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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. Computer simulations and experimental recordings in human and canine ventricular tissue were used to investigate the ionic basis of QTI and action potential duration (APD) to abrupt changes in HR with a protocol commonly used in clinical studies. The time for 90% QTI adaptation is 3.5 min in simulations, in agreement with experimental and clinical data in humans. APD adaptation follows similar dynamics, being faster in mid-myocardial cells (2.5 min) than in endocardial and 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 and slow-delayed rectifier potassium current, and a second slow phase of >2 min driven by intracellular sodium concentration ([Na(+)](i)) dynamics. Alterations in [Na(+)](i) dynamics due to Na(+)/K(+) pump current inhibition result in protracted rate adaptation and are associated with increased proarrhythmic risk, as indicated by action potential triangulation and faster L-type calcium current recovery from inactivation, leading to the formation of early afterdepolarizations. In conclusion, this study suggests that protracted QTI adaptation could be an indicator of altered [Na(+)](i) dynamics following Na(+)/K(+) pump inhibition as it occurs in patients with ischemia or heart failure. An increased risk of cardiac arrhythmias in patients with protracted rate adaptation may be due to an increased risk of early after-depolarization formation.

Original publication




Journal article


Am J Physiol Heart Circ Physiol

Publication Date





H1577 - H1587


Action Potentials, Adaptation, Physiological, Animals, Arrhythmias, Cardiac, Calcium Channels, L-Type, Computer Simulation, Delayed Rectifier Potassium Channels, Dogs, Electrocardiography, Heart Rate, Heart Ventricles, Humans, Ion Channels, Kinetics, Myocardial Contraction, Myocytes, Cardiac, Predictive Value of Tests, Risk Assessment, Sodium, Sodium-Potassium-Exchanging ATPase