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Cellular Biology |
From the Department of Medicine (S.M.P.), University of Illinois, Chicago, Ill, and Department of Physiology and Cardiovascular Institute (K.S., L.L., W.Y., D.M.B.), Loyola University Chicago.
Correspondence to Donald M. Bers, PhD, Department of Physiology, Loyola University Chicago, 2160 S First Ave, Maywood, IL 60153. E-mail dbers{at}luc.edu
Abstract
AbstractVentricular
arrhythmias and contractile dysfunction are the main causes of
death in human heart failure (HF). In a rabbit HF model reproducing
these same aspects of human HF, we demonstrate that a 2-fold functional
upregulation of
Na+-Ca2+ exchange
(NaCaX) unloads sarcoplasmic reticulum (SR)
Ca2+ stores, reducing
Ca2+ transients and contractile function.
Whereas ß-adrenergic receptors (ß-ARs) are progressively
downregulated in HF, residual ß-AR responsiveness at this critical HF
stage allows SR Ca2+ load to increase,
causing spontaneous SR Ca2+ release and
transient inward current carried by NaCaX. A given
Ca2+ release produces greater arrhythmogenic
inward current in HF (as a result of NaCaX upregulation), and
50%
less Ca2+ release is required to trigger an
action potential in HF. The inward rectifier potassium current
(IK1) is
reduced by 49% in HF, and this allows greater depolarization for a
given NaCaX current. Partially blocking
IK1 in
control cells with barium mimics the greater depolarization for a given
current injection seen in HF. Thus, we present data to support a
novel paradigm in which changes in NaCaX and
IK1, and
residual ß-AR responsiveness, conspire to greatly increase the
propensity for triggered arrhythmias in HF. In addition, NaCaX
upregulation appears to be a critical link between contractile
dysfunction and arrhythmogenesis.
Key Words: heart failure excitation-contraction coupling Na+-Ca2+ exchange Ca2+ transport K+ currents
Heart failure (HF), which affects more than two million Americans, is associated with high mortality as a result of contractile dysfunction (pump failure) or sudden death caused by ventricular arrhythmias.1 The genesis of HF syndromes is complex and multifactorial, but altered cellular Ca2+ regulation may be a final common pathway in both pump failure and arrhythmogenesis.2 3 4 5
Decreased Ca2+ transients in HF reduce myofilament activation and depress contractility.2 Although it is unknown why Ca2+ transients are depressed, it is likely due to a decrease in sarcoplasmic reticulum (SR) Ca2+ release or Ca2+ influx via Ca2+ current (ICa). Many, although not all, HF studies show that ICa is unchanged.3 4 6 Decreased SR Ca2+ release could reflect either reduced SR Ca2+ release channel sensitivity to ICa4 or reduced SR Ca2+ content. Reduced SR Ca2+ load can be caused by decreased SR Ca2+-ATPase (SERCA) and/or increased Na+-Ca2+ exchange (NaCaX), because these transporters compete for [Ca2+]i during relaxation and diastole.7 Moreover in HF, data indicate lower SERCA expression8 9 and increased NaCaX expression,6 10 11 but direct assessment of SR Ca2+ content in HF is limited. It is also unclear what role altered NaCaX plays with respect to contractile dysfunction in HF. These issues are addressed here.
Electrical reentry contributes to ventricular tachycardia (VT) in many pathophysiological states, but 3-dimensional mapping studies show that most fatal arrhythmias in HF initiate by a nonreentrant mechanism12 13 14 15 such as delayed afterdepolarizations (DADs) and early afterdepolarizations.16 17 This is true for 100% of VTs in human nonischemic cardiomyopathy (and 50% in ischemic cardiomyopathy).18 19 At normal action potential (AP) duration and heart rates, DADs may predominate over early afterdepolarizations. DADs, which are enhanced by ß-adrenergic receptor (ß-AR) stimulation,16 occur after AP repolarization and are initiated by spontaneous SR Ca2+ release. This leads to activation of a Ca2+-activated transient inward current (Iti), which has been proposed to be carried by any of the following different Ca2+-activated currents: (1) NaCaX current (INa-Ca), (2) Ca2+-activated chloride current (ICl(Ca)), or (3) a non-selective cationic current (INS(Ca)).16 20 21 22 The inward rectifying K current IK1 is crucial in stabilizing the resting membrane potential (Em). Although IK1 is reduced in human HF,23 it is unclear, especially from a quantitative standpoint, how this may destabilize resting Em and ultimately contribute to the genesis of DADs, triggered APs, and arrhythmogenesis in HF.
The goal of this study was to define molecular mechanisms underlying both arrhythmogenesis and contractile dysfunction in HF. Studies were performed in an arrhythmogenic rabbit HF model of combined aortic insufficiency and constriction. This rabbit HF model resembles human nonischemic HF in exhibiting marked left ventricular (LV) dilation and hypertrophy, severely reduced systolic function, moderately decreased ß-AR density, and nonreentrant ventricular arrhythmias.6 13 15 24 25 We previously found an increase in heart weight/body weight (by 80%), average myocyte size (89%), and LV end-diastolic diameter (41%).6 LV fractional shortening is reduced by 36%, and isolated ventricular myocyte shortening is reduced by 30%. Greater than 10% of the HF rabbits die from sudden cardiac death, and during 24-hour Holter monitoring 90% of these animals show runs of nonsustained VT.6 Three-dimensional mapping showed that these arrhythmias all initiate by a nonreentrant mechanism.13 Thus, this arrhythmogenic rabbit HF model exhibits the contractile and electrophysiological alterations seen in human HF at the critical stage at which arrhythmogenesis and contractile dysfunction are manifest. This provides a unique opportunity for assessment of the underlying molecular mechanisms.
Here we demonstrate that INa/Ca is the current producing DADs in HF and that upregulated NaCaX, reduced IK1, and residual ß-AR responsiveness work together to greatly increase arrhythmogenesis in HF. We also show that NaCaX plays a central role in mediating both arrhythmogenesis and contractile dysfunction in HF (by lowering SR Ca2+ load).
Materials and Methods
Rabbit HF Model and Myocyte Isolation
In New Zealand White rabbits (
3.5 kg), HF was
induced by aortic insufficiency and 2 to 4 weeks later by thoracic
aortic constriction (both induced during ketamine/pentobarbital
anesthesia) as previously
described.6 Progression was
assessed by 2-dimensional
echocardiography.6
Rabbits were studied 9.5±2.0 months after aortic constriction, when
the LV end-systolic dimension exceeded 1.20
cm.6 At this stage,
intravenous infusion of isoproterenol (1 µg/kg per
minute) for 3 minutes was performed in conscious control and HF rabbits
with monitoring of the surface ECG. Protocols were approved by the
University of Illinois at Chicago Animal Studies Committee. Rabbit LV
myocytes were isolated as
described,6 with back flow
across the incompetent aortic valve in HF rabbits blocked by a
balloon-tipped catheter inflated in the LV outflow
tract.
Contraction
[Ca2+]i and Patch
Clamp
Myocyte shortening was measured by video edge
detection and
[Ca2+]i was
measured by indo-1 and fluo-3
epifluorescence.26 27
The normal Tyrodes (NT) solution contained (in mmol/L) NaCl 140,
KCl 4, MgCl2 1, CaCl2 2,
glucose 10, and HEPES 5 (pH 7.4). Myocytes were studied at 23°C or
37°C.
Some myocytes were field-stimulated in NT (Figure 1B
).
Perforated patch voltage clamp was done in experiments illustrated in
Figures 1C
through 1F, 2B, 3A, 3B, and 3D with pipettes
containing (in mmol/L) cesium methanesulfonate 70, CsCl 55, NaCl
8, MgCl2 1, HEPES 10, and EGTA 0.1 (pH 7.3), as
well as 200 µg/mL amphotericin B, at 23°C. For potassium currents
(Figures 5B
, 5C
, and 6B
[left]), ruptured patch voltage clamp was
used, and pipettes (resistance=0.8 to 2 M
) contained (in
mmol/L) potassium glutamate 120, KCl 15, MgCl2
2, potassium HEPES 10, K5-EGTA 5, and Mg-ATP 2
(pH 7.2) at 23°C (Figures 5B
and 5C
) or 37°C (Figure 6B
). For
current clamp (Figures 4
, 5A
, 6A
, and 6B
, right) and voltage clamp in
Figure 3C
, sharper pipettes (5 to 20 M
) contained (in mmol/L)
potassium aspartate 120, KCl 8, NaCl 7, HEPES 10,
MgCl2 1, Mg-ATP 5, Li-GTP 0.3, and
K5indo-1 0.05 (pH 7.2) at 37°C, and cells
were preloaded with indo-1acetoxymethyl
ester.22
INa/Ca
integral (in C/F) was multiplied by 71.8 µmolxF/(CxL
cytosol),28 yielding SR
Ca2+ load in µmol/L cytosol. Cells were
either voltage clamped in NT (Figure 3C
), voltage clamped in NT with
6 mmol/L cesium replacing potassium (Figures 1C
through 1F, 2B,
2C, 3A, 3B, and 3D), voltage clamped in NT plus 0.3 mmol/L cadmium
(Figures 5B
and 5C
), or current clamped in NT (Figures 2A
, 4
, 5A
, 6A
, and 6B
[right]). Membrane capacitance was measured from responses to
5-mV hyperpolarizing and depolarizing
pulses.29
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SR Ca2+ load was varied before
caffeine application by changing AP frequency, pulse number, or rest
interval. For testing
Iti
effects on
Em, we
applied a synthetic current waveform chosen to match
Itis
measured in rabbit
myocytes.22 This injected
pseudo-Iti
was varied in amplitude. Data are mean±SE, and statistical
significance was based on
P<0.05 (Student
t test, ANOVA, and
2).
An expanded Materials and Methods section can be found in the online data supplement available at http://www.circresaha.org.
Results
Figure 1A
shows cardiac enlargement and spontaneous
nonsustained VT that are typical of HF rabbits used in the present
study. Isolated LV myocytes from HF rabbit
(Figure 1B
) also show spontaneous closely coupled
aftercontractions and Ca2+ transients after
1-Hz stimulation at 37°C, seen only after isoproterenol 1 µmol/L
(blockable by 1 µmol/L propranolol). All HF myocytes (7
of 7 from 5 hearts) exhibited such aftercontractions, versus a minority
of control myocytes with this protocol (2 of 7 from 3 hearts;
P<0.01). Thus, HF rabbit
myocytes exhibit enhanced susceptibility to aftercontractions. As
discussed elsewhere, control myocytes have safety factors that limit
the ability of a spontaneous SR Ca2+ release
to trigger an
AP.22
Ca2+ Transients,
ICa,
and ß-Adrenergic Stimulation
In voltage-clamped HF myocytes,
Ca2+ transients
(
[Ca2+]i) were
smaller than control, but peak
ICa was
unaltered
(Figures 1C
and 1D
). This agrees with previous
ICa data
in which Ca2+ transients were
prevented.6 If the coupling
between the L-type Ca2+ channel and SR
Ca2+ release channel were altered in HF, SR
Ca2+ release would cause less
Ca2+-dependent
ICa
inactivation in HF.4 However,
we found no HF-associated change in time constants of
ICa
inactivation (
fast or
slow) or fraction of inactivation in the fast
phase
(Figure 1F
). Ca2+ transients and
ICa were
increased by exposure to isoproterenol in both control and HF myocytes
(Figures 1C
and 1E
). Whereas the ß-AR stimulation of
ICa in
HF was significantly less than in control, the
[Ca2+]i response
was comparable (65% in HF versus 78% in control). Thus, HF cells
exhibit clear residual ß-AR responsiveness, consistent with
the progressive but incomplete ß-AR downregulation seen both in human
HF30 31 and in
this rabbit HF
model.25
Contractile Dysfunction, Reduced SR
Ca2+, and Enhanced NaCaX
Steady-state twitch Ca2+
transients and contractions in nondialyzed and non-voltageclamped HF
myocytes at 37°C (1 Hz) were reduced by
40%. This was
paralleled by a 40% decrease in SR Ca2+
content
(Figure 2A
), as assessed by caffeine-induced
Ca2+
transients.26 This lower SR
Ca2+ load is sufficient to explain the
reduced twitches and
[Ca2+]i in HF.
At constant
ICa, the
ratio of
[Ca2+]i
for twitch:caffeine is a useful index of fractional SR
Ca2+ release and excitation-contraction
coupling. This ratio was unchanged in the HF rabbit, in contrast to
previous results in failing rat
heart.4 There was also
no reason to infer altered myofilament Ca2+
sensitivity, because changes in
[Ca2+]i
paralleled those of contraction. To completely rule out changes in
myofilament Ca2+ sensitivity or ryanodine
receptor responsiveness, more detailed study is required.
Although reduced SR Ca2+ content
is the simplest interpretation of the lower
Ca2+ transients induced by APs and caffeine,
increased cytosolic Ca2+ buffering could
also be involved.
Figures 2B
and 2C
show cytosolic
Ca2+ buffering measured by the method of
Trafford et al.32 Rapid
caffeine-induced Ca2+ release
activates Ca2+ extrusion via
INa/Ca
(Figure 2B
, top). The amount of total
Ca2+
([Ca2+]Tot) removed
is given by the
INa/Ca
integral, and that Ca2+ removal causes
[Ca2+]i to change
(Figure 2C
, left). The Ca2+
buffering slope
(
[Ca2+]Tot/
[Ca2+]i)
for physiological
[Ca2+]i is
unaltered in HF. Nevertheless, instantaneous inward
INa/Ca
for any given
[Ca2+]i was much
larger in HF
(Figure 2B
, bottom), indicating that
INa/Ca
is functionally upregulated during dynamic
Ca2+ transients (confirming our data showing
2-fold increases in NaCaX mRNA, protein, and
INa/Ca,
where [Ca2+]i was
clamped).6 The enhanced
inward
INa/Ca
means that NaCaX must compete better with SERCA during twitch
relaxation and diastole and thereby directly explains the
reduced SR Ca2+ and contractile dysfunction
in HF (even if SERCA was relatively unchanged; see
Discussion).
SR Ca2+ Load,
Spontaneous SR Ca2+ Release, and
Arrhythmogenesis
How might these Ca2+
alterations be involved in arrhythmogenesis? Indeed, if SR
Ca2+ load is reduced, one may expect less
spontaneous SR Ca2+ release and triggered
APs in HF. One resolution to this paradox might be that in HF a
lower-threshold SR Ca2+ load causes
spontaneous SR Ca2+ release and
Iti. We
measured this threshold in voltage-clamped myocytes
(Figures 3A
and 3B
) by driving increasing amounts of
Ca2+ into the cell and SR by varying the
duration of a loading pulse at +50 mV and also by increasing
[Ca2+]o to 4
mmol/L and adding 1 to 10 µmol/L isoproterenol. On repolarization to
-80 mV, we monitored appearance of aftercontractions,
[Ca2+]i and
Itis.
Finally, caffeine was applied to release all SR
Ca2+. These
Ca2+-activated inward currents in HF
were carried entirely by
INa/Ca,
because they were abolished by blocking NaCaX
(Figure 3C
) as in
control.29 Thus,
ICl(Ca)
and
INS(Ca)
do not contribute significantly to
Itis,
and our preliminary data suggest that this is also true in human HF
ventricular myocytes at 37°C (S.M.P., K.S., D.M.B.,
unpublished data, 2000). As such, the
INa/Ca
(including
Itis) in
Figure 3A
can be integrated to evaluate the SR
Ca2+ load that was present at the moment
the first spontaneous
Iti
occurred. Although
Itis in
Figures 3A
and 3B
were seen only with isoproterenol, for a
given depolarizing pulse,
Itis
were more readily induced in HF than control (8 of 10 versus 3 of 9;
P<0.05; for 10 µmol/L
isoproterenol,
[Ca2+]o=2
mmol/L). We attribute this to the upregulated NaCaX and greater
Ca2+ influx while holding at +50 mV.
However, the crucial result is that the threshold SR
Ca2+ load for
Iti
induction was unchanged in HF
(Figure 3B
).
A typical
Iti
removes 15 to 20 µmol Ca2+/L cytosol from
the cell (and SR). Thus, in cells in which SR
Ca2+ was driven to the highest levels (as in
Figure 3A
), two or more
Itis
were reproducibly observed and the second
Iti
brought the SR Ca2+ load below threshold. At
more modest SR Ca2+ load (eg,
115
µmol/L cytosol), a single
Iti was
sufficient to bring SR Ca2+ load below
threshold.
If SR Ca2+ load is low in HF
myocyte and threshold SR Ca2+ load for
triggering an
Iti is
unaltered, how does it increase to produce
Itis?
This paradox can be explained by sympathetic bursts, which stimulate
the SERCA,33 raising SR
Ca2+ load above threshold. This is supported
by our findings above that ß-AR activation significantly enhanced
aftercontractions (in 100% of HF cells) and
Itis (in
80% of HF cells) by increasing SR Ca2+
(Figures 1B
, 3A
, and 3B
) and also induced
ventricular arrhythmias including nonsustained VT
in 3 of 3 intact HF rabbits (versus 0 of 3 controls). This may also
explain why sudden arrhythmic deaths are more common before end-stage
HF, ie, before ß-AR responsiveness is largely
lost.31 34 Thus,
some residual ß-AR responsiveness may be critical in enabling the
spontaneous SR Ca2+ releases that trigger
arrhythmias.
[Ca2+]i
Required to Trigger an AP
If the threshold SR Ca2+ for
release is unchanged, perhaps the increased propensity for triggered
arrhythmias in HF reflects the way the cell responds to a given
SR Ca2+ release. Indeed, in HF peak
INa/Ca
during spontaneous
Itis was
larger, even for a comparable amount of net charge moved (integrated
Iti,
Figure 3D
). This higher peak
Iti
agrees with greater inward
INa/Ca
versus [Ca2+]i
during caffeine-induced contractions
(Figure 2B
). This is expected to cause greater depolarization
(
Em)
in HF for a given
[Ca2+]i,
bringing
Em
closer to threshold to fire an AP.
We tested this quantitatively by measuring
Em in
current-clamped myocytes and applying caffeine to produce controlled
[Ca2+]i.
Figures 4A
and 4B
show APs, twitch
[Ca2+]i and
subsequent caffeine-induced Ca2+ transients,
and the associated caffeine-induced afterdepolarizations (or
cDADs).22 In HF, the AP
duration was 19% longer and the increase in twitch
[Ca2+]i with
frequency was blunted (as in human
HF).2 At low frequency and SR
Ca2+ load, cDADs are subthreshold. As SR
Ca2+ increases with frequency, we can
measure a threshold for AP induction with respect to
[Ca2+]i and
Em
(Figure 4A
). As for
Iti,
three different Ca2+-activated
currents have been suggested to play a role in DADs
(INa/Ca,
ICl(Ca),
and
INS(Ca)).
Figure 4C
shows that cDADs in HF cells are virtually
abolished when
INa/Ca
is blocked by removing extracellular Na+ and
Ca2+ (which should still allow both
ICl(Ca)
and
INS(Ca)).
Note also that
[Ca2+]i decline is
drastically slowed by blocking NaCaX, which is the main means of
Ca2+ removal in the presence of
caffeine.22 29
Blocking
ICl(Ca)
with niflumate hardly affected cDADs, which confirms that DADs are
driven almost exclusively by
INa/Ca.
The same approach can be used to induce cDADs and APs in human HF
ventricular myocytes (S.M.P., K.S., D.M.B., unpublished
observations, 2000).
Figure 5A
shows quantitatively that in HF versus control, a
given
[Ca2+]i
produces greater depolarization
(
Em
doubles for each 59 versus 105 nmol/L
[Ca2+]i) for
subthreshold cDADs (curves and small points). In HF, the mean
[Ca2+]i
threshold for a triggered AP is also reduced by nearly 50% (280 versus
515 nmol/L, large squares). Although the stimulation frequencies at
which caffeine triggered APs were comparable for HF and controls
(
1.5 to 2 Hz), this may merely reflect a lower-baseline SR
Ca2+ load in HF coincidentally offset by the
decreased level of
[Ca2+]i
necessary to trigger an AP. The crucial result is that lower
[Ca2+]i is
required for a cDAD to trigger an AP in HF (as expected from the
increased
INa/Ca).
However,
Em might
also respond differently to a given
INa/Ca
in HF (eg, as a result of other currents).
Altered Potassium Currents:
Ca2+- Independent Changes
Figures 5B
and 5C
show that in HF rabbits, transient outward
and inward rectifier potassium currents
(Ito and
IK1)
were reduced significantly (by 34% and 49%, respectively), as has
been reported in human HF.23
Notably, the 49% reduction in
IK1 was
observed at all
Em
values and would tend to destabilize the resting
Em
(Figure 5C
, inset). Thus, a given
Iti
might produce greater depolarization in the face of reduced
IK1.
Figure 6A
tests this expectation quantitatively
using current injections of varying amplitude, with time courses that
simulate real
Itis
(but without changing
[Ca2+]i or
Ca2+-activated currents). Increasing
the amplitude of these
pseudo-Itis
results in larger
depolarization,22 and with
sufficient injected charge (ie, threshold charge) an AP is triggered.
In HF, any given
pseudo-Iti
produces greater depolarization (small points and curves in
Figure 6A
). More importantly, the threshold current integral
(or charge) to trigger an AP is
25% smaller in HF (large squares;
P<0.05).
To test whether the reduction in
IK1 in
HF would be quantitatively sufficient to explain the
Ca2+-independent shifts seen in
Figure 6A
, we partially blocked
IK1 in
control cells
(Figure 6B
) to see whether that could mimic the shift seen in
HF. Barium blocked
IK1 with
an IC50 of 5 to 15 µmol/L (depending slightly
on Em).
Subthreshold
pseudo-Itis
in a representative control cell are shown in the
absence and presence of 3 µmol/L barium. Barium shifted the relation
just as seen in HF. Mean barium effects were to shift doubling charge
from 0.45±0.06 to 0.21±0.03 C/F at 3 µmol/L barium and to
0.157±0.013 C/F at 5 µmol/L barium (n=14, 4, and 4,
P<0.05). Therefore, the 49%
IK1
reduction in HF is sufficient to completely and quantitatively explain
the greater depolarization for a given current injection in HF
(Figure 6A
).
Discussion
We conclude
(Figure 7
) that three major factors conspire to greatly
enhance the propensity for arrhythmogenesis in HF: (1) increased NaCaX
(providing more arrhythmogenic
Iti for
any given SR Ca2+ release), (2) reduced
IK1
(allowing greater depolarization for any given
Iti),
and (3) residual ß-AR responsiveness (required to raise the low SR
Ca2+ load in HF to the point at which more
spontaneous SR Ca2+ release
occurs).
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The current(s) responsible for DADs has been controversial,
but we have shown that
INa/Ca
is the current that underlies
Iti and
DAD in myocytes from HF rabbits at 37°C (similar to
Iti data
at 20°C in human HF).35
Although other Ca2+-activated
currents may occur, particularly in other species or cell types in the
heart, they do not contribute quantitatively to
Iti or
DADs under physiological conditions in
ventricular myocytes from rabbits (and likely, humans) with
HF. Moreover, the 2-fold upregulation of NaCaX in rabbit and human HF
indicates that larger
Itis and
DADs would be expected for a given
[Ca2+]i (and we
have demonstrated this quantitatively for
Itis and
cDADs).
IK1
was decreased by 49% in HF rabbit myocytes (similar to human
HF23 ). No quantitative
functional link has previously been developed for
IK1 in
arrhythmogenesis in HF. We show that the reduction of
IK1 is
quantitatively sufficient to explain the greater depolarization seen
for a given inward current (Ca2+-independent
pseudo-Iti)
in HF. Thus, reduced
IK1 in
HF is of paramount importance in lowering the threshold for an
Iti-triggered
AP. Although
INa/Ca
is almost entirely responsible for
Itis (in
control and HF), reduced
IK1 in
HF allows that
INa/Ca
to produce greater depolarization. Based on the HF shifts in
Figures 5A
and 6A
and computer models (J.L. Puglisi and D.M.
Bers, unpublished observations, 2000), the increased
INa/Ca
and reduced
IK1
contribute about equally to the altered
[Ca2+]i
threshold and propensity for triggered arrhythmias.
The role of SR Ca2+ load in arrhythmogenesis has been unclear, especially because of the paradoxical lower SR Ca2+ load in HF versus high SR Ca2+ required to cause spontaneous SR Ca2+ release. Here we resolve this paradox by demonstrating directly that HF cells can be readily driven to high SR Ca2+ load and spontaneous SR Ca2+ release (which causes arrhythmias initiated by DADs). This is where residual ß-AR responsiveness in our paradigm is critical. Indeed, we found that 100% of HF cells exhibit spontaneous SR Ca2+ release and aftercontractions after isoproterenol (although an IC50 for isoproterenol was not determined). Moreover, in very-late-stage human HF, there are fewer sudden arrhythmic deaths, and this corresponds to the time when there is more complete loss of ß-AR responsiveness.31 34 At this stage as pump failure continues, arrhythmias may be less likely because the SR Ca2+ load never gets high enough for spontaneous SR Ca2+ release (although elevated NaCaX and reduced IK1 may persist).
The higher NaCaX in HF also contributes to contractile
dysfunction by competing with the SERCA and unloading the SR. In this
rabbit HF model, we had not detected alteration in SERCA on Northern or
Western blots, but function in HF myocytes appeared to be decreased by
up to 24%.6 This minimal
SERCA alteration (compared with some HF models) illustrates that the
large increase in NaCaX alone may be sufficient to unload the SR and
hence cause contractile dysfunction. Of course, any reduction in SERCA
versus NaCaX would further shift this balance and lower the SR
Ca2+ load more severely. This demonstrates a
novel dual role for elevated NaCaX as a central causative factor in
both arrhythmogenesis and contractile dysfunction. This also relates to
human HF, in which Hasenfuss et
al11 found that 44% of
failing human hearts (their group I, with preserved
diastolic function) had
2-fold increase in NaCaX protein
expression and
25% decrease in SERCA, which is very similar to our
HF rabbits. Additional reduction of SERCA seen in HF patients with
diastolic dysfunction slows twitch relaxation and further
decreases SR Ca2+ load and systolic
function.11 Although
increased NaCaX expression in HF could enhance
Ca2+ entry (via outward
INa/Ca),36 37
this seems likely only for very prolonged APs in HF. This effect was
not seen here.
This work and novel paradigm
(Figure 7
) raise the issue of molecular targets for
therapeutics in HF. Inhibiting NaCaX might improve contractile function
and acutely limit arrhythmias but is dangerous because of the
crucial role of NaCaX in removing the Ca2+,
which enters at each beat via
ICa.
Partially blocking NaCaX could worsen cellular
Ca2+ overload, ultimately causing
spontaneous SR Ca2+ release and
arrhythmia (as seen with Na/K-ATPase inhibition in digitalis
toxicity). Such spontaneous SR Ca2+ release
can seriously exacerbate contractile dysfunction by desynchronizing
contractions in cells, which are in series with each
other,7 even if
arrhythmogenic
INa/Ca
was less. Increasing SERCA (eg, by gene transfer or phospholamban
inhibition)38 39
would help the SERCA compete better with NaCaX to maintain more normal
SR Ca2+ load and improve contractile
function, but it may increase the propensity for
Ca2+ overload and DADs. SR
Ca2+-pump stimulation could be the reason
why phosphodiesterase inhibitory inotropes (which increase
cAMP) are proarrhythmic and increase
mortality.40 Blocking
ß-ARs could prevent spontaneous SR Ca2+
release by reducing the increment in SR Ca2+
load (induced by adrenergic surges). This would account for the
effectiveness of ß-AR blockers in reducing sudden death in
HF.41 Enhancing
IK1 to
stabilize resting
Em could
also be beneficial but could also reduce excitability, propagation
rate, and AP duration. Overall, a balance must be sought to enhance
SERCA function without increasing arrhythmogenesis.
HF and its etiologies are extremely complex, but altered myocyte Ca2+ regulation and ion channels appear to be crucial in the final common pathways of sudden death and pump failure. The data here support a novel paradigm of three key factors (increased NaCaX, reduced IK1, and residual ß-adrenergic responsiveness) that conspire to greatly increase arrhythmogenesis in HF. The increased NaCaX is unique in contributing to both contractile dysfunction (reducing SR Ca2+ load) and arrhythmogenesis. This novel paradigm provides both a framework and a challenge for further understanding and therapeutic development.
Acknowledgments
Financial support was provided by NIH Grants HL-46929 (to S.M.P.) and HL-30077 and HL-64724 (to D.M.B.). We appreciate the technical contributions of S. Scaglione and L. Leach.
Footnotes
Original received January 29, 2001; revision received April 6, 2001; accepted April 9, 2001.
1 Both authors contributed equally to this study. ![]()
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W. Xiong, Y. Tian, D. DiSilvestre, and G. F. Tomaselli Transmural Heterogeneity of Na+-Ca2+ Exchange: Evidence for Differential Expression in Normal and Failing Hearts Circ. Res., August 5, 2005; 97(3): 207 - 209. [Abstract] [Full Text] [PDF] |
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S. R. Houser Can Novel Therapies for Arrhythmias Caused by Spontaneous Sarcoplasmic Reticulum Ca2+ Release be Developed Using Mouse Models? Circ. Res., May 27, 2005; 96(10): 1031 - 1032. [Full Text] [PDF] |
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J. Rose, A. A. Armoundas, Y. Tian, D. DiSilvestre, M. Burysek, V. Halperin, B. O'Rourke, D. A. Kass, E. Marban, and G. F. Tomaselli Molecular correlates of altered expression of potassium currents in failing rabbit myocardium Am J Physiol Heart Circ Physiol, May 1, 2005; 288(5): H2077 - H2087. [Abstract] [Full Text] [PDF] |
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M. T. Ziolo, J. L. Martin, J. Bossuyt, D. M. Bers, and S. M. Pogwizd Adenoviral Gene Transfer of Mutant Phospholamban Rescues Contractile Dysfunction in Failing Rabbit Myocytes With Relatively Preserved SERCA Function Circ. Res., April 29, 2005; 96(8): 815 - 817. [Abstract] [Full Text] [PDF] |
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N. D'Avanzo, H. C. Cho, I. Tolokh, R. Pekhletski, I. Tolokh, C. Gray, S. Goldman, and P. H. Backx Conduction through the Inward Rectifier Potassium Channel, Kir2.1, Is Increased by Negatively Charged Extracellular Residues J. Gen. Physiol., April 25, 2005; 125(5): 493 - 503. [Abstract] [Full Text] [PDF] |
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H. J. Knot, I. Laher, E. A. Sobie, S. Guatimosim, L. Gomez-Viquez, H. Hartmann, L.-S. Song, W.J. Lederer, W. F. Graier, R. Malli, et al. Twenty Years of Calcium Imaging: Cell Physiology to Dye For Mol. Interv., April 1, 2005; 5(2): 112 - 127. [Abstract] [Full Text] [PDF] |
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A. Collins, H. Wang, and M. K. Larson Differential Sensitivity of Kir2 Inward-Rectifier Potassium Channels to a Mitochondrial Uncoupler: Identification of a Regulatory Site Mol. Pharmacol., April 1, 2005; 67(4): 1214 - 1220. [Abstract] [Full Text] [PDF] |
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D. M. Harris, G. D. Mills, X. Chen, H. Kubo, R. M. Berretta, V. S. Votaw, L. F. Santana, and S. R. Houser Alterations in Early Action Potential Repolarization Causes Localized Failure of Sarcoplasmic Reticulum Ca2+ Release Circ. Res., March 18, 2005; 96(5): 543 - 550. [Abstract] [Full Text] [PDF] |
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P. S Spector Diagnosis and management of sudden cardiac death Heart, March 1, 2005; 91(3): 408 - 413. [Full Text] [PDF] |
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X. Ai and S. M. Pogwizd Connexin 43 Downregulation and Dephosphorylation in Nonischemic Heart Failure Is Associated With Enhanced Colocalized Protein Phosphatase Type 2A Circ. Res., January 7, 2005; 96(1): 54 - 63. [Abstract] [Full Text] [PDF] |
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A. Baartscheer, C. A. Schumacher, M. M.G.J. van Borren, C. N.W. Belterman, R. Coronel, T. Opthof, and J. W.T. Fiolet Chronic inhibition of Na+/H+-exchanger attenuates cardiac hypertrophy and prevents cellular remodeling in heart failure Cardiovasc Res, January 1, 2005; 65(1): 83 - 92. [Abstract] [Full Text] [PDF] |
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L. H. Opie Cellular Basis for Therapeutic Choices in Heart Failure Circulation, October 26, 2004; 110(17): 2559 - 2561. [Full Text] [PDF] |
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B. N. Eigel, H. Gursahani, and R. W. Hadley Na+/Ca2+ exchanger plays a key role in inducing apoptosis after hypoxia in cultured guinea pig ventricular myocytes Am J Physiol Heart Circ Physiol, October 1, 2004; 287(4): H1466 - H1475. [Abstract] [Full Text] [PDF] |
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J. M. McCurley, S. U. Hanlon, S.-k. Wei, E. F. Wedam, M. Michalski, and M. C. Haigney Furosemide and the progression of left ventricular dysfunction in experimental heart failure J. Am. Coll. Cardiol., September 15, 2004; 44(6): 1301 - 1307. [Abstract] [Full Text] [PDF] |
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R. A. Bassani, J. Altamirano, J. L. Puglisi, and D. M. Bers Action potential duration determines sarcoplasmic reticulum Ca2+ reloading in mammalian ventricular myocytes J. Physiol., September 1, 2004; 559(2): 593 - 609. [Abstract] [Full Text] [PDF] |
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I. A. Hobai, C. Maack, and B. O'Rourke Partial Inhibition of Sodium/Calcium Exchange Restores Cellular Calcium Handling in Canine Heart Failure Circ. Res., August 6, 2004; 95(3): 292 - 299. [Abstract] [Full Text] [PDF] |
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M. Zaugg and M. C. Schaub Cellular mechanisms in sympatho-modulation of the heart Br. J. Anaesth., July 1, 2004; 93(1): 34 - 52. [Abstract] [Full Text] [PDF] |
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R. Bouchard, R. B. Clark, A. E. Juhasz, and W. R. Giles Changes in extracellular K+ concentration modulate contractility of rat and rabbit cardiac myocytes via the inward rectifier K+ current IK1 J. Physiol., May 1, 2004; 556(3): 773 - 790. [Abstract] [Full Text] [PDF] |
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Y. Chen, B. Escoubet, F. Prunier, J. Amour, W. S. Simonides, B. Vivien, C. Lenoir, M. Heimburger, C. Choqueux, B. Gellen, et al. Constitutive Cardiac Overexpression of Sarcoplasmic/Endoplasmic Reticulum Ca2+-ATPase Delays Myocardial Failure After Myocardial Infarction in Rats at a Cost of Increased Acute Arrhythmias Circulation, April 20, 2004; 109(15): 1898 - 1903. [Abstract] [Full Text] [PDF] |
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M. J Janse Electrophysiological changes in heart failure and their relationship to arrhythmogenesis Cardiovasc Res, February 1, 2004; 61(2): 208 - 217. [Abstract] [Full Text] [PDF] |
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T.-J. Cha, J. R. Ehrlich, L. Zhang, Y.-F. Shi, J.-C. Tardif, T. K. Leung, and S. Nattel Dissociation Between Ionic Remodeling and Ability to Sustain Atrial Fibrillation During Recovery From Experimental Congestive Heart Failure Circulation, January 27, 2004; 109(3): 412 - 418. [Abstract] [Full Text] [PDF] |
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K. TASKEN and E. M. AANDAHL Localized Effects of cAMP Mediated by Distinct Routes of Protein Kinase A Physiol Rev, January 1, 2004; 84(1): 137 - 167. [Abstract] [Full Text] [PDF] |
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R. R. Makkar, M. Lill, and P.-S. Chen Stem cell therapy for myocardial repair: Is it arrhythmogenic? J. Am. Coll. Cardiol., December 17, 2003; 42(12): 2070 - 2072. [Full Text] [PDF] |
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C. I. Spencer and J. S. K. Sham Effects of Na+/Ca2+ exchange induced by SR Ca2+ release on action potentials and afterdepolarizations in guinea pig ventricular myocytes Am J Physiol Heart Circ Physiol, December 1, 2003; 285(6): H2552 - H2562. [Abstract] [Full Text] [PDF] |
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D. W. Rodenbaugh, H. L. Collins, D. G. Nowacek, and S. E. DiCarlo Increased susceptibility to ventricular arrhythmias is associated with changes in Ca2+ regulatory proteins in paraplegic rats Am J Physiol Heart Circ Physiol, December 1, 2003; 285(6): H2605 - H2613. [Abstract] [Full Text] [PDF] |
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F R Quinn, S Currie, A M Duncan, S Miller, R Sayeed, S M Cobbe, and G L Smith Myocardial infarction causes increased expression but decreased activity of the myocardial Na+--Ca2+ exchanger in the rabbit J. Physiol., November 15, 2003; 553(1): 229 - 242. [Abstract] [Full Text] [PDF] |
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C. R. Weber, V. Piacentino III, S. R. Houser, and D. M. Bers Dynamic Regulation of Sodium/Calcium Exchange Function in Human Heart Failure Circulation, November 4, 2003; 108(18): 2224 - 2229. [Abstract] [Full Text] [PDF] |
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D. M. Roden A Surprising New Arrhythmia Mechanism in Heart Failure Circ. Res., October 3, 2003; 93(7): 589 - 591. [Full Text] [PDF] |
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T. R. Shannon, S. M. Pogwizd, and D. M. Bers Elevated Sarcoplasmic Reticulum Ca2+ Leak in Intact Ventricular Myocytes From Rabbits in Heart Failure Circ. Res., October 3, 2003; 93(7): 592 - 594. [Abstract] [Full Text] [PDF] |
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D. M. Bers, D. A. Eisner, and H. H. Valdivia Sarcoplasmic Reticulum Ca2+ and Heart Failure: Roles of Diastolic Leak and Ca2+ Transport Circ. Res., September 19, 2003; 93(6): 487 - 490. [Full Text] [PDF] |
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J. R Ehrlich, T.-J. Cha, L. Zhang, D. Chartier, P. Melnyk, S. H Hohnloser, and S. Nattel Cellular electrophysiology of canine pulmonary vein cardiomyocytes: action potential and ionic current properties J. Physiol., September 15, 2003; 551(3): 801 - 813. [Abstract] [Full Text] [PDF] |
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L. Venetucci, A.W. Trafford, and D.A. Eisner Illuminating Sarcoplasmic Reticulum Calcium Circ. Res., July 11, 2003; 93(1): 4 - 5. [Full Text] [PDF] |
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T. R. Shannon, T. Guo, and D. M. Bers Ca2+ Scraps: Local Depletions of Free [Ca2+] in Cardiac Sarcoplasmic Reticulum During Contractions Leave Substantial Ca2+ Reserve Circ. Res., July 11, 2003; 93(1): 40 - 45. [Abstract] [Full Text] [PDF] |
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A. A. Armoundas, I. A. Hobai, G. F. Tomaselli, R. L. Winslow, and B. O'Rourke Role of Sodium-Calcium Exchanger in Modulating the Action Potential of Ventricular Myocytes From Normal and Failing Hearts Circ. Res., July 11, 2003; 93(1): 46 - 53. [Abstract] [Full Text] [PDF] |
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F. Brette and C. Orchard T-Tubule Function in Mammalian Cardiac Myocytes Circ. Res., June 13, 2003; 92(11): 1182 - 1192. [Abstract] [Full Text] [PDF] |
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L. S. Maier, T. Zhang, L. Chen, J. DeSantiago, J. H. Brown, and D. M. Bers Transgenic CaMKII{delta}C Overexpression Uniquely Alters Cardiac Myocyte Ca2+ Handling: Reduced SR Ca2+ Load and Activated SR Ca2+ Release Circ. Res., May 2, 2003; 92(8): 904 - 911. [Abstract] [Full Text] [PDF] |
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S.-k. Wei, A. Ruknudin, S. U. Hanlon, J. M. McCurley, D. H. Schulze, and M. C.P. Haigney Protein Kinase A Hyperphosphorylation Increases Basal Current but Decreases {beta}-Adrenergic Responsiveness of the Sarcolemmal Na+-Ca2+ Exchanger in Failing Pig Myocytes Circ. Res., May 2, 2003; 92(8): 897 - 903. [Abstract] [Full Text] [PDF] |
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A. G. Brittsan, K. S. Ginsburg, G. Chu, A. Yatani, B. M. Wolska, A. G. Schmidt, M. Asahi, D. H. MacLennan, D. M. Bers, and E. G. Kranias Chronic SR Ca2+-ATPase Inhibition Causes Adaptive Changes in Cellular Ca2+ Transport Circ. Res., April 18, 2003; 92(7): 769 - 776. [Abstract] [Full Text] [PDF] |
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H. Honjo, M. R. Boyett, R. Niwa, S. Inada, M. Yamamoto, K. Mitsui, T. Horiuchi, N. Shibata, K. Kamiya, and I. Kodama Pacing-Induced Spontaneous Activity in Myocardial Sleeves of Pulmonary Veins After Treatment With Ryanodine Circulation, April 15, 2003; 107(14): 1937 - 1943. [Abstract] [Full Text] [PDF] |
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D. M. Bers Dynamic Imaging in Living Cells: Windows into Local Signaling Sci. Signal., April 8, 2003; 2003(177): pe13 - pe13. [Abstract] [Full Text] [PDF] |
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