Role of the Calcium-Independent Transient Outward Current
            <i>I</i>
            <sub>to1</sub>
            in Shaping Action Potential Morphology and Duration

Greenstein, Joseph L.; Wu, Richard C.; Po, Sunny S.; Tomaselli, Gordon F.; Winslow, Raimond L.

doi:10.1161/01.res.87.11.1026

Cited by 191 publications

(169 citation statements)

References 40 publications

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“…In that case, peak I to exceeds 14 pA/pF, which results in early deactivation of I Ca,L . Similar observations have been reported by Greenstein et al 18 with models of ventricular membrane behavior.…”

Section: Isosarcometric Contractionsupporting

confidence: 90%

“…Since the model is capable of reproducing the complex interaction between I to and I Ca,L as described by Greenstein et al 18 for ventricular models, we conclude that the model is representative for cardiomyocytes in general. By adjusting I Ca,L gating variable d, our model is capable of reproducing a larger I Ca,L current and slower decrease of I Ca,L during the plateau phase, which results in an increased APD and plateau height and is in agreement with the experimental results of Plotnikov et al 49 Although we obtain qualitative agreement, fitting I Ca,L kinetics to the data provided by Plotnikov et al 49 may require a recent ventricular model such as the Winslow-Rice-Jafri model of the canine ventricle 71 (including the new formulation of I to1 by Greenstein et al 18 ) or the model by Ten Tusscher et al 66 Ca 2+ -Force Relation Cardiac electromechanical behavior in our model is described by combining the models of Courtemanche et al 12 and Rice et al 53,54 To model the Ca 2+ -force relation, we apply model 4 of Rice et al, 53,54 which approximates the contractile force measured during isosarcometric twitches from RV rat trabeculae. 25 In model 4, the affinity of troponin for Ca 2+ does not increase in the presence of strongly bound cross bridges.…”

Section: Ionic Membrane Currentssupporting

confidence: 52%

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Mechanoelectric Feedback as a Trigger Mechanism for Cardiac Electrical Remodeling: A Model Study

et al. 2008

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Abstract-Regional variation in ionic membrane currents causes differences in action potential duration (APD) and is proarrhythmic. After several weeks of ventricular pacing, AP morphology and duration are changed due to electrical remodeling of the transient outward potassium current (I to ) and the L-type calcium current (I Ca,L ). It is not clear what mechanism drives electrical remodeling. By modeling the cardiac muscle as a string of segments that are electrically and mechanically coupled, we investigate the hypothesis that electrical remodeling is triggered by changes in mechanical load. Contractile force generated by the sarcomeres depends on the calcium transient and on the sarcomere length. Stroke work is determined for each segment by simulating the cardiac cycle. Electrical remodeling is simulated by adapting I Ca,L kinetics such that a homogeneous distribution of stroke work is obtained. With electrical remodeling, a more homogeneous shortening of the fiber is obtained, while heterogeneity in APD increases and the repolarization wave reverses. Our results are in agreement with experimentally observed homogeneity in mechanics and heterogeneity in electrophysiology. In conclusion, electrical remodeling is a possible mechanism to reduce heterogeneity in cardiomechanics induced by ventricular pacing.

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Section: Isosarcometric Contractionsupporting

confidence: 90%

Section: Ionic Membrane Currentssupporting

confidence: 52%

Mechanoelectric Feedback as a Trigger Mechanism for Cardiac Electrical Remodeling: A Model Study

et al. 2008

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“…Previous experiments and simulation studies have suggested that I to1 , by increasing phase 1 repolarization, increases peak I Ca,L (the trigger for SR release) and, consequently, SR Ca 2ϩ release (14,38). These studies showed enhanced I Ca,L and SR Ca 2ϩ release when phase 1 repolarization increases the I Ca,L driving force.…”

Section: Discussionmentioning

confidence: 99%

Properties and ionic mechanisms of action potential adaptation, restitution, and accommodation in canine epicardium

