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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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Related in: MedlinePlus

VM and PFC carrying the SCN5A ΔKPQ mutation exhibit similarly severe APD prolongation.Panel A and B) Effect of a 2 second pause for VM and PFC, respectively, compared with 1000 msec (last beat of drive train shown for WT, black trace, and mutant cells, blue trace). Panels C and D) Steady state rate adaptation for VM and PFC, respectively (30 BPM: blue trace, 40 BPM: red trace, 60 BPM: black trace). E) Summary results for APD prolongation for each cell type for different stimulus protocols; VM: black bars, PF: gray bars.
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pone-0097720-g003: VM and PFC carrying the SCN5A ΔKPQ mutation exhibit similarly severe APD prolongation.Panel A and B) Effect of a 2 second pause for VM and PFC, respectively, compared with 1000 msec (last beat of drive train shown for WT, black trace, and mutant cells, blue trace). Panels C and D) Steady state rate adaptation for VM and PFC, respectively (30 BPM: blue trace, 40 BPM: red trace, 60 BPM: black trace). E) Summary results for APD prolongation for each cell type for different stimulus protocols; VM: black bars, PF: gray bars.

Mentions: Figure 3 shows the resulting APs using a rate constant for the bursting transition that produces 0.5% persistent current, corresponding to previous studies[8], [16]. At 1 Hz, APD is prolonged by 69% and 61% in VM and PFC, respectively. After a 2 second pause, VM APD carrying the mutation is prolonged to 866 ms (increase of 185%), compared to PFC at 892 ms (increase of 146%). Similarly, more severe APD prolongation is noted in both tissue types during bradycardia (pacing at 30 BPM and 40 BPM, panels C and D), as summarized in Figure 4E.


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)

VM and PFC carrying the SCN5A ΔKPQ mutation exhibit similarly severe APD prolongation.Panel A and B) Effect of a 2 second pause for VM and PFC, respectively, compared with 1000 msec (last beat of drive train shown for WT, black trace, and mutant cells, blue trace). Panels C and D) Steady state rate adaptation for VM and PFC, respectively (30 BPM: blue trace, 40 BPM: red trace, 60 BPM: black trace). E) Summary results for APD prolongation for each cell type for different stimulus protocols; VM: black bars, PF: gray bars.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0097720-g003: VM and PFC carrying the SCN5A ΔKPQ mutation exhibit similarly severe APD prolongation.Panel A and B) Effect of a 2 second pause for VM and PFC, respectively, compared with 1000 msec (last beat of drive train shown for WT, black trace, and mutant cells, blue trace). Panels C and D) Steady state rate adaptation for VM and PFC, respectively (30 BPM: blue trace, 40 BPM: red trace, 60 BPM: black trace). E) Summary results for APD prolongation for each cell type for different stimulus protocols; VM: black bars, PF: gray bars.
Mentions: Figure 3 shows the resulting APs using a rate constant for the bursting transition that produces 0.5% persistent current, corresponding to previous studies[8], [16]. At 1 Hz, APD is prolonged by 69% and 61% in VM and PFC, respectively. After a 2 second pause, VM APD carrying the mutation is prolonged to 866 ms (increase of 185%), compared to PFC at 892 ms (increase of 146%). Similarly, more severe APD prolongation is noted in both tissue types during bradycardia (pacing at 30 BPM and 40 BPM, panels C and D), as summarized in Figure 4E.

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