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Changes in Intracellular Na(+) following Enhancement of Late Na(+) Current in Virtual Human Ventricular Myocytes

The slowly inactivating or late Na(+) current, I(Na-L), can contribute to the initiation of both atrial and ventricular rhythm disturbances in the human heart. However, the cellular and molecular mechanisms that underlie these pro-arrhythmic influences are not fully understood. At present, the major...

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Detalles Bibliográficos
Autores principales: Cardona, Karen, Trenor, Beatriz, Giles, Wayne R.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5119830/
https://www.ncbi.nlm.nih.gov/pubmed/27875582
http://dx.doi.org/10.1371/journal.pone.0167060
Descripción
Sumario:The slowly inactivating or late Na(+) current, I(Na-L), can contribute to the initiation of both atrial and ventricular rhythm disturbances in the human heart. However, the cellular and molecular mechanisms that underlie these pro-arrhythmic influences are not fully understood. At present, the major working hypothesis is that the Na(+) influx corresponding to I(Na-L) significantly increases intracellular Na(+), [Na(+)](i); and the resulting reduction in the electrochemical driving force for Na(+) reduces and (may reverse) Na(+)/Ca(2+) exchange. These changes increase intracellular Ca(2+), [Ca(2+)](i); which may further enhance I(Na-L) due to calmodulin-dependent phosphorylation of the Na(+) channels. This paper is based on mathematical simulations using the O’Hara et al (2011) model of baseline or healthy human ventricular action potential waveforms(s) and its [Ca(2+)](i) homeostasis mechanisms. Somewhat surprisingly, our results reveal only very small changes (≤ 1.5 mM) in [Na(+)](i) even when I(Na-L) is increased 5-fold and steady-state stimulation rate is approximately 2 times the normal human heart rate (i.e. 2 Hz). Previous work done using well-established models of the rabbit and human ventricular action potential in heart failure settings also reported little or no change in [Na(+)](i) when I(Na-L) was increased. Based on our simulations, the major short-term effect of markedly augmenting I(Na-L) is a significant prolongation of the action potential and an associated increase in the likelihood of reactivation of the L-type Ca(2+) current, I(Ca-L). Furthermore, this action potential prolongation does not contribute to [Na(+)](i) increase.