Decker¹,

Heijman²,

Silva³

et al. 2009

American Journal of Physiology-Heart and Circulatory Physiology

117

121

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Decker KF, Heijman J, Silva JR, Hund TJ, Rudy Y. Properties and ionic mechanisms of action potential adaptation, restitution, and accommodation in canine epicardium. Am J Physiol Heart Circ Physiol 296: H1017-H1026, 2009. First published January 23, 2009 doi:10.1152/ajpheart.01216.2008.-Computational models of cardiac myocytes are important tools for understanding ionic mechanisms of arrhythmia. This work presents a new model of the canine epicardial myocyte that reproduces a wide range of experimentally observed rate-dependent behaviors in cardiac cell and tissue, including action potential (AP) duration (APD) adaptation, restitution, and accommodation. Model behavior depends on updated formulations for the 4-aminopyridine-sensitive transient outward current (Ito1), the slow component of the delayed rectifier K ϩ current (IKs), the L-type Ca 2ϩ channel current (ICa,L), and the Na ϩ -K ϩ pump current (INaK) fit to data from canine ventricular myocytes. We found that Ito1 plays a limited role in potentiating peak ICa,L and sarcoplasmic reticulum Ca 2ϩ release for propagated APs but modulates the time course of APD restitution. IKs plays an important role in APD shortening at short diastolic intervals, despite a limited role in AP repolarization at longer cycle lengths. In addition, we found that ICa,L plays a critical role in APD accommodation and rate dependence of APD restitution. Ca 2ϩ entry via ICa,L at fast rate drives increased Na ϩ -Ca 2ϩ exchanger Ca 2ϩ extrusion and Na ϩ entry, which in turn increases Na ϩ extrusion via outward INaK. APD accommodation results from this increased outward INaK. Our simulation results provide valuable insight into the mechanistic basis of rate-dependent phenomena important for determining the heart's response to rapid and irregular pacing rates (e.g., arrhythmia). Accurate simulation of rate-dependent phenomena and increased understanding of their mechanistic basis will lead to more realistic multicellular simulations of arrhythmia and identification of molecular therapeutic targets. arrhythmia; cardiac electrophysiology; mathematical modeling; ion channels CARDIAC ARRHYTHMIAS and sudden death involve complex myocardial activation patterns, including unidirectional block, reentry, and fibrillation. To understand the relations and transitions between these patterns, the ionic determinants of the response of healthy and diseased cardiac myocytes to complex patterns of excitation must be understood. The single-cell response to such excitation patterns depends on the complex interaction between ionic currents, intracellular ion concentrations, and membrane voltage. Computational cell models provide critical tools for exploring these interactions, allowing the development and testing of hypotheses about underlying ionic mechanisms based on careful integration of available experimental data (37). The dog is a common animal model for studying cell electrophysiology in a range of disease states. Our group and others have developed detailed mathematical models of the canine action ...

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“…CaMKII phosphorylates the SR, 6 targeting SERCA2a (SR Ca 2ϩ -ATPase) 7 and PLB, 8,10 which associates with SERCA2a to inhibit uptake. PLB phosphorylation shifts the Ca 2ϩ -binding K 0.5 and relieves inhibition, 9 whereas direct SERCA2a phosphorylation increases the maximum uptake rate, 7 although this is controversial 9 (online-only Data Supplement section K).…”

Section: Sr Ca 2؉ -Atpase and Plbmentioning

confidence: 99%

Rate Dependence and Regulation of Action Potential and Calcium Transient in a Canine Cardiac Ventricular Cell Model

2004

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Background-Computational biology is a powerful tool for elucidating arrhythmogenic mechanisms at the cellular level, where complex interactions between ionic processes determine behavior. A novel theoretical model of the canine ventricular epicardial action potential and calcium cycling was developed and used to investigate ionic mechanisms underlying Ca 2ϩ transient (CaT) and action potential duration (APD) rate dependence. Methods and Results-The Ca 2ϩ /calmodulin-dependent protein kinase (CaMKII) regulatory pathway was integrated into the model, which included a novel Ca 2ϩ -release formulation, Ca 2ϩ subspace, dynamic chloride handling, and formulations for major ion currents based on canine ventricular data. Decreasing pacing cycle length from 8000 to 300 ms shortened APD primarily because of I Ca(L) reduction, with additional contributions from I to1 , I NaK , and late I Na . CaT amplitude increased as cycle length decreased from 8000 to 500 ms. This positive rate-dependent property depended on CaMKII activity. Key Words: electrophysiology Ⅲ action potentials Ⅲ calcium Ⅲ ion channels T he dependence of action potential duration (APD) and the Ca 2ϩ transient (CaT) on pacing rate is a fundamental property of cardiac myocytes that, when altered, may promote life-threatening cardiac arrhythmias. We have developed a detailed and physiologically based mathematical canine ventricular cell model (Hund-Rudy dynamic [HRd] cell model) that simulates rate-dependent phenomena associated with ion-channel kinetics, AP properties, and Ca handling. The dog is commonly used to investigate cardiac electrophysiology, making it a logical choice for modeling. An epicardial myocyte was chosen rather than endocardial or midmyocardial myocytes because epicardial cells contain the highest density of I to1 (transient outward K ϩ current), producing a unique and complex AP morphology. Conclusions-CaMKII MethodsComplete HRd equations, definitions, and detailed comments appear in the online-only Data Supplement. Important model properties (schematic in Figure 1A) are summarized here. Figure 1B) is introduced through a multiplicative factor dependent on the I Ca(L) driving force. Though controversial (online-only Data Supplement section J), CaMKII phosphorylation is thought to promote RyR channel opening. 5,14,20 Accordingly, the I rel inactivation time constant ( ri ) depends on CaMKII activity. A 10-ms maximal CaMKII-dependent increase in ri yields a steady-state CaT amplitude (CaT amp ) 95% 20 greater for control than with CaMKII suppressed at rapid pacing (CLϭ300 ms). Variable 1-second prepulse (V pre ) was followed by 10-ms holding interval at Ϫ50 mV and ϩ80 mV test pulse. Right, I Ca(L) recovery from voltage-dependent inactivation compared with canine ventricular data. 52 Prepulse of 350 ms to ϩ20 mV was followed by varying interpulse interval at Ϫ40 mV and ϩ20 mV test pulse. Model Ca 2ϩ -dependent inactivation gates were held constant to isolate voltage-dependent inactivation. E, Peak I Ks and I Kr tail currents on repolariz...

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Role of the Calcium-Independent Transient Outward Current I _to1 in Shaping Action Potential Morphology and Duration

Cited by 191 publications

References 40 publications

Mechanoelectric Feedback as a Trigger Mechanism for Cardiac Electrical Remodeling: A Model Study

Mechanoelectric Feedback as a Trigger Mechanism for Cardiac Electrical Remodeling: A Model Study

Properties and ionic mechanisms of action potential adaptation, restitution, and accommodation in canine epicardium

Rate Dependence and Regulation of Action Potential and Calcium Transient in a Canine Cardiac Ventricular Cell Model

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Role of the Calcium-Independent Transient Outward Current I to1 in Shaping Action Potential Morphology and Duration

Cited by 191 publications

References 40 publications

Mechanoelectric Feedback as a Trigger Mechanism for Cardiac Electrical Remodeling: A Model Study

Mechanoelectric Feedback as a Trigger Mechanism for Cardiac Electrical Remodeling: A Model Study

Properties and ionic mechanisms of action potential adaptation, restitution, and accommodation in canine epicardium

Rate Dependence and Regulation of Action Potential and Calcium Transient in a Canine Cardiac Ventricular Cell Model

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Role of the Calcium-Independent Transient Outward Current I _to1 in Shaping Action Potential Morphology and Duration