Enhanced Depolarization Drive in Failing Rabbit Ventricular Myocytes

作者：Bence Hegyi, Stefano Morotti, Caroline Liu, Kenneth S. Ginsburg, Julie Bossuyt, Luiz Belardinelli, Leighton T. Izu, Ye Chen‐Izu, Tamás Bányász, Eleonora Grandi, Donald M. Bers · 发表于：Circulation Arrhythmia and Electrophysiology · 年份：2019 · DOI：10.1161/circep.118.007061 · 被引用次数：43 · 研究领域：Cardiac electrophysiology and arrhythmias、Ion channel regulation and function、ECG Monitoring and Analysis

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 physio...