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This Article Full Text Full Text (PDF) All Versions of this Article: 297/4/H1436    most recent 00263.2009v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Romero, L. Articles by Rodríguez, B. PubMed PubMed Citation Articles by Romero, L. Articles by Rodríguez, B.

Impact of ionic current variability on human ventricular cellular electrophysiology

¹Instituto de Investigación Interuniversitario en Bioingeniería y Tecnología Orientada al Ser Humano, Universidad Politécnica de Valencia, Valencia, Spain; ²Oxford University Computing Laboratory, University of Oxford, Oxford, United Kingdom; ³Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom; and ⁴Instituto de Investigación en Ingeniería de Aragón, Universidad de Zaragoza, Zaragoza, Spain

Submitted March 18, 2009 ; accepted in final form July 24, 2009

Abnormalities in repolarization and its rate dependence are known to be related to increased proarrhythmic risk. A number of repolarization-related electrophysiological properties are commonly used as preclinical biomarkers of arrhythmic risk. However, the variability and complexity of repolarization mechanisms make the use of cellular biomarkers to predict arrhythmic risk preclinically challenging. Our goal is to investigate the role of ionic current properties and their variability in modulating cellular biomarkers of arrhythmic risk to improve risk stratification and identification in humans. A systematic investigation into the sensitivity of the main preclinical biomarkers of arrhythmic risk to changes in ionic current conductances and kinetics was performed using computer simulations. Four stimulation protocols were applied to the ten Tusscher and Panfilov human ventricular model to quantify the impact of ±15 and ±30% variations in key model parameters on action potential (AP) properties, Ca²⁺ and Na⁺ dynamics, and their rate dependence. Simulations show that, in humans, AP duration is moderately sensitive to changes in all repolarization current conductances and in L-type Ca²⁺ current (I_CaL) and slow component of the delayed rectifier current (I_Ks) inactivation kinetics. AP triangulation, however, is strongly dependent only on inward rectifier K⁺ current (I_K1) and delayed rectifier current (I_Kr) conductances. Furthermore, AP rate dependence (i.e., AP duration rate adaptation and restitution properties) and intracellular Ca²⁺ and Na⁺ levels are highly sensitive to both I_CaL and Na⁺/K⁺ pump current (I_NaK) properties. This study provides quantitative insights into the sensitivity of preclinical biomarkers of arrhythmic risk to variations in ionic current properties in humans. The results show the importance of sensitivity analysis as a powerful method for the in-depth validation of mathematical models in cardiac electrophysiology.

biological variability; arrhythmia; computer simulation