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Modeling tissue- and mutation- specific electrophysiological effects in the long QT syndrome: role of the Purkinje fiber.

Iyer V, Sampson KJ, Kass RS - PLoS ONE (2014)

Bottom Line: The LQT3 mutation S1904L demonstrated striking effects on action potential duration restitution and more severe action potential prolongation in Purkinje fiber cells at higher heart rates.We conclude that arrhythmia formation in long QT syndrome may depend not only on the basis of mutation and biophysical alteration, but also upon tissue of expression.The Purkinje fiber network may represent an important therapeutic target in the management of patients with heritable channelopathies.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, College of Physicians and Surgeons of Columbia University, New York, New York, United States of America.

ABSTRACT
Congenital long QT syndrome is a heritable family of arrhythmias caused by mutations in 13 genes encoding ion channel complex proteins. Mounting evidence has implicated the Purkinje fiber network in the genesis of ventricular arrhythmias. In this study, we explore the hypothesis that long QT mutations can demonstrate different phenotypes depending on the tissue type of expression. Using computational models of the human ventricular myocyte and the Purkinje fiber cell, the biophysical alteration in channel function in LQT1, LQT2, LQT3, and LQT7 are modeled. We identified that the plateau potential was important in LQT1 and LQT2, in which mutation led to minimal action potential prolongation in Purkinje fiber cells. The phenotype of LQT3 mutation was dependent on the biophysical alteration induced as well as tissue type. The canonical ΔKPQ mutation causes severe action potential prolongation in both tissue types. For LQT3 mutation F1473C, characterized by shifted channel availability, a more severe phenotype was seen in Purkinje fiber cells with action potential prolongation and early afterdepolarizations. The LQT3 mutation S1904L demonstrated striking effects on action potential duration restitution and more severe action potential prolongation in Purkinje fiber cells at higher heart rates. Voltage clamp simulations highlight the mechanism of effect of these mutations in different tissue types, and impact of drug therapy is explored. We conclude that arrhythmia formation in long QT syndrome may depend not only on the basis of mutation and biophysical alteration, but also upon tissue of expression. The Purkinje fiber network may represent an important therapeutic target in the management of patients with heritable channelopathies.

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The S1904L mutation, characterized clinically by arrhythmia at low levels of exertion, simulated at clinically relevant pacing frequencies.The mutation exhibits minimal response in VM (panel A, traces overlap) and greater APD prolongation in PF (panel B), with APD alternans seen at 120 BPM (lower row). WT cells: black trace, S1904L: blue trace.
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pone-0097720-g005: The S1904L mutation, characterized clinically by arrhythmia at low levels of exertion, simulated at clinically relevant pacing frequencies.The mutation exhibits minimal response in VM (panel A, traces overlap) and greater APD prolongation in PF (panel B), with APD alternans seen at 120 BPM (lower row). WT cells: black trace, S1904L: blue trace.

Mentions: This channel behavior is recapitulated by reducing the inactivation rate constant and reducing the rate constant of entry into deeper buried inactivated states by a factor of 5 and 6, respectively, generating 0.28% late current (as seen experimentally[9]). Figure 5A shows the predicted consequence of the S1904L in the VM model. As previously shown at 1 Hz[9], the impact on VM is minimal (no prolongation). In contrast, PFC bearing this mutation exhibit 120 ms APD prolongation at 1 Hz. More rapid pacing (120 BPM) exacerbates this phenotype, prolonging PFC APD by 200 ms but still with minimal change in VM. The result is a markedly flattened restitution curve for the PFC model even with a mild increase in rate. A predominant rate-dependent effect on PFC explains the emergence of the clinical phenotype with exercise as well as the propensity for arrhythmia formation despite minimal QT interval prolongation.


Modeling tissue- and mutation- specific electrophysiological effects in the long QT syndrome: role of the Purkinje fiber.

Iyer V, Sampson KJ, Kass RS - PLoS ONE (2014)

The S1904L mutation, characterized clinically by arrhythmia at low levels of exertion, simulated at clinically relevant pacing frequencies.The mutation exhibits minimal response in VM (panel A, traces overlap) and greater APD prolongation in PF (panel B), with APD alternans seen at 120 BPM (lower row). WT cells: black trace, S1904L: blue trace.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4043730&req=5

pone-0097720-g005: The S1904L mutation, characterized clinically by arrhythmia at low levels of exertion, simulated at clinically relevant pacing frequencies.The mutation exhibits minimal response in VM (panel A, traces overlap) and greater APD prolongation in PF (panel B), with APD alternans seen at 120 BPM (lower row). WT cells: black trace, S1904L: blue trace.
Mentions: This channel behavior is recapitulated by reducing the inactivation rate constant and reducing the rate constant of entry into deeper buried inactivated states by a factor of 5 and 6, respectively, generating 0.28% late current (as seen experimentally[9]). Figure 5A shows the predicted consequence of the S1904L in the VM model. As previously shown at 1 Hz[9], the impact on VM is minimal (no prolongation). In contrast, PFC bearing this mutation exhibit 120 ms APD prolongation at 1 Hz. More rapid pacing (120 BPM) exacerbates this phenotype, prolonging PFC APD by 200 ms but still with minimal change in VM. The result is a markedly flattened restitution curve for the PFC model even with a mild increase in rate. A predominant rate-dependent effect on PFC explains the emergence of the clinical phenotype with exercise as well as the propensity for arrhythmia formation despite minimal QT interval prolongation.

Bottom Line: The LQT3 mutation S1904L demonstrated striking effects on action potential duration restitution and more severe action potential prolongation in Purkinje fiber cells at higher heart rates.We conclude that arrhythmia formation in long QT syndrome may depend not only on the basis of mutation and biophysical alteration, but also upon tissue of expression.The Purkinje fiber network may represent an important therapeutic target in the management of patients with heritable channelopathies.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, College of Physicians and Surgeons of Columbia University, New York, New York, United States of America.

ABSTRACT
Congenital long QT syndrome is a heritable family of arrhythmias caused by mutations in 13 genes encoding ion channel complex proteins. Mounting evidence has implicated the Purkinje fiber network in the genesis of ventricular arrhythmias. In this study, we explore the hypothesis that long QT mutations can demonstrate different phenotypes depending on the tissue type of expression. Using computational models of the human ventricular myocyte and the Purkinje fiber cell, the biophysical alteration in channel function in LQT1, LQT2, LQT3, and LQT7 are modeled. We identified that the plateau potential was important in LQT1 and LQT2, in which mutation led to minimal action potential prolongation in Purkinje fiber cells. The phenotype of LQT3 mutation was dependent on the biophysical alteration induced as well as tissue type. The canonical ΔKPQ mutation causes severe action potential prolongation in both tissue types. For LQT3 mutation F1473C, characterized by shifted channel availability, a more severe phenotype was seen in Purkinje fiber cells with action potential prolongation and early afterdepolarizations. The LQT3 mutation S1904L demonstrated striking effects on action potential duration restitution and more severe action potential prolongation in Purkinje fiber cells at higher heart rates. Voltage clamp simulations highlight the mechanism of effect of these mutations in different tissue types, and impact of drug therapy is explored. We conclude that arrhythmia formation in long QT syndrome may depend not only on the basis of mutation and biophysical alteration, but also upon tissue of expression. The Purkinje fiber network may represent an important therapeutic target in the management of patients with heritable channelopathies.

Show MeSH
Related in: MedlinePlus