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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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Arrhythmias in Andersen-Tawil syndrome, modeled as dominant negative suppression of IK1 current, have different mechanisms in VM (panel A) versus PF (panel B) myocytes.For VM, compared to WT (black trace) reduction of IK1 conductance by 90% (blue) leads to a large delayed afterdepolarization. Further reduction to 95% (red) increases the size of the DAD, triggering repetitive action potentials. For PF, reduction of IK1 conductance maximum diastolic potential is less polarized, leading to increased automaticity. Unstimulated PF APs show basic cycle length of automaticity of 2250 msec, which decreases to 1260 with 90% IK1 reduction.
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pone-0097720-g002: Arrhythmias in Andersen-Tawil syndrome, modeled as dominant negative suppression of IK1 current, have different mechanisms in VM (panel A) versus PF (panel B) myocytes.For VM, compared to WT (black trace) reduction of IK1 conductance by 90% (blue) leads to a large delayed afterdepolarization. Further reduction to 95% (red) increases the size of the DAD, triggering repetitive action potentials. For PF, reduction of IK1 conductance maximum diastolic potential is less polarized, leading to increased automaticity. Unstimulated PF APs show basic cycle length of automaticity of 2250 msec, which decreases to 1260 with 90% IK1 reduction.

Mentions: In Figure 2, dominant negative IK1 suppression is simulated in both VM and PFC. Arrhythmias occur via different mechanisms in the two cell types. In the VM model, progressive downregulation of IK1 leads to DADs of increasing amplitude occurring immediately after the AP (panel A), until another AP is triggered leading to repetitive membrane depolarization. The mechanism is identical to that observed in guinea pig VM[14]. Analogous downregulation of IK1 in PFC shows no DADs (panel B). The slow diastolic depolarization underlying PFC automaticity reaches threshold for AP formation earlier than in VM, with a less polarized maximum diastolic potential. The result is an approximate doubling of the intrinsic firing rate stemming from unopposed HCN current. Our simulations show that VM carrying ATS mutations are capable of triggered activity as an arrhythmic mechanism, while corresponding PFC show no DADs but display enhanced automaticity, another potential mechanism for arrhythmia.


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)

Arrhythmias in Andersen-Tawil syndrome, modeled as dominant negative suppression of IK1 current, have different mechanisms in VM (panel A) versus PF (panel B) myocytes.For VM, compared to WT (black trace) reduction of IK1 conductance by 90% (blue) leads to a large delayed afterdepolarization. Further reduction to 95% (red) increases the size of the DAD, triggering repetitive action potentials. For PF, reduction of IK1 conductance maximum diastolic potential is less polarized, leading to increased automaticity. Unstimulated PF APs show basic cycle length of automaticity of 2250 msec, which decreases to 1260 with 90% IK1 reduction.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0097720-g002: Arrhythmias in Andersen-Tawil syndrome, modeled as dominant negative suppression of IK1 current, have different mechanisms in VM (panel A) versus PF (panel B) myocytes.For VM, compared to WT (black trace) reduction of IK1 conductance by 90% (blue) leads to a large delayed afterdepolarization. Further reduction to 95% (red) increases the size of the DAD, triggering repetitive action potentials. For PF, reduction of IK1 conductance maximum diastolic potential is less polarized, leading to increased automaticity. Unstimulated PF APs show basic cycle length of automaticity of 2250 msec, which decreases to 1260 with 90% IK1 reduction.
Mentions: In Figure 2, dominant negative IK1 suppression is simulated in both VM and PFC. Arrhythmias occur via different mechanisms in the two cell types. In the VM model, progressive downregulation of IK1 leads to DADs of increasing amplitude occurring immediately after the AP (panel A), until another AP is triggered leading to repetitive membrane depolarization. The mechanism is identical to that observed in guinea pig VM[14]. Analogous downregulation of IK1 in PFC shows no DADs (panel B). The slow diastolic depolarization underlying PFC automaticity reaches threshold for AP formation earlier than in VM, with a less polarized maximum diastolic potential. The result is an approximate doubling of the intrinsic firing rate stemming from unopposed HCN current. Our simulations show that VM carrying ATS mutations are capable of triggered activity as an arrhythmic mechanism, while corresponding PFC show no DADs but display enhanced automaticity, another potential mechanism for arrhythmia.

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