Limits...
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.

Show MeSH

Related in: MedlinePlus

Voltage clamp protocols demonstrate themechanism of late current generation in LQT3 mutations.Panel A illustrates the voltage clamp waveform used. Panel Bdemonstrates the important role of resting membrane potential and plateaupotential on degree of late sodium current in ΔKPQ (red bar)and F1473C mutations (blue bar) compared to WT (black bar).For a “VM-like” voltage clamp protocol (holding −100 mV,step potential 20 mV, top row), similar persistent current isseen for KPQ and F1473C mutations. When holding potential ischanged to −80 mV mimicking PF AP resting potential, second row,persistent current is less for the KPQ mutation than for the F1473C mutation (whichhas increased availability at this potential). Third andfourth rows show the individual effect of altering plateau and resting potentials.Panel C) Response of step potentials simulating VM (black)and PF (blue) in cells carrying the S1904L mutation.The “PF-like” voltage clamp waveform produces more inwardcurrent at all time points, leading to more accumulated inward charge as demonstratedbelow in the bar graph.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4043730&req=5

pone-0097720-g006: Voltage clamp protocols demonstrate themechanism of late current generation in LQT3 mutations.Panel A illustrates the voltage clamp waveform used. Panel Bdemonstrates the important role of resting membrane potential and plateaupotential on degree of late sodium current in ΔKPQ (red bar)and F1473C mutations (blue bar) compared to WT (black bar).For a “VM-like” voltage clamp protocol (holding −100 mV,step potential 20 mV, top row), similar persistent current isseen for KPQ and F1473C mutations. When holding potential ischanged to −80 mV mimicking PF AP resting potential, second row,persistent current is less for the KPQ mutation than for the F1473C mutation (whichhas increased availability at this potential). Third andfourth rows show the individual effect of altering plateau and resting potentials.Panel C) Response of step potentials simulating VM (black)and PF (blue) in cells carrying the S1904L mutation.The “PF-like” voltage clamp waveform produces more inwardcurrent at all time points, leading to more accumulated inward charge as demonstratedbelow in the bar graph.

Mentions: The differential response of the PFC AP to ΔKPQ and F1473C suggests that the shift in channel availability (proarrhythmic) may counteract the effect of hyperpolarized diastolic potential in PFC (antiarrhythmic). To directly test the contributions of these factors individually, voltage clamp simulations were performed at different holding potentials (−100 mV and −80 mV, corresponding to the diastolic potential of VM and PFC, respectively) with steps to different test potentials (+20 and 0 were selected, corresponding to plateau potentials). Absolute late sodium current at 100 ms was calculated, alongside percent persistent current (normalized to peak) for WT, ΔKPQ, and F1473C. At a holding potential of −100 mV, both ΔKPQ and F1473C show similar amounts of late current, regardless of step potential (and driving force), in contrast to WT cells (first two sets in Figure 6A). At a holding potential of −80 mV, F1473C exhibits a far greater late current than ΔKPQ. Lesser late current is produced by ΔKPQ at depolarized resting potentials due to gating of channels into unavailable states (top row of states in Figure 1B of Clancy[19]) from which they cannot burst nor conduct current during the plateau of the AP. Thus, the higher driving force for current entry is counterbalanced by lower fractional occupancy of bursting states that carry INaL. When availability is shifted in F1473C channels, direct comparison of the -100 to +20 mV simulation (mimicking a VM AP profile) and −80 to 0 mV simulation (mimicking a PFC AP profile) shows more absolute late current in the PFC-like profile. This substantial increase in late current underlies the more severe prolongation of APD in PFCs for the F1473C mutation.


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)

Voltage clamp protocols demonstrate themechanism of late current generation in LQT3 mutations.Panel A illustrates the voltage clamp waveform used. Panel Bdemonstrates the important role of resting membrane potential and plateaupotential on degree of late sodium current in ΔKPQ (red bar)and F1473C mutations (blue bar) compared to WT (black bar).For a “VM-like” voltage clamp protocol (holding −100 mV,step potential 20 mV, top row), similar persistent current isseen for KPQ and F1473C mutations. When holding potential ischanged to −80 mV mimicking PF AP resting potential, second row,persistent current is less for the KPQ mutation than for the F1473C mutation (whichhas increased availability at this potential). Third andfourth rows show the individual effect of altering plateau and resting potentials.Panel C) Response of step potentials simulating VM (black)and PF (blue) in cells carrying the S1904L mutation.The “PF-like” voltage clamp waveform produces more inwardcurrent at all time points, leading to more accumulated inward charge as demonstratedbelow in the bar graph.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0097720-g006: Voltage clamp protocols demonstrate themechanism of late current generation in LQT3 mutations.Panel A illustrates the voltage clamp waveform used. Panel Bdemonstrates the important role of resting membrane potential and plateaupotential on degree of late sodium current in ΔKPQ (red bar)and F1473C mutations (blue bar) compared to WT (black bar).For a “VM-like” voltage clamp protocol (holding −100 mV,step potential 20 mV, top row), similar persistent current isseen for KPQ and F1473C mutations. When holding potential ischanged to −80 mV mimicking PF AP resting potential, second row,persistent current is less for the KPQ mutation than for the F1473C mutation (whichhas increased availability at this potential). Third andfourth rows show the individual effect of altering plateau and resting potentials.Panel C) Response of step potentials simulating VM (black)and PF (blue) in cells carrying the S1904L mutation.The “PF-like” voltage clamp waveform produces more inwardcurrent at all time points, leading to more accumulated inward charge as demonstratedbelow in the bar graph.
Mentions: The differential response of the PFC AP to ΔKPQ and F1473C suggests that the shift in channel availability (proarrhythmic) may counteract the effect of hyperpolarized diastolic potential in PFC (antiarrhythmic). To directly test the contributions of these factors individually, voltage clamp simulations were performed at different holding potentials (−100 mV and −80 mV, corresponding to the diastolic potential of VM and PFC, respectively) with steps to different test potentials (+20 and 0 were selected, corresponding to plateau potentials). Absolute late sodium current at 100 ms was calculated, alongside percent persistent current (normalized to peak) for WT, ΔKPQ, and F1473C. At a holding potential of −100 mV, both ΔKPQ and F1473C show similar amounts of late current, regardless of step potential (and driving force), in contrast to WT cells (first two sets in Figure 6A). At a holding potential of −80 mV, F1473C exhibits a far greater late current than ΔKPQ. Lesser late current is produced by ΔKPQ at depolarized resting potentials due to gating of channels into unavailable states (top row of states in Figure 1B of Clancy[19]) from which they cannot burst nor conduct current during the plateau of the AP. Thus, the higher driving force for current entry is counterbalanced by lower fractional occupancy of bursting states that carry INaL. When availability is shifted in F1473C channels, direct comparison of the -100 to +20 mV simulation (mimicking a VM AP profile) and −80 to 0 mV simulation (mimicking a PFC AP profile) shows more absolute late current in the PFC-like profile. This substantial increase in late current underlies the more severe prolongation of APD in PFCs for the F1473C mutation.

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