© 1999 American Heart Association, Inc.
Editorials |
Sodium "Channelopathies" and Sudden Death
Must You Be So Sensitive?
From the Departments of Anesthesiology and Pharmacology, Vanderbilt University School of Medicine, Nashville, Tenn.
Correspondence to Jeffrey R. Balser, MD, PhD, Room 560, MRB II, Vanderbilt University School of Medicine, Nashville, TN 37232. E-mail jeff.balser{at}mcmail.vanderbilt.edu
Key Words: Na+ channel • inactivation • Brugada syndrome • antiarrhythmic drug
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Introduction |
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 Top Introduction References |
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Recognizing the diverse cascade of ionic currents that compose the cardiac action potential, and the wisdom of nature to provide redundant systems that protect us from environmental insults, one wonders whether the heart could really notice the aberrant behavior of a single group of excitable proteins. Nonetheless, the first linkage of Na+ channel mutations to an inherited form of the long-QT syndrome (LQT3)1 made it amply clear that badly behaved Na+ channels are not well tolerated. Even more surprising were the functional studies of channels carrying the LQT3-linked mutations. Although Na+ channels normally open only briefly (and then inactivate) as the action potential commences, channels carrying these autosomal dominant mutations occasionally "forget" to inactivate, causing a small inward current that persists during the action potential plateau.2 It appears that this excess current, essentially a gain of Na+ channel function, delays cellular repolarization, prolongs the QT interval, and predisposes patients to torsades de pointes.
Surprisingly, the size of this "pathologic" current is minuscule
compared with the overall size of the Na+ current
(INa) in its full glory (so-called "peak
INa"). For the 1505-1507 
KPQ III-IV
interdomain linker deletion mutant,3 and the recently
identified C-terminus mutation E1784K,4 the sustained
current accounts for only 
2% of the peak
INa. Even more striking, the R1644H long-QT
mutation produces a sustained current that is 0.5% of the peak
current.3 5 Nonetheless, a mechanistic linkage
between this small defect, action potential prolongation, and
proarrhythmic triggered activity ("EADs") was recently validated in
an elegant quantitative model,6 a result that expanded our
intuition for the nonlinear relationship between
Na+ channel function and the risk of sudden
death.
In this context, it was not altogether surprising to learn that another class of inherited ventricular arrhythmias, collectively known as the "Brugada syndrome,"7 traces its lineage to the Na+ channel. However, in contrast to the long-QT mutations, which made heuristic (if not quantitative) sense, the functional effects of Brugada syndrome mutations have been diverse and puzzling. In the first report,8 two mutations were identified (a frameshift and a splice donor) that rendered the Na+ channel entirely nonfunctional. This would imply that a loss of Na+ channel function is conducive to the Brugada syndrome, in contrast to the gain of function mutations linked to the long-QT syndrome. However, functional studies of a third mutation (T1620M) that cosegregated with a small Brugada kindred provided an unexpected result. The mutation did not suppress INa but rather seemed to destabilize the inactivation process, reminiscent of the long-QT mutations. Although a plateau of noninactivating current was not identified, the mutation shifted the voltage dependence of steady-state inactivation to more positive membrane potentials and sped recovery from inactivation by nearly 30%, thereby increasing the overall availability of Na+ channels.
These T1620M functional effects have remained unreconciled with the clinical syndrome, as the evidence supporting a loss of Na+ channel function in the Brugada phenotype has strengthened. Two additional mutations in the III-IV interdomain linker (R1512W) and the C terminus (A1924T) have recently been linked to the Brugada syndrome.9 Although these mutations do not eliminate channel function, they shift the voltage dependence of steady-state inactivation to more negative membrane potentials, thereby reducing the "functional" availability of channels to open when the membrane is depolarized. In addition, it is increasingly clear that Na+ channel blocking agents exacerbate the ECG pattern of Brugada syndrome10 and in some cases may elicit both the "Brugada ECG" and ventricular fibrillation de novo.11 12
Mechanistic insight into how a loss of Na+ channel function (either genetic or pharmacological) may induce ventricular fibrillation predates the Brugada syndrome-Na+ channel linkage studies.13 14 In short, the duration of the epicardial myocardial cell action potential is more "sensitive" to a reduction in INa than is the endocardial action potential. In the epicardium, a prominent transient outward K+ current (Ito) counterbalances INa during the earliest phases of the action potential; hence, any misadventure (ischemia,15 class I drugs,12 16 or mutations16 ) that suppresses INa can trigger "all-or-none" repolarization in the epicardium, grotesquely shrinking the duration of the epicardial action potential. This condition creates a temporal imbalance between endocardial and epicardial repolarization, and such heterogeneity across the right ventricular outflow tract may engender reentry and thus explain the ECG pattern and arrhythmic manifestations of the Brugada syndrome.16 This mechanism may also underlie the toxicity of Na+ channel blockers in CAST (Cardiac Arrhythmia Suppression Trial), particularly because that outcome seems to have been exaggerated by ischemia.17
Given all of the momentum swinging toward "loss of
Na+ channel function" as the molecular basis of
the Brugada phenotype, how can we rationalize the gain of
function originally noted for T1620M? The report by Dumaine and
coworkers18 in this issue of Circulation
Research provides an answer, and at the same time, reminds us of
the surprising (and even nonlinear) effect experimental conditions may
impose on ion channel functional behavior. Most would concede that the
rapid character of the Na+ current poses a
challenge when attempting to accurately measure the channel gating
kinetics using whole-cell voltage-clamp recordings at
"physiological" (37°C) temperatures. This
technical difficulty may be managed by making measurements at lower
temperatures that slow the gating kinetics and then extrapolating the
results to warmer temperatures. However, a more
physiological but technically demanding approach is
to optimize the voltage-clamp conditions at higher temperatures. In the
present study, this was accomplished partly by using cultured
mammalian cells (tsA-201) instead of Xenopus oocytes.
Conditions were further improved by juggling the ionic conditions
(reducing the Na+ gradient by raising
[Na+]i to 35 mmol/L)
and by reducing the amount of transfected cDNA to reduce the overall
size of the current. In addition, low-resistance patch electrodes (0.6
to 1.0 M
) were used to minimize voltage errors.
Under these conditions, with the temperature raised to 32°C, the
effects of T1620M on Na+ channel gating were
vastly different than at room temperature. In particular, the mutation
hastened the decay of INa by a factor of
2. As the temperature was further raised to approach 42°C, a
condition that no doubt pushes the limits of clamp accuracy despite
efforts to optimize, the gradient in decay rate between wild type and
mutant persisted and may even have increased. In addition, the kinetics
of recovery from fast inactivation were slowed in T1620M at 32°C, in
sharp contrast to the hastening of recovery observed at room
temperature in this study and in the original recordings of
T1620M in Xenopus oocytes.8 At warm
temperatures, the voltage dependence of activation was also shifted to
more positive membrane potentials (+10 mV). Each of these gating
effects would tend to decrease the magnitude of
INa during an action potential, suggesting
that T1620M actually renders functional effects on
INa that are directionally
consistent with the other mutations and drug effects linking
Na+ channels to the Brugada syndrome.
It is worth noting that T1620 sits on the external linker between the
third and fourth (S3 and S4) transmembrane segments in domain IV. The
outermost S4 arginine (R1623), only 3 residues C-terminal to this
position, figures critically in the voltage-dependent gating function
of the S4 segment, tightly coupling inactivation to
activation.19 20 Intriguingly, a charge deletion at this
position (R1623Q) has been implicated in a sporadic case of the long-QT
syndrome in Japan,21 and functional studies show that the
R1623Q gating phenotype is a mirror image of T1620M: the decay
of whole-cell INa is
slowed.22 23 The opposite effects of these mutations,
despite their close proximity, may be surprising. However, although
III-IV linker mutations are known to disrupt
inactivation24 and clinically are linked to a long-QT
phenotype,5 a recently identified Brugada syndrome
mutation (R1512W) stabilized inactivation and lies in the III-IV linker
only 5 residues away from the KPQ long-QT deletion.9
The diverse functional effects of these vicinal mutations underscore
the complex relationship between ion channel structure at an amino acid
level, as well as functional behavior at a whole-protein level.
Dumaine et al18 rose to the challenge of simulating the functional effects of T1620M at warm temperatures on the cardiac action potential. Using a modified version of the action potential model developed by Luo and Rudy,25 their findings suggest that the right ventricular epicardium may be more sensitive than the endocardium or left ventricular epicardium to hastening the INa decay rate. Although this simulation empirically confirms that "loss of function" is sufficient to shorten the epicardial action potential, it may fall short of convincing us that the observed increase in the INa decay rate is singularly responsible for the clinical phenotype. The empiric 2-fold change in the rate constants for inactivation speeds INa decay but also reduces the simulated peak INa by 32%, an effect that might either prevent (per the authors' speculation)18 or exacerbate the clinical phenotype. For example, we know that other mutations that eliminate Na+ channel function (and thus reduce peak INa) also produce the Brugada syndrome.8 It remains to be shown whether reduced peak INa is a genuine feature of T1620M and whether the other gating effects of the mutation (activation and recovery from fast inactivation) are also important. Additionally, as the authors suggest, single-channel experiments will be required to determine whether the mutation-induced speeding of INa decay actually results from an effect on inactivation gating, or rather from more rapid activation gating.26
Given the highly nonlinear relationship between ion channel gating and transmembrane voltage, the challenges in implementing action potential models that incorporate subtle ion channel gating effects in a manner that recapitulates physiology in a genuine way are formidable. Recent studies linking complex ion channel functional defects to the action potential configuration using computational approaches are providing new insights into the factors that critically influence the long-QT phenotype (gating behavior, cell layers, pacing rate).6 27 Moreover, as the number of ion channel mutations and "therapeutic" agents linked to cardiac arrhythmias exponentially expand, strategies that allow us to view the downstream effects of miniscule changes in ion channel function on the electrophysiology of the whole heart will become ever more essential.
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Acknowledgments |
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Support was provided by the National Institutes of Health (R01 GM56307, P01 HL46681). Dr Balser holds the James Taloe Gwathmey Clinician Scientist Chair at Vanderbilt University.
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Footnotes |
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The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
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References |
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TopIntroductionReferences |
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