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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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Differential response of VM (panel A) and PF (panel B) to mutation in IKs and IKr channels, leading to LQT1 and LQT2, respectively.Compared to wild type (WT, black trace), heterozygous LQT1 (blue trace) and LQT2 (red trace), modeled as a 50% reduction in whole cell conductance, VM APs are prolonged, while PF are mildly affected. Homozygous LQT1 (100% reduction in IKs conductance, dashed blue trace) leads to substantial APD prolongation in VM, and trivial further prolongation in PF.
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pone-0097720-g001: Differential response of VM (panel A) and PF (panel B) to mutation in IKs and IKr channels, leading to LQT1 and LQT2, respectively.Compared to wild type (WT, black trace), heterozygous LQT1 (blue trace) and LQT2 (red trace), modeled as a 50% reduction in whole cell conductance, VM APs are prolonged, while PF are mildly affected. Homozygous LQT1 (100% reduction in IKs conductance, dashed blue trace) leads to substantial APD prolongation in VM, and trivial further prolongation in PF.

Mentions: As LQT1 and LQT2 mutations often result in complete loss-of-function of the affected KCNQ1 or HERG allele, respectively (through defective trafficking or biophysical changes in channel function)[1], idealized heterozygous mutations were simulated by reducing peak conductance of IKs or IKr by 50% to simulate heterozygous LQT1 or LQT2, respectively. Figure 1 shows the resulting APs obtained at 1 Hz stimulation frequency. Heterozygous LQT1 mutation prolonged APD by only 8 ms in PFC, in contrast to VM, in which a 36 ms APD prolongation is seen. Mutation in LQT2 prolongs PFC APD by 28 ms and VM APD by 46 ms. Clinically, homozygous LQT1 mutation leads to the Jervell-Lange-Nielsen syndrome[1], which is characterized by severe QT prolongation. Homozygous LQT1, simulated as IKs deletion, results in further prolongation of VM APD (408 ms versus 304 ms WT), which is in stark contrast to the PFC APD which exhibits minimal prolongation of 15 ms.


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)

Differential response of VM (panel A) and PF (panel B) to mutation in IKs and IKr channels, leading to LQT1 and LQT2, respectively.Compared to wild type (WT, black trace), heterozygous LQT1 (blue trace) and LQT2 (red trace), modeled as a 50% reduction in whole cell conductance, VM APs are prolonged, while PF are mildly affected. Homozygous LQT1 (100% reduction in IKs conductance, dashed blue trace) leads to substantial APD prolongation in VM, and trivial further prolongation in PF.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0097720-g001: Differential response of VM (panel A) and PF (panel B) to mutation in IKs and IKr channels, leading to LQT1 and LQT2, respectively.Compared to wild type (WT, black trace), heterozygous LQT1 (blue trace) and LQT2 (red trace), modeled as a 50% reduction in whole cell conductance, VM APs are prolonged, while PF are mildly affected. Homozygous LQT1 (100% reduction in IKs conductance, dashed blue trace) leads to substantial APD prolongation in VM, and trivial further prolongation in PF.
Mentions: As LQT1 and LQT2 mutations often result in complete loss-of-function of the affected KCNQ1 or HERG allele, respectively (through defective trafficking or biophysical changes in channel function)[1], idealized heterozygous mutations were simulated by reducing peak conductance of IKs or IKr by 50% to simulate heterozygous LQT1 or LQT2, respectively. Figure 1 shows the resulting APs obtained at 1 Hz stimulation frequency. Heterozygous LQT1 mutation prolonged APD by only 8 ms in PFC, in contrast to VM, in which a 36 ms APD prolongation is seen. Mutation in LQT2 prolongs PFC APD by 28 ms and VM APD by 46 ms. Clinically, homozygous LQT1 mutation leads to the Jervell-Lange-Nielsen syndrome[1], which is characterized by severe QT prolongation. Homozygous LQT1, simulated as IKs deletion, results in further prolongation of VM APD (408 ms versus 304 ms WT), which is in stark contrast to the PFC APD which exhibits minimal prolongation of 15 ms.

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