Abstract
BACKGROUND: Heart failure (HF) is characterized by electrophysiological remodeling resulting in increased risk of cardiac arrhythmias. Previous reports suggest that elevated inward ionic currents in HF promote action potential (AP) prolongation, increased short-term variability of AP repolarization, and delayed afterdepolarizations. However, the underlying changes in late Na(+) current (I(NaL)), L-type Ca(2+) current, and NCX (Na(+)/Ca(2+) exchanger) current are often measured in nonphysiological conditions (square-pulse voltage clamp, slow pacing rates, exogenous Ca(2+) buffers). METHODS: We measured the major inward currents and their Ca(2+)- and β-adrenergic dependence under physiological AP clamp in rabbit ventricular myocytes in chronic pressure/volume overload-induced HF (versus age-matched control). RESULTS: AP duration and short-term variability of AP repolarization were increased in HF, and importantly, inhibition of I(NaL) decreased both parameters to the control level. I(NaL) was slightly increased in HF versus control even when intracellular Ca(2+) was strongly buffered. But under physiological AP clamp with normal Ca(2+) cycling, I(NaL) was markedly upregulated in HF versus control (dependent largely on CaMKII [Ca(2+)/calmodulin-dependent protein kinase II] activity). β-Adrenergic stimulation (often elevated in HF) further enhanced I(NaL). L-type Ca(2+) current was decreased in HF when Ca(2+) was buffered, but CaMKII-mediated Ca(2+)-dependent facilitation upregulated physiological L-type Ca(2+) current to the control level. Furthermore, L-type Ca(2+) current response to β-adrenergic stimulation was significantly attenuated in HF. Inward NCX current was upregulated at phase 3 of AP in HF when assessed by combining experimental data and computational modeling. CONCLUSIONS: Our results suggest that CaMKII-dependent upregulation of I(NaL) in HF significantly contributes to AP prolongation and increased short-term variability of AP repolarization, which may lead to increased arrhythmia propensity, and is further exacerbated by adrenergic stress.