Mechanisms of ventricular rate adaptation as a predictor of arrhythmic risk.

Pueyo, Esther and Husti, Zoltán and Hornyik, Tibor and Baczkó, István and Laguna, Pablo and Varró, András (2010) Mechanisms of ventricular rate adaptation as a predictor of arrhythmic risk. AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY, 298 (5). H1577-H1587. ISSN 0363-6135

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Abstract

Background: Protracted QT interval (QTI) adaptation to abrupt heart rate (HR) changes has been identified as a clinical arrhythmic risk marker. This study investigates the ionic mechanisms of QTI rate adaptation and its relationship to arrhythmic risk. Methods and Results: Computer simulations and experimental recordings in human and canine ventricular tissue were used to investigate the ionic basis of QTI and action potential (AP) duration (APD) to abrupt changes in HR with a protocol commonly used in clinical studies. Time for 90% QTI adaptation is 3.5 min in simulations, in agreement with experimental and clinical data in human. APD adaptation follows similar dynamics, being faster in midmyocardial cells (2.5 min) than in endocardial/epicardial cells (3.5 min). Both QTI and APD adapt in two phases following an abrupt HR change: a fast initial phase with time constant <30 s, mainly related to L-type calcium (ICaL) and slow-delayed rectifier potassium current; and a second slow phase of >2 min driven by [Na(+)]i dynamics. Alterations in [Na(+)]i dynamics due to Na(+)/K(+) pump (INaK) inhibition result in protracted rate adaptation, and is associated with increased proarrhythmic risk, as indicated by AP triangulation and faster ICaL recovery from inactivation, leading to formation of early afterdepolarizations (EADs). Conclusions: This study suggests that protracted QTI adaptation could be an indicator of altered [Na(+)]i dynamics following INaK inhibition as it occurs in patients with ischemia or heart failure. Increased risk of cardiac arrhythmias in patients with protracted rate adaptation may be due to increased risk of EAD formation. Key words: action potentials, ventricles, ion channels, arrhythmia.

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