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Am J Physiol Heart Circ Physiol 290: H2176 –H2177, 2006;
doi:10.1152/ajpheart.00186.2006.
Editorial Focus
Aldosterone, ion channels, and sudden death: another piece of the circle?
Geoffrey S. Pitt1 and Bertram Pitt2
1
Departments of Medicine and Pharmacology and Center for Molecular Cardiology, College of Physicians and Surgeons,
Columbia University, New York, New York; and 2Department of Medicine, University of Michigan, Ann Arbor, Michigan, and
William Beaumont Hospital, Department of Internal Medicine, Royal Oak, Michigan
Address for reprint requests and other correspondence: G. S. Pitt, Columbia
Univ., Dept. of Pharmacology, 630 W. 168th St., PH 7W 318, New York, NY
10032 (email: [email protected]).
H2176
tricular myocardium and the bundle branches, as well as
abnormal distribution of connexin 43, the gap junction responsible for propagation of electrical activity in ventricular myocytes (18, 21). Fibrosis may affect the conduction disturbances
in BrS, too. A histopathological study of an explanted heart
from a BrS patient showed extensive fibroelastosis and fatty
infiltration within the right ventricle (6). Together, these suggest that a reduction in sodium channels might activate gene
expression cascades that result in fibrosis. Indeed, the early
growth response-1 transcription factor (Egr-1), a master regulator that influences the expression of many other genes, was
found to be upregulated in the Scn5a⫹/⫺ mice. Nevertheless,
there are several missing links in these signaling pathways, and
their identification could open the possibility of pharmacological intervention. In this context, a report in this issue offers
new insight and perhaps therapeutic promise.
Measuring sodium channel currents in cultured mouse ventricular myocytes, Boixel et al. (5) in a study in this issue of the
American Journal of Physiology-Heart and Circulatory Physiology found that incubation with aldosterone for 24 h increased
current density in a dose-dependent manner and lengthened the
action potential duration. This effect appeared dependent on the
mineralocorticoid receptor (MR) because it was blocked with the
MR antagonist spironolactone but not with the glucocorticoid
receptor antagonist RU-38486. Confirming previous results from
Bénitah and colleagues, this report also demonstrated that aldosterone, acting through the MR, increased Ca2⫹ channel current
density (13) and fits well with a growing literature that shows how
aldosterone influences the electrical properties of cardiac myocytes and increases action potential duration.
These results are compelling for at least two reasons. First,
aldosterone has been shown to activate a number of mediators
that can lead to myocardial fibrosis (15). One only has to
implicate a homeostatic process whereby decreased sodium
channel current density triggers a feedback loop that increases
aldosterone to appreciate how haploinsufficiency for SCN5A
could lead to fibrosis. Indeed, Egr-1, the transcription factor
upregulated in Scn5a⫹/⫺ mice, is activated specifically in the
hearts of transgenic mice overexpressing the mineralocorticoid
receptor but not in other aldosterone target tissues (10). Thus
PCCD, the most common cause worldwide for pacemaker
implantation, is ripe for testing whether aldosterone antagonism prevents or delays the development of conduction block.
Second, we may now be seeing part of the molecular basis for
the striking clinical finding that a significant portion of the
mortality benefit of aldosterone antagonism in heart failure
derives from a reduction in sudden death (14). Blockade of a
mechanism that increases sodium channel density (this report)
or increases calcium channel density and then decreases the
transient outward current (Ito) (4) would ameliorate QT prolongation, a common finding and an independent risk factor for
sudden death in heart failure (3, 19, 20, 22).
0363-6135/06 $8.00 Copyright © 2006 the American Physiological Society
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of the genetic basis for many inherited and
certain acquired cardiac arrhythmias during the last decade, the
connection between identified mutations and consequent arrhythmias remains unclear in many cases. For some, the
mechanisms for arrhythmogenesis are well understood. Lossof-function mutations in ether-à-go-go-related gene (HERG),
the pore-forming subunit of inwardly rectifying K⫹ current
(IKr), decrease the “repolarization reserve” and render patients
susceptible to reentry-induced arrhythmias during the late
phase of the action potential, thus forming the basis for Long
QT Syndrome 2 (LQTS2) and certain acquired (drug-induced)
Long QT Syndromes (17). Certain mutations in SCN5A, the
gene for the cardiac sodium channel, affect how the channel
inactivates; the mutant channels thereby generate a persistent
inward depolarizing Na⫹ current during the action potential
plateau phase, especially at slow heart rates, which forms the
substrate for arrhythmia-triggering early afterdepolarizations in
LQTS3 (8). For several arrhythmogenic disorders resulting
from haploinsufficiency of the sodium channel, the age-related
slowing of cardiac conduction that leads to atrioventricular
block, which defines progressive cardiac conduction defect
(PCCD) or a subset of the autosomal dominantly inherited
Brugada syndrome (BrS), for example, the molecular basis has
been more difficult to understand.
There are at least two puzzling features about the connection
between loss-of-function mutations in one SCN5A allele and the
resultant arrhythmias. First, despite the presence of mutations that
reduce the number of sodium channels from birth, patients with
these disorders do not generally become symptomatic before the
third or fourth decade of life. PCCD is clearly age related.
Arrhythmogenic sudden death from BrS, the most common cause
of death for men in Southeast Asia other than accidents (1), is rare
in children; in a study of the natural history of BrS, the mean age
at the time of the index cardiac event was 33 ⫾ 13 y (16). Second,
modeling of the cardiac action potential suggests a large safety
factor for the sodium current; reducing the sodium current even by
one-half should not, in itself, lead to conduction slowing or block
(9). What additional factor(s) contribute and why symptoms occur
primarily in older patients are now becoming clear from a number
of recent studies.
Analysis of mice with a knockout of the SCN5A gene
suggested that the development of fibrosis may be a major
contributor to these arrhythmias (18). Homozygous Scn5a⫺/⫺
mice died before birth, but heterozygous (Scn5a⫹/⫺) mice
(viable and fertile) showed slowing of cardiac conduction and
various degrees of block as they aged, similar to patients with
PCCD (12). Correlating with the appearance of conduction
slowing was extensive heterogeneous fibrosis within the venDESPITE DISCOVERY
Editorial Focus
H2177
GRANTS
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17.
This paper was supported by National Heart, Lung, and Blood Institute
Grant HL-71165 (to G. S. Pitt) and the American Heart Association Grant
0555875T. G. S. Pitt is a recipient of the Irma T. Hirschl Career Scientist
Award and is the Aboodi Assistant Professor of Cardiology.
18.
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A recent report (11) showing that loss-of-function mutations
in SCN5A also underlie some forms of inherited dilated cardiomyopathy (DCM) makes it tempting to speculate even more
broadly. Loss-of-function sodium channelopathies may represent different manifestations of a common starting point in
which a reduction in sodium channels increases aldosterone.
The distinct consequences inherent to specific syndromes could
reflect the interactions of unique contributing factors that may
derive, at least in part, from specific differences in effects of
the mutations. “Loss-of-function” mutations (which implies
that mutant channels, expressed in heterologous systems, fail to
display the full complement of wild-type sodium channel
functions) may produce channels that lack any inward current,
channels that support a reduced inward current, or may instead
affect channel trafficking, targeting, or interaction with other
regulatory proteins. These defects may differentially alter the
net sodium current or its kinetics, changing electrical activation
and thereby the cardiac load within the complex milieu of the
cardiac cycle so that over time the effects are mainly rightsided effects in some cases (BrS) or more global in others
(DCM). The data in Boixel et al. (5) hint at this complexity:
aldosterone increased sodium channel current density without
changing channel protein or mRNA levels, but inhibitors of
protein synthesis or trafficking blocked the increase, suggesting that aldosterone affected the expression and trafficking of
a sodium channel regulatory protein.
Under certain circumstances, aldosterone may also have
other effects that could contribute to sudden death, including
stimulation of central sympathetic drive (7), release of norepinephrine from peripheral sympathetic nerves (2), and a decrease in heart rate variability and baroreceptor function (23).
Regardless, the new information reported by Boixel et al. (5)
suggests that MR blockade may have an important role in
reducing sudden death in a far broader spectrum of circumstances than hitherto thought possible.