac) a myocyte to an invariable voltage source (E =−10 mV).
Results: In control LV, ICa density in subepicardial (SEP) myocytes was significantly larger than in subendocardial (SEN) cells. In failing LV, ICa density was increased proportionately in both cell types, and ICa inactivation was significantly slowed. The robust increases we observed in fast (τ1) and slow (τ2) time constants in sham-operated (n=18) and HF myocytes (n=19) would be expected to predispose to EADs. Consistent with this, APD30 and APD90 were significantly prolonged and Gsac-induced EADs were observed in all myocytes from failing LV (38/38) but in only ≈10% of myocytes from sham-operated mice (6/58). To test the role of APD prolongation per se, 4-aminopyrodine (4-AP), a K+ channel blocker, was used. In control myocytes, 2 mM 4-AP significantly prolonged APD90 from 26.5±3.3 to 164±14 ms (n=9, p<0.05). However, this dramatic prolongation of APD did not enhance susceptibility to Gsac-induced EADs or automaticity. In contrast, application of isoproterenol (1μM ISO) prolonged APDs significantly, and EADs and automaticity were triggered reproducibly. Similarly, the L-type Ca2+ channel opener S(−)Bay K 8644 1μM significantly facilitated induction of abnormal impulses. To probe the contribution of transmembrane Ca2+ current, as opposed to Ca2+-dependent activation of signaling pathways, we simulated ventricular myocyte action potentials numerically. Here, normal values of ICa were not associated with Gsac-induced automaticity, whereas increased ICa was sufficient to trigger automaticity.
Conclusion: These findings are consistent with a significant role of CaMKII-dependent increases in ICa in the pathogenesis of HF-associated arrhythmias.