Circulation Research. 2000;87:966-968
(Circulation Research. 2000;87:966.)
© 2000 American Heart Association, Inc.
Local Ca2+ Release in Heart Failure
Timing Is Important
Karin R. Sipido
From the Laboratory of Experimental Cardiology, University of Leuven,
Belgium.
Correspondence to Karin R. Sipido, MD, PhD, Laboratory of Experimental Cardiology, KUL, Campus Gasthuisberg O/N 7th floor, Herestraat 49, B-3000 Leuven, Belgium. E-mail Karin.Sipido{at}med.kuleuven.ac.be
Key Words: myocyte heart failure sparks
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Introduction
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For many years,
the treatment of heart failure has focused,
successfully, on the
neurohumoral pathways, but recently more
attention has again been given
to the heart itself and ways
to improve the phenotype of the failing
cardiomyocyte.
[Ca
2+]
i transients
from myocytes of failing human hearts typically have
a low amplitude
and slow decline at normal
frequencies.
1 2 3
The slower decline has been attributed to a decreased
Ca
2+ uptake into the sarcoplasmic reticulum
(SR), as evidenced by
decreased expression levels of the SR
Ca
2+-ATPase, SERCA, at
both the mRNA and
protein levels.
4 Such
deficiency of SERCA
will lead to a decrease in SR
content.
5 Consequently, much
attention
has been dedicated to the potential treatment of heart
failure
by improving SERCA function either by pharmacological block
of
the inhibitory protein phospholamban
(PLB)
6 or by gene therapy
targeted
at SERCA itself or PLB. Such strategies have been successful
in
improving function in animal
models
7 8 and in
isolated human
myocytes.
9
Although this seems a promising therapeutic venue,
it should not
mislead us into thinking that SERCA deficiency
is the major (or even
the only) defect responsible for the failing
phenotype.
8 In the last
years, a number of other mechanisms have been identified
that may
contribute to the phenotype of human end-stage heart
failure and may be
targets for therapy. Upregulation of the
Na
+-Ca
2+ exchange
has been proposed as a compensatory mechanism for the
decrease in SERCA
function and could improve
relaxation.
10 However,
upregulation of
Na
+-Ca
2+ exchange
may have negative
consequences as well, such as prolongation of the
action potential
11 and
further depletion of the SR. Experimental data on human
myocytes
suggest that the exchanger contributes to
Ca
2+ loading
during the latter part of the
action potential.
12 The
exact
function of the exchanger in heart failure is still unresolved,
and
whether any benefit of block or of further upregulation can
be
expected remains to be seen. Most recently, Marx et
al
13 reported that in
end-stage human heart failure, the ryanodine
receptor was
hyperphosphorylated, which would lead to increased
opening probability.
As an isolated event, changes in ryanodine
receptor opening probability
would be expected to affect contraction
only
transiently,
14 but in the
setting of concomitantly decreased
SERCA activity, loss of SR
Ca
2+ is likely.
With the limited availability of human tissue and the
difficulty of obtaining proper controls, animal models have been most
useful; similar decreases in SERCA activity and upregulation of
Na+-Ca2+ exchange
have been found in various animal models of heart failure (eg,
Reference 1515 ). Some of these studies have even led to novel concepts,
as yet unexplored in human studies. In the failing rat heart, a
decrease in SR Ca2+ release was observed
despite unchanged Ca2+ current and SR
Ca2+
content.16 The authors
speculated that this decrease in gain or efficiency of
Ca2+ release was related to local changes in
the narrow cleft between sarcolemma and junctional SR resulting in a
defective coupling between the ryanodine receptor and the
Ca2+ channel.
In this issue of Circulation
Research, another novel and exciting concept is advanced by
Litwin et al.17 In a rabbit
model of heart failure after myocardial infarction, they observe
temporal and spatial heterogeneities in local
Ca2+ release events. Absent and delayed
Ca2+ sparks can account for not only the
slower upstroke of the averaged whole-cell
Ca2+ transient but also for the slower
relaxation, analogous to the late opening of single
Ca2+ channels contributing to the rate of
inactivation of the whole-cell current. One of the perspectives offered
by the authors is that we should revise our conventional approach, in
which we consider mechanisms of systolic and diastolic dysfunction
separately. Although any of the changes in human heart failure
mentioned above are expected to affect both systolic and diastolic
function, this is indeed not necessarily expected for isolated changes
in Ca2+ release. However, it is in line with
recent clinical evidence indicating that, in heart failure, mostly both
systolic and diastolic dysfunction are present.
 |
What Are the Mechanisms Underlying the Observed
Dyssynchrony in Ca2 Release?
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The present data do not yet offer an explanation, but
certainly
it is worthwhile to consider what is presently known about
the
properties of L-type Ca
2+ channels. In
the study by Litwin et
al,
17
the whole-cell Ca
2+ current is decreased,
but more details
are not yet available. Changes in whole-cell
Ca
2+ current density
have been observed in
some but not all studies of human heart
failure.
18 Studies into the
dynamic behavior of the whole-cell current
and of single channels may
be more revealing. In human end-stage
failure cells, lack of
frequency-dependent
facilitation
18 and
slow
recovery from inactivation have been
described.
3 The latter
may be
related to slow decay of the Ca
2+ transient
and will
lead to loss of channel availability with
stimulation.
3 In
the study by
Litwin et al,
17 such a
mechanism may have contributed
to the lower values for
ICaL,
measured after a train of conditioning
pulses, and it is noteworthy
that the dyssynchrony was more
pronounced at the higher stimulation
frequency, consistent with
further decrease of
Ca
2+ channel activity.
Clustering of channels with patches of membrane devoid of
functional channels could be another explanation for the local failure
of early release in the data of Litwin et
al.17 Presently, little
experimental evidence exists for this, and it may be hard to
demonstrate. However, Schroder et
al19 found that the activity
of single L-type channels in cell-attached patches was higher, which,
in combination with an unchanged whole-cell current, would imply that
channels are more sparse and may thus form clusters in the surface
membrane, which are either hyperactive or deficient in L-type
channels.
To understand the present results and, in particular, the
occurrence of the late sparks, a study of local gain and single
Ca2+ channel activity will be helpful. In
normal cells, the timing of sparks has been linked to the first opening
of Ca2+
channels.20 In Figures 2 and
3 of Litwin et al,17 the
delay for some sparks seems to exceed 200 ms. This could imply a much
prolonged first latency or altered gating with more pronounced active
late pattern and
reopenings,21 which could
then activate previously unresponsive release channels. While altered
gating may be an intrinsic property of the
Ca2+ channels, one could also postulate that
the primary failure is in the ryanodine receptor and that it is the
lack of release-dependent inactivation of the
Ca2+ channels that allows reopening.
Whatever the primary event, altered gating of L-type
Ca2+ channels or SR
Ca2+ release channels with reduced L-type
Ca2+ channel inactivation, one expects a
slowing of the inactivation of the macroscopic
ICaL.
This was not observed by Litwin et
al,17 but may have been
confounded by simultaneous alterations in the
Na+-Ca2+ exchange
current.
Can We Expect Dyssynchrony to Be Present in
Heart Failure in General? Relevance of Animal Models
Too often, discussions of cellular mechanisms
underlying contractile dysfunction tend to lump together findings from
human studies, different models with variable degree of failure, and
different animal species. It is important to keep in mind that in human
patients, heart failure is a multifactorial disease with various
etiologies and, most likely, various underlying cellular mechanisms.
Heterogeneity in human data can sometimes be
demonstrated,3 10
but because of the difficulties involved, large studies on cellular
characteristics that take into account such variables as etiology and
medication are not yet available. From animal studies, it is clear that
etiology does matter, as illustrated by one example. The present
study17 and others by the
same authors22 can be
contrasted with reports on the rabbit model of heart failure by
combined aortic stenosis and
insufficiency.23 In this
latter model, Ca2+ currents are not
decreased and, also in contrast, SR Ca2+
content tended to be reduced. Besides model and species differences,
the stage of remodeling after the insult is of prime importance and
relevance for extrapolation to human pathology, because compensated
hypertrophy may be very different from later-stage
failure.24 25
Dyssynchrony of local Ca2+
release events is a novel and exciting finding, and its presence in
human cells and other animal models certainly merits further
investigation. The possibility of improving synchrony may open new
perspectives for treatment, although in light of previous experience,
we should avoid using drugs that increase
cAMP,26 even if
isoproterenol was found to be effective in the present study. However,
if we can pinpoint dyssynchrony to specific channel properties,
targeted approaches, such as those devised for SERCA and phospholamban,
may be considered.
 |
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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