Enhanced Depolarization Drive in Failing Rabbit Ventricular Myocytes: Calcium-Dependent and β-Adrenergic Effects on Late Sodium, L-Type Calcium, and Sodium-Calcium Exchange Currents

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 Ca²⁺ current, and NCX (Na⁺/Ca²⁺ exchanger) current are often measured in nonphysiological conditions (square-pulse voltage clamp, slow pacing rates, exogenous Ca²⁺ buffers).

Methods: We measured the major inward currents and their Ca²⁺- 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 Ca²⁺ was strongly buffered. But under physiological AP clamp with normal Ca²⁺ cycling, I_NaL was markedly upregulated in HF versus control (dependent largely on CaMKII [Ca²⁺/calmodulin-dependent protein kinase II] activity). β-Adrenergic stimulation (often elevated in HF) further enhanced I_NaL. L-type Ca²⁺ current was decreased in HF when Ca²⁺ was buffered, but CaMKII-mediated Ca²⁺-dependent facilitation upregulated physiological L-type Ca²⁺ current to the control level. Furthermore, L-type Ca²⁺ 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.

Keywords: action potential; buffers; electrophysiology; heart failure; rabbits